National Library of Energy BETA

Sample records for latent cancer fatalities

  1. Latent effects decision analysis

    DOE Patents [OSTI]

    Cooper, J. Arlin; Werner, Paul W.

    2004-08-24

    Latent effects on a system are broken down into components ranging from those far removed in time from the system under study (latent) to those which closely effect changes in the system. Each component is provided with weighted inputs either by a user or from outputs of other components. A non-linear mathematical process known as `soft aggregation` is performed on the inputs to each component to provide information relating to the component. This information is combined in decreasing order of latency to the system to provide a quantifiable measure of an attribute of a system (e.g., safety) or to test hypotheses (e.g., for forensic deduction or decisions about various system design options).

  2. ARM - Measurement - Latent heat flux

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    heat flux ARM Data Discovery Browse Data Comments? We would love to hear from you Send us a note below or call us at 1-888-ARM-DATA. Send Measurement : Latent heat flux The time ...

  3. Interim Action Determination

    Office of Energy Efficiency and Renewable Energy (EERE) Indexed Site

    ... for vitrification in DWPF would result in 0.07 latent cancer fatalities (or, zero) in the offsite population, and 0.11 latent cancer fatalities (or, zero) in the worker population. ...

  4. Monitoring bat and bird fatalities at the Casselman Wind Energy...

    Office of Energy Efficiency and Renewable Energy (EERE) Indexed Site

    Monitoring bat and bird fatalities at the Casselman Wind Energy Center in Pennsylvania Monitoring bat and bird fatalities at the Casselman Wind Energy Center in Pennsylvania ...

  5. Type A Investigation - Subcontractor Fatality at the Savannah...

    Office of Energy Efficiency and Renewable Energy (EERE) Indexed Site

    Fatality at the Savannah River Site Pond B Dam Upgrade Project, July 26, 2004 Type A Investigation - Subcontractor Fatality at the Savannah River Site Pond B Dam Upgrade ...

  6. Investigation of the September 13, 2011, Fatality at the Strategic...

    Office of Energy Efficiency and Renewable Energy (EERE) Indexed Site

    September 13, 2011, Fatality at the Strategic Petroleum Reserve Bryan Mound Site Investigation of the September 13, 2011, Fatality at the Strategic Petroleum Reserve Bryan Mound ...

  7. Investigation Results from Fatal Mishap | Jefferson Lab

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    Investigation Results from Fatal Mishap April 22 Briefing: Investigation Results from Florida State Univ. Fatal Mishap On October 21, 2015, two National High Magnetic Field Laboratory (NHMFL) mechanical technicians were involved in an incident while attempting to remove a Victaulic blind flange from supply piping on a Magnet Cooling Water (MCW) System. The mechanical technicians were assisting a welder to obtain final measurements to make final connections from the MCW system to a new Cell 14

  8. Project Profile: Heat Transfer and Latent Heat Storage in Inorganic...

    Office of Energy Efficiency and Renewable Energy (EERE) Indexed Site

    Heat Transfer and Latent Heat Storage in Inorganic Molten Salts for CSP Plants Project Profile: Heat Transfer and Latent Heat Storage in Inorganic Molten Salts for CSP Plants ...

  9. Level 1 Accident Investigation Report of August 17, 2004, Fatal...

    Office of Environmental Management (EM)

    Investigation Report of August 17, 2004, Fatal Aircraft Accident on the Grand Coulee-Bell No.6, 500 kV Line Level 1 Accident Investigation Report of August 17, 2004, Fatal Aircraft ...

  10. Detection of latent prints by Raman imaging

    DOE Patents [OSTI]

    Lewis, Linda Anne; Connatser, Raynella Magdalene; Lewis, Sr., Samuel Arthur

    2011-01-11

    The present invention relates to a method for detecting a print on a surface, the method comprising: (a) contacting the print with a Raman surface-enhancing agent to produce a Raman-enhanced print; and (b) detecting the Raman-enhanced print using a Raman spectroscopic method. The invention is particularly directed to the imaging of latent fingerprints.

  11. Accident Investigation of the July 30, 2013, Electrical Fatality...

    Energy Savers [EERE]

    Accident Investigation of the July 30, 2013, Electrical Fatality on the Bandon-Rogue No. 1 ... (BPA) Chief Safety Officer, a Level I Accident Investigation was convened to ...

  12. Independent Review of the July 8, 2010 Fatality at the Strategic...

    Office of Energy Efficiency and Renewable Energy (EERE) Indexed Site

    Independent Review of the July 8, 2010 Fatality at the Strategic Petroleum Reserve Bryan ... Independent Review of the July 8, 2010 Fatality at the Strategic Petroleum Reserve Bryan ...

  13. Fatal pediatric poisoning from leaded paint--Wisconsin, 1990

    SciTech Connect (OSTI)

    Not Available

    1991-03-29

    Although fatal lead poisoning among children occurs rarely in the United States, it represents a medical and public health emergency. This report summarizes the investigation of a child who died from poisoning associated with ingestion of lead-based paint.

  14. Investigation of the September 13, 2011, Fatality at the Strategic

    Energy Savers [EERE]

    Petroleum Reserve Bryan Mound Site | Department of Energy September 13, 2011, Fatality at the Strategic Petroleum Reserve Bryan Mound Site Investigation of the September 13, 2011, Fatality at the Strategic Petroleum Reserve Bryan Mound Site November 2011 On September 13, 2011, a recently-hired, untrained subcontractor employee struck three large elevated pipes while operating a front deck mower at the Cavern 5 area of the Strategic Petroleum Reserve Bryan Mound (SPR-BM) site. The employee

  15. Fluctuations, Phase Transitions, and Latent Heat in Short Diblock...

    Office of Scientific and Technical Information (OSTI)

    Phase Transitions, and Latent Heat in Short Diblock Copolymers: Comparison of Experiment, Simulation, and Theory Citation Details In-Document Search Title: Fluctuations, Phase...

  16. Type A Investigation - Subcontractor Fatality at the Savannah River Site

    Energy Savers [EERE]

    Pond B Dam Upgrade Project, July 26, 2004 | Department of Energy - Subcontractor Fatality at the Savannah River Site Pond B Dam Upgrade Project, July 26, 2004 Type A Investigation - Subcontractor Fatality at the Savannah River Site Pond B Dam Upgrade Project, July 26, 2004 September 14, 2004 On July 26, 2004, at approximately 3:15 p.m., a truck driver (driver) was critically injured at the Savannah River Site, while loading a rented excavator onto a lowboy trailer for return to the rental

  17. Influence of civil defense on strategic countervalue fatalities

    SciTech Connect (OSTI)

    Harvey, T.F.

    1982-04-28

    Two modeling studies were conducted to simulate the effect of fallout shelters on the outcome of a massive countervalue nuclear exchange between the Soviet Union and the United States. One was to determine the number of nuclear weapons required to mount an effective fallout attack against a country with dispersed population; the other was to determine the number of expected US fatalities resulting from a countervalue attack against US urban population centers. The results of these studies indicate that the number of weapons required to mount such an attack depends on the adequacy of the shelter system and that the evacuation of urban populations can substantially reduce expected fatality levels.

  18. Type A Accident Report of the June 26, 2009 Vehicle Fatality...

    Office of Energy Efficiency and Renewable Energy (EERE) Indexed Site

    Type A Accident Report of the June 26, 2009 Vehicle Fatality at Lawrence Livermore ... PDF icon Type A Accident Report of the June 26, 2009 Vehicle Fatality at Lawrence ...

  19. Topo II: An Enzyme Target for Antibacterial and Cancer Drugs

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    a cell's DNA is fatal to the cell, which is why drugs that target topo II serve as agents against bacterial infections and some forms of cancer. This first ever structural...

  20. Analysis of a graphite foam-NaCl latent heat storage system for...

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    Analysis of a graphite foam-NaCl latent heat storage system for supercritical CO2 power cycles for concentrated solar power Title Analysis of a graphite foam-NaCl latent heat...

  1. Level 1 Accident Report of the March 1, 2010 Bobcat Fatality at BPA's White

    Energy Savers [EERE]

    Bluffs Substation | Department of Energy Report of the March 1, 2010 Bobcat Fatality at BPA's White Bluffs Substation Level 1 Accident Report of the March 1, 2010 Bobcat Fatality at BPA's White Bluffs Substation March 31, 2010 On March 2, 2010 at the request of the Bonneville Power Administration (BPA) Chief Safety Officer, a Level I Accident Investigation was convened to investigate an accident in which a supplemental labor contractor was fatally injured in a Bobcat/backhoe accident at the

  2. Monitoring bat and bird fatalities at the Casselman Wind Energy Center in

    Office of Energy Efficiency and Renewable Energy (EERE) Indexed Site

    Pennsylvania | Department of Energy Monitoring bat and bird fatalities at the Casselman Wind Energy Center in Pennsylvania Monitoring bat and bird fatalities at the Casselman Wind Energy Center in Pennsylvania Monitoring bat and bird fatalities at the Casselman Wind Energy Center in Pennsylvania PDF icon Curtailment_2008_Final_Report.pdf More Documents & Publications Featured Publications from the Bats and Wind Energy Cooperative EA-1782: Avian and Bat Assessment Annual Report CX-007915:

  3. Fatal accidents involving roof falls in coal mining, 1996--1998

    SciTech Connect (OSTI)

    Not Available

    1999-01-01

    This publication presents information on fatalities involving roof and rib falls that occurred in coal mining operations from January 1996 through December 1998. It includes statistics for the fatalities, as well as abstracts, best practices and illustrations. Conclusion statements have been substituted for best practices where no Title 30 Code of Regulations violations were cited during the accident investigation. From January 1996 through December 1998, 36 miners died at coal operations from accidents classified as roof falls. The information in the report is based on statistics taken from the 1996 through 1998 MSHA Fatal Illustration Programs: Roof Fall Fatalities by District.

  4. Fatal accidents involving roof falls in coal mining, 1996--1998

    SciTech Connect (OSTI)

    1999-11-01

    This publication presents information on fatalities involving roof and rib falls that occurred in coal mining operations from January 1996 through December 1998. It includes statistics for the fatalities, as well as abstracts, best practices and illustrations. Conclusion statements have been substituted for best practices where no Title 30 Code of Regulations violations were cited during the accident investigation. From January 1996 through December 1998, 36 miners died at coal operations from accidents classified as roof falls. The information in the report is based on statistics taken from the 1996 through 1998 MSHA Fatal Illustration Programs: Roof Fall Fatalities by District.

  5. Search tool plug-in: imploements latent topic feedback

    Energy Science and Technology Software Center (OSTI)

    2011-09-23

    IRIS is a search tool plug-in that is used to implement latent topic feedback for enhancing text navigation. It accepts a list of returned documents from an information retrieval wywtem that is generated from keyword search queries. Data is pulled directly from a topic information database and processed by IRIS to determine the most prominent and relevant topics, along with topic-ngrams, associated with the list of returned documents. User selected topics are then used tomore » expand the query and presumabley refine the search results.« less

  6. Final Complex Transformation Supplemental Programmatic Environmental...

    Office of Energy Efficiency and Renewable Energy (EERE) Indexed Site

    ... (continued) Common Name Scientific Name ... would receive a radiation dose of 11 millirem per year and the associated excess latent cancer fatality risk would be 6.6 in ...

  7. Effectiveness of Changing Wind Turbine Cut-in Speed to Reduce Bat Fatalities at Wind Facilities

    SciTech Connect (OSTI)

    Huso, Manuela M. P.; Hayes, John P.

    2009-04-01

    This report details an experiment on the effectiveness of changing wind turbine cut-in speed on reducing bat fatality from wind turbines at the Casselman Wind Project in Somerset County, Pennsylvania.

  8. Accident Investigation of the September 20, 2012 Fatal Fall from the

    Energy Savers [EERE]

    Dworshak-Taft #1 Transmission Tower, at the Bonneville Power Marketing Administration | Department of Energy September 20, 2012 Fatal Fall from the Dworshak-Taft #1 Transmission Tower, at the Bonneville Power Marketing Administration Accident Investigation of the September 20, 2012 Fatal Fall from the Dworshak-Taft #1 Transmission Tower, at the Bonneville Power Marketing Administration November 30, 2012 On September 21, 2012, at the request of the Bonneville Power Administration (BPA) Chief

  9. Independent Review of the July 8, 2010 Fatality at the Strategic Petroleum

    Energy Savers [EERE]

    Reserve Bryan Mound Site - May 25, 2011 Addendum closing the Investigation based upon the Galveston County Medical Examiner's Report | Department of Energy Independent Review of the July 8, 2010 Fatality at the Strategic Petroleum Reserve Bryan Mound Site - May 25, 2011 Addendum closing the Investigation based upon the Galveston County Medical Examiner's Report Independent Review of the July 8, 2010 Fatality at the Strategic Petroleum Reserve Bryan Mound Site - May 25, 2011 Addendum closing

  10. Type A Accident Report of the June 26, 2009 Vehicle Fatality at Lawrence

    Energy Savers [EERE]

    Livermore National Laboratory | Department of Energy Report of the June 26, 2009 Vehicle Fatality at Lawrence Livermore National Laboratory Type A Accident Report of the June 26, 2009 Vehicle Fatality at Lawrence Livermore National Laboratory October 1, 2009 On June 26, 2009, a Lawrence Livermore National Security (LLNS) employee was in the process of transporting six boxes containing personal property to his new office in preparation for a routine transfer to another position within the

  11. Formation of nanometer-size wires using infiltration into latent nuclear tracks

    DOE Patents [OSTI]

    Musket, Ronald G. (Danville, CA); Felter, Thomas E. (Livermore, CA)

    2002-01-01

    Nanometer-size wires having a cross-sectional dimension of less than 8 nm with controllable lengths and diameters are produced by infiltrating latent nuclear or ion tracks formed in trackable materials with atomic species. The trackable materials and atomic species are essentially insoluble in each other, thus the wires are formed by thermally driven, self-assembly of the atomic species during annealing, or re-crystallization, of the damage in the latent tracks. Unlike conventional ion track lithography, the inventive method does not require etching of the latent tracks.

  12. Level 1 Accident Investigation Report of August 17, 2004, Fatal Aircraft

    Energy Savers [EERE]

    Accident on the Grand Coulee-Bell No.6, 500 kV Line | Department of Energy Investigation Report of August 17, 2004, Fatal Aircraft Accident on the Grand Coulee-Bell No.6, 500 kV Line Level 1 Accident Investigation Report of August 17, 2004, Fatal Aircraft Accident on the Grand Coulee-Bell No.6, 500 kV Line OCTOBER 1, 2004 On August 17, 2004, at approximately 0940, a Bonneville Power Administration (BPA) pilot was killed in the crash of a Bell 206BIII helicopter while stringing "sock

  13. Accident Investigation of the July 30, 2013, Electrical Fatality on the

    Energy Savers [EERE]

    Bandon-Rogue No. 1 115kV Line at the Bonneville Power Administration | Department of Energy July 30, 2013, Electrical Fatality on the Bandon-Rogue No. 1 115kV Line at the Bonneville Power Administration Accident Investigation of the July 30, 2013, Electrical Fatality on the Bandon-Rogue No. 1 115kV Line at the Bonneville Power Administration July 30, 2013 On August 7, 2013, at the request of the Bonneville Power Administration (BPA) Chief Safety Officer, a Level I Accident Investigation was

  14. Project Profile: Hybrid Organic Silicone HTF Utilizing Endothermic Chemical Reactions for Latent Heat Storage

    Broader source: Energy.gov [DOE]

    Los Alamos National Laboratory, under an ARRA CSP Award, is developing a thermally stable, working heat transfer fluid (HTF) that is integrated with chemical reactions as a methodology to store large amounts of latent heat.

  15. Assessment of Latent Heat Reservoirs for Thermal Management of QCW Laser

    Office of Scientific and Technical Information (OSTI)

    Diodes (Technical Report) | SciTech Connect Assessment of Latent Heat Reservoirs for Thermal Management of QCW Laser Diodes Citation Details In-Document Search Title: Assessment of Latent Heat Reservoirs for Thermal Management of QCW Laser Diodes There is great interest in improving the thermal management of laser diodes intended for use as pumps in inertial confinement fusion systems. Laser diode power is currently constrained by heat dissipation in the diodes. Diodes typically dissipate a

  16. Analysis of a graphite foam-NaCl latent heat storage system for

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    supercritical CO2 power cycles for concentrated solar power | Argonne National Laboratory Analysis of a graphite foam-NaCl latent heat storage system for supercritical CO2 power cycles for concentrated solar power Title Analysis of a graphite foam-NaCl latent heat storage system for supercritical CO2 power cycles for concentrated solar power Publication Type Journal Article Year of Publication 2015 Authors Singh, D, Zhao, W, Yu, W, France, DM, Kim, T Journal Solar Energy Volume 118 Start

  17. Reducing Bat Fatalities From Interactions with Operating Wind Turbines (Fact Sheet)

    SciTech Connect (OSTI)

    Lawson, M.

    2013-11-01

    One of the biggest advantages of wind energy is that, overall, it has fewer negative impacts on the environment than fossil fuel-generated energy. Most professionals in the wind industry would like to reduce the impact of energy generation on plants, animals, and their habitats. This is why the industry is highly motivated to find out why migrating bats have unexpectedly high fatality rates near operating wind farms. New research has provided quantitative data that indicates barotrauma is not a major cause of bat deaths around operating turbines.

  18. Recombination enhances HIV-1 envelope diversity by facilitating the survival of latent genomic fragments in the plasma virus population

    SciTech Connect (OSTI)

    Immonen, Taina T.; Conway, Jessica M.; Romero-Severson, Ethan O.; Perelson, Alan S.; Leitner, Thomas; Kouyos, Roger Dimitri

    2015-12-22

    HIV-1 is subject to immune pressure exerted by the host, giving variants that escape the immune response an advantage. Virus released from activated latent cells competes against variants that have continually evolved and adapted to host immune pressure. Nevertheless, there is increasing evidence that virus displaying a signal of latency survives in patient plasma despite having reduced fitness due to long-term immune memory. We investigated the survival of virus with latent envelope genomic fragments by simulating within-host HIV-1 sequence evolution and the cycling of viral lineages in and out of the latent reservoir. Our model incorporates a detailed mutation process including nucleotide substitution, recombination, latent reservoir dynamics, diversifying selection pressure driven by the immune response, and purifying selection pressure asserted by deleterious mutations. We evaluated the ability of our model to capture sequence evolution in vivo by comparing our simulated sequences to HIV-1 envelope sequence data from 16 HIV-infected untreated patients. Empirical sequence divergence and diversity measures were qualitatively and quantitatively similar to those of our simulated HIV-1 populations, suggesting that our model invokes realistic trends of HIV-1 genetic evolution. Moreover, reconstructed phylogenies of simulated and patient HIV-1 populations showed similar topological structures. Our simulation results suggest that recombination is a key mechanism facilitating the persistence of virus with latent envelope genomic fragments in the productively infected cell population. Recombination increased the survival probability of latent virus forms approximately 13-fold. Prevalence of virus with latent fragments in productively infected cells was observed in only 2% of simulations when we ignored recombination, while the proportion increased to 27% of simulations when we allowed recombination. We also found that the selection pressures exerted by different fitness landscapes influenced the shape of phylogenies, diversity trends, and survival of virus with latent genomic fragments. Furthermore, our model predicts that the persistence of latent genomic fragments from multiple different ancestral origins increases sequence diversity in plasma for reasonable fitness landscapes.

  19. Estimating a model discrepancy term for the Community Land Model using latent heat and runoff observations

    Office of Scientific and Technical Information (OSTI)

    458C Estimating a model discrepancy term for the Community Land Model using latent heat and runoff observations J. Ray, L. Swiler, M. Huang and Z. Hou Contact: jairay@sandia.gov Sandia National Laboratories, CA & NM and Pacific Northwest National Laboratory. SAND2015-abcd IVAOiJ4 National Nuclear Security Administration Sandia National Laboratories is a multi-program laboratory managed and operated by Sandia Corporation, a wholly owned subsidiary of Lockheed Martin Corporation, for the U.S.

  20. Recombination enhances HIV-1 envelope diversity by facilitating the survival of latent genomic fragments in the plasma virus population

    DOE Public Access Gateway for Energy & Science Beta (PAGES Beta)

    Immonen, Taina T.; Conway, Jessica M.; Romero-Severson, Ethan O.; Perelson, Alan S.; Leitner, Thomas; Kouyos, Roger Dimitri

    2015-12-22

    HIV-1 is subject to immune pressure exerted by the host, giving variants that escape the immune response an advantage. Virus released from activated latent cells competes against variants that have continually evolved and adapted to host immune pressure. Nevertheless, there is increasing evidence that virus displaying a signal of latency survives in patient plasma despite having reduced fitness due to long-term immune memory. We investigated the survival of virus with latent envelope genomic fragments by simulating within-host HIV-1 sequence evolution and the cycling of viral lineages in and out of the latent reservoir. Our model incorporates a detailed mutation processmore » including nucleotide substitution, recombination, latent reservoir dynamics, diversifying selection pressure driven by the immune response, and purifying selection pressure asserted by deleterious mutations. We evaluated the ability of our model to capture sequence evolution in vivo by comparing our simulated sequences to HIV-1 envelope sequence data from 16 HIV-infected untreated patients. Empirical sequence divergence and diversity measures were qualitatively and quantitatively similar to those of our simulated HIV-1 populations, suggesting that our model invokes realistic trends of HIV-1 genetic evolution. Moreover, reconstructed phylogenies of simulated and patient HIV-1 populations showed similar topological structures. Our simulation results suggest that recombination is a key mechanism facilitating the persistence of virus with latent envelope genomic fragments in the productively infected cell population. Recombination increased the survival probability of latent virus forms approximately 13-fold. Prevalence of virus with latent fragments in productively infected cells was observed in only 2% of simulations when we ignored recombination, while the proportion increased to 27% of simulations when we allowed recombination. We also found that the selection pressures exerted by different fitness landscapes influenced the shape of phylogenies, diversity trends, and survival of virus with latent genomic fragments. Furthermore, our model predicts that the persistence of latent genomic fragments from multiple different ancestral origins increases sequence diversity in plasma for reasonable fitness landscapes.« less

  1. Indirectly heated fluidized bed biomass gasification using a latent heat ballast

    SciTech Connect (OSTI)

    Pletka, R.; Brown, R.; Smeenk, J.

    1998-12-31

    The objective of this study is to improve the heating value of gas produced during gasification of biomass fuels using an indirectly heated gasifier based on latent heat ballasting. The latent heat ballast consists of lithium fluoride salt encased in tubes suspended in the reactor. The lithium fluoride has a melting point that is near the desired gasification temperature. With the ballast a single reactor operating in a cyclic mode stores energy during a combustion phase and releases it during a pyrolysis phase. Tests were carried out in a fluidized bed reactor to evaluate the concept. The time to cool the reactor during the pyrolysis phase from 1,172 K (1,650 F) to 922 K (1,200 F) increased 102% by use of the ballast system. This extended pyrolysis time allowed 33% more biomass to be gasified during a cycle. Additionally, the total fuel fraction pyrolyzed to produce useful gas increased from 74--80%. Higher heating values of 14.2 to 16.6 MJ/Nm{sup 3} (382--445 Btu/scf) on a dry basis were obtained from the ballasted gasifier.

  2. Genetic disruption of KSHV major latent nuclear antigen LANA enhances viral lytic transcriptional program

    SciTech Connect (OSTI)

    Li Qiuhua; Zhou Fuchun; Ye Fengchun; Gao Shoujiang

    2008-09-30

    Following primary infection, KSHV establishes a lifelong persistent latent infection in the host. The mechanism of KSHV latency is not fully understood. The latent nuclear antigen (LANA or LNA) encoded by ORF73 is one of a few viral genes expressed during KSHV latency, and is consistently detected in all KSHV-related malignancies. LANA is essential for KSHV episome persistence, and regulates the expression of viral lytic genes through epigenetic silencing, and inhibition of the expression and transactivation function of the key KSHV lytic replication initiator RTA (ORF50). In this study, we used a genetic approach to examine the role of LANA in regulating KSHV lytic replication program. Deletion of LANA did not affect the expression of its adjacent genes vCyclin (ORF72) and vFLIP (ORF71). In contrast, the expression levels of viral lytic genes including immediate-early gene RTA, early genes MTA (ORF57), vIL-6 (ORF-K2) and ORF59, and late gene ORF-K8.1 were increased before and after viral lytic induction with 12-O-tetradecanoyl-phorbol-13-acetate and sodium butyrate. This enhanced expression of viral lytic genes was also observed following overexpression of RTA with or without simultaneous chemical induction. Consistent with these results, the LANA mutant cells produced more infectious virions than the wild-type virus cells did. Furthermore, genetic repair of the mutant virus reverted the phenotypes to those of wild-type virus. Together, these results have demonstrated that, in the context of viral genome, LANA contributes to KSHV latency by regulating the expression of RTA and its downstream genes.

  3. From Bombs to Breast Cancer Imaging: Los Alamos National Laboratory

    SciTech Connect (OSTI)

    Martineau, Rebecca M

    2012-07-26

    In the United States, one in eight women will be affected by breast cancer. According to the American Cancer Society, breast cancer is the most commonly diagnosed - as well as the second most fatal - cancer in American women. It is estimated that there will be nearly 200,000 diagnoses of breast cancer this year; more than 40,000 of these will be fatal. Although advances in medical technologies have greatly increased the odds of surviving the disease, the increase in screenings has not resulted in a significant reduction in the breast cancer mortality rate. Moreover, recent studies have even suggested that an increase in these methods might, in itself, cause cancer. A new tool for early detection and diagnosis of breast cancer, supported by an award from the Breast Cancer Research Program (BCRP) of the Congressionally Directed Medical Research Programs of Department of Defense, could give women a new advantage in the fight against breast cancer. This LANL-led project will integrate ultrasound tomography (UST) with recent discoveries in the field of cell and tissue biomechanics to improve breast cancer detection and characterization. UST uses ultrasound waves instead of X-rays to identify and characterize breast tumors. This technology reveals small mechanical-property changes within the breast. These changes are often the earliest signs of breast cancer. Additionally, UST is effective for women with dense breast tissue, who have a higher risk of developing breast cancer. Because the technology does not use radiation, UST can also be used as frequently as needed for women with a high risk of developing breast cancer. In contrast, mammography, the only routine breast-cancer screening tool currently available, is not effective for women with dense breast tissue and may come with unwanted side-effects caused by ionizing radiation. UST has great potential to become an alternative breast-cancer screening tool because of UST's advantages and benefits over mammography. Currently, there is fierce debate surrounding the age at which breast cancer screening should begin, and once begun, how often it should occur. The American Cancer Society recommends yearly mammograms starting at age 40. On the other hand, the U.S. Preventive Services Task Force recommends against routine so early. Rather, the Task Force recommends biennial mammography screening for women aged 50 to 74 years. The ten-year discrepancy in the onset of screening results from recent data suggesting that the frequent use of X-ray radiation during screenings could potentially increase the likelihood of developing cancer. This danger is increased by the low sensitivity and accuracy of mammograms, which sometimes require multiple screenings to yield results. Furthermore, mammograms are often not only inaccurate, but average appalling misdiagnoses rates: about 80% false positives and 15% false negatives. These misdiagnoses lead to unwarranted biopsies at an estimated health care cost of $2 billion per year, while at the same time, resulting in excessive cases of undetected cancer. As such, the National Cancer Institute recommends more studies on the advantages of types and frequency of screenings, as well as alternative screening options. The UST technology developed at LANL could be an alternative option to greatly improve the specificity and sensitivity of breast cancer screening without using ionizing radiation. LANL is developing high-resolution ultrasound tomography algorithms and a clinical ultrasound tomography scanner to conduct patient studies at the UNM Hospital. During UST scanning, the patient lies face-down while her breast, immersed in a tank of warm water, is scanned by phased-transducer arrays. UST uses recorded ultrasound signals to reconstruct a high-resolution three-dimensional image of the breast, showing the spatial distribution of mechanical properties within the breast. Breast cancers are detected by higher values of mechanical properties compared to surrounding tissues. Thus, high-resolution breast images obtained using LANL's novel UST algorithms ha

  4. Heat Transfer and Latent Heat Storage in Inorganic Molten Salts for Concentrating Solar Power Plants

    SciTech Connect (OSTI)

    Mathur, Anoop

    2013-08-14

    A key technological issue facing the success of future Concentrating Solar Thermal Power (CSP) plants is creating an economical Thermal Energy Storage (TES) system. Current TES systems use either sensible heat in fluids such as oil, or molten salts, or use thermal stratification in a dual-media consisting of a solid and a heat-transfer fluid. However, utilizing the heat of fusion in inorganic molten salt mixtures in addition to sensible heat , as in a Phase change material (PCM)-based TES, can significantly increase the energy density of storage requiring less salt and smaller containers. A major issue that is preventing the commercial use of PCM-based TES is that it is difficult to discharge the latent heat stored in the PCM melt. This is because when heat is extracted, the melt solidifies onto the heat exchanger surface decreasing the heat transfer. Even a few millimeters of thickness of solid material on heat transfer surface results in a large drop in heat transfer due to the low thermal conductivity of solid PCM. Thus, to maintain the desired heat rate, the heat exchange area must be large which increases cost. This project demonstrated that the heat transfer coefficient can be increase ten-fold by using forced convection by pumping a hyper-eutectic salt mixture over specially coated heat exchanger tubes. However,only 15% of the latent heat is used against a goal of 40% resulting in a projected cost savings of only 17% against a goal of 30%. Based on the failure mode effect analysis and experience with pumping salt at near freezing point significant care must be used during operation which can increase the operating costs. Therefore, we conclude the savings are marginal to justify using this concept for PCM-TES over a two-tank TES. The report documents the specialty coatings, the composition and morphology of hypereutectic salt mixtures and the results from the experiment conducted with the active heat exchanger along with the lessons learnt during experimentation.

  5. Modeling threat assessments of water supply systems using markov latent effects methodology.

    SciTech Connect (OSTI)

    Silva, Consuelo Juanita

    2006-12-01

    Recent amendments to the Safe Drinking Water Act emphasize efforts toward safeguarding our nation's water supplies against attack and contamination. Specifically, the Public Health Security and Bioterrorism Preparedness and Response Act of 2002 established requirements for each community water system serving more than 3300 people to conduct an assessment of the vulnerability of its system to a terrorist attack or other intentional acts. Integral to evaluating system vulnerability is the threat assessment, which is the process by which the credibility of a threat is quantified. Unfortunately, full probabilistic assessment is generally not feasible, as there is insufficient experience and/or data to quantify the associated probabilities. For this reason, an alternative approach is proposed based on Markov Latent Effects (MLE) modeling, which provides a framework for quantifying imprecise subjective metrics through possibilistic or fuzzy mathematics. Here, an MLE model for water systems is developed and demonstrated to determine threat assessments for different scenarios identified by the assailant, asset, and means. Scenario assailants include terrorists, insiders, and vandals. Assets include a water treatment plant, water storage tank, node, pipeline, well, and a pump station. Means used in attacks include contamination (onsite chemicals, biological and chemical), explosives and vandalism. Results demonstrated highest threats are vandalism events and least likely events are those performed by a terrorist.

  6. Complications associated with brachytherapy alone or with laser in lung cancer

    SciTech Connect (OSTI)

    Khanavkar, B.; Stern, P.; Alberti, W.; Nakhosteen, J.A. )

    1991-05-01

    Relatively little has been reported about destruction through brachytherapy of mucosa-perforating and extraluminary tumors with probable large vessel involvement causing major hemorrhagic or fistular complications. We report 12 patients subjected to laser and brachytherapy for centrally occluding lung cancer, whom we have periodically followed up from June 1986 until they died. Although all laser procedures were free from complications, necrotic cavitation in five cases, two of which were accompanied by large bronchoesophageal fistulas, and massive fatal hemoptysis occurred in six. Minor complications included radiation mucositis (two), noncritical mucosal scarring (two), and cough (four). Characteristics that will identify patients at risk of developing fatal hemoptysis and fistulas should be better defined by imaging and endoscopic techniques. In such cases, modifying the protocol or using alternative procedures should be considered. Minor complications, such as cough, can be avoided by using topical steroid therapy (eg, beclomethasone dipropionate).

  7. Type A Accident Investigation Report on the June 25, 1997, Contractor Inspector Fatality on the Satsop-Aberdeen #2 & #3 230 kV Line

    Office of Energy Efficiency and Renewable Energy (EERE)

    On June 27, 1997, I established a Type-A Accident Investigation Board to investigate the June 25, 1997 fatal contractor accident which occurred on BPA’s Satsop-Aberdeen #2 and #3 230-kV transmission lines right-of-way.

  8. Type A Accident Investigation Board Report on the February 13, 1997, Welding/Cutting Fatality at the K-33 Building, K-25 Site, Oak Ridge, Tennessee

    Broader source: Energy.gov [DOE]

    On February 13, 1997, at approximately 11:10 a.m., a welder (referred to as “the Welder”) using a cutting torch at the K-33 Building, Oak Ridge K-25 Site, Oak Ridge Reservation, was fatally burned after being totally engulfed in flames when his anti-contamination coveralls and blue general-purpose coveralls burned.

  9. Type A Accident Investigation Board Report of the April 25, 1997, Contractor Fatality on the Olympia-White River #1 230 kV Line

    Broader source: Energy.gov [DOE]

    On April 25, 1997, at approximately 1510 hours, a lineman for Great Southwestern Construction Inc. was fatally electrocuted when he came in direct contact with a deenergized 230-kilovolt (kV) transmission power line conductor which contained an induced voltage.

  10. Validity of Five Satellite-Based Latent Heat Flux Algorithms for Semi-arid Ecosystems

    DOE Public Access Gateway for Energy & Science Beta (PAGES Beta)

    Feng, Fei; Chen, Jiquan; Li, Xianglan; Yao, Yunjun; Liang, Shunlin; Liu, Meng; Zhang, Nannan; Guo, Yang; Yu, Jian; Sun, Minmin

    2015-12-09

    Accurate estimation of latent heat flux (LE) is critical in characterizing semiarid ecosystems. Many LE algorithms have been developed during the past few decades. However, the algorithms have not been directly compared, particularly over global semiarid ecosystems. In this paper, we evaluated the performance of five LE models over semiarid ecosystems such as grassland, shrub, and savanna using the Fluxnet dataset of 68 eddy covariance (EC) sites during the period 2000–2009. We also used a modern-era retrospective analysis for research and applications (MERRA) dataset, the Normalized Difference Vegetation Index (NDVI) and Fractional Photosynthetically Active Radiation (FPAR) from the moderate resolutionmore » imaging spectroradiometer (MODIS) products; the leaf area index (LAI) from the global land surface satellite (GLASS) products; and the digital elevation model (DEM) from shuttle radar topography mission (SRTM30) dataset to generate LE at region scale during the period 2003–2006. The models were the moderate resolution imaging spectroradiometer LE (MOD16) algorithm, revised remote sensing based Penman–Monteith LE algorithm (RRS), the Priestley–Taylor LE algorithm of the Jet Propulsion Laboratory (PT-JPL), the modified satellite-based Priestley–Taylor LE algorithm (MS-PT), and the semi-empirical Penman LE algorithm (UMD). Direct comparison with ground measured LE showed the PT-JPL and MS-PT algorithms had relative high performance over semiarid ecosystems with the coefficient of determination (R2) ranging from 0.6 to 0.8 and root mean squared error (RMSE) of approximately 20 W/m2. Empirical parameters in the structure algorithms of MOD16 and RRS, and calibrated coefficients of the UMD algorithm may be the cause of the reduced performance of these LE algorithms with R2 ranging from 0.5 to 0.7 and RMSE ranging from 20 to 35 W/m2 for MOD16, RRS and UMD. Sensitivity analysis showed that radiation and vegetation terms were the dominating variables affecting LE Fluxes in global semiarid ecosystem.« less

  11. Validity of Five Satellite-Based Latent Heat Flux Algorithms for Semi-arid Ecosystems

    SciTech Connect (OSTI)

    Feng, Fei; Chen, Jiquan; Li, Xianglan; Yao, Yunjun; Liang, Shunlin; Liu, Meng; Zhang, Nannan; Guo, Yang; Yu, Jian; Sun, Minmin

    2015-12-09

    Accurate estimation of latent heat flux (LE) is critical in characterizing semiarid ecosystems. Many LE algorithms have been developed during the past few decades. However, the algorithms have not been directly compared, particularly over global semiarid ecosystems. In this paper, we evaluated the performance of five LE models over semiarid ecosystems such as grassland, shrub, and savanna using the Fluxnet dataset of 68 eddy covariance (EC) sites during the period 2000–2009. We also used a modern-era retrospective analysis for research and applications (MERRA) dataset, the Normalized Difference Vegetation Index (NDVI) and Fractional Photosynthetically Active Radiation (FPAR) from the moderate resolution imaging spectroradiometer (MODIS) products; the leaf area index (LAI) from the global land surface satellite (GLASS) products; and the digital elevation model (DEM) from shuttle radar topography mission (SRTM30) dataset to generate LE at region scale during the period 2003–2006. The models were the moderate resolution imaging spectroradiometer LE (MOD16) algorithm, revised remote sensing based Penman–Monteith LE algorithm (RRS), the Priestley–Taylor LE algorithm of the Jet Propulsion Laboratory (PT-JPL), the modified satellite-based Priestley–Taylor LE algorithm (MS-PT), and the semi-empirical Penman LE algorithm (UMD). Direct comparison with ground measured LE showed the PT-JPL and MS-PT algorithms had relative high performance over semiarid ecosystems with the coefficient of determination (R2) ranging from 0.6 to 0.8 and root mean squared error (RMSE) of approximately 20 W/m2. Empirical parameters in the structure algorithms of MOD16 and RRS, and calibrated coefficients of the UMD algorithm may be the cause of the reduced performance of these LE algorithms with R2 ranging from 0.5 to 0.7 and RMSE ranging from 20 to 35 W/m2 for MOD16, RRS and UMD. Sensitivity analysis showed that radiation and vegetation terms were the dominating variables affecting LE Fluxes in global semiarid ecosystem.

  12. Modeling the effects of vorinostat in vivo reveals both transient and delayed HIV transcriptional activation and minimal killing of latently infected cells

    SciTech Connect (OSTI)

    Ke, Ruian; Lewin, Sharon R.; Elliott, Julian H.; Perelson, Alan S.; Chakraborty, Arup K.

    2015-10-23

    Recent efforts to cure human immunodeficiency virus type-1 (HIV-1) infection have focused on developing latency reversing agents as a first step to eradicate the latent reservoir. The histone deacetylase inhibitor, vorinostat, has been shown to activate HIV RNA transcription in CD4+ T-cells and alter host cell gene transcription in HIV-infected individuals on antiretroviral therapy. In order to understand how latently infected cells respond dynamically to vorinostat treatment and determine the impact of vorinostat on reservoir size in vivo, we have constructed viral dynamic models of latency that incorporate vorinostat treatment. We fitted these models to data collected from a recent clinical trial in which vorinostat was administered daily for 14 days to HIV-infected individuals on suppressive ART. The results show that HIV transcription is increased transiently during the first few hours or days of treatment and that there is a delay before a sustained increase of HIV transcription, whose duration varies among study participants and may depend on the long term impact of vorinostat on host gene expression. Parameter estimation suggests that in latently infected cells, HIV transcription induced by vorinostat occurs at lower levels than in productively infected cells. Lastly, the estimated loss rate of transcriptionally induced cells remains close to baseline in most study participants, suggesting vorinostat treatment does not induce latently infected cell killing and thus reduce the latent reservoir in vivo.

  13. Modeling the effects of vorinostat in vivo reveals both transient and delayed HIV transcriptional activation and minimal killing of latently infected cells

    DOE Public Access Gateway for Energy & Science Beta (PAGES Beta)

    Ke, Ruian; Lewin, Sharon R.; Elliott, Julian H.; Perelson, Alan S.; Chakraborty, Arup K.

    2015-10-23

    Recent efforts to cure human immunodeficiency virus type-1 (HIV-1) infection have focused on developing latency reversing agents as a first step to eradicate the latent reservoir. The histone deacetylase inhibitor, vorinostat, has been shown to activate HIV RNA transcription in CD4+ T-cells and alter host cell gene transcription in HIV-infected individuals on antiretroviral therapy. In order to understand how latently infected cells respond dynamically to vorinostat treatment and determine the impact of vorinostat on reservoir size in vivo, we have constructed viral dynamic models of latency that incorporate vorinostat treatment. We fitted these models to data collected from a recentmore » clinical trial in which vorinostat was administered daily for 14 days to HIV-infected individuals on suppressive ART. The results show that HIV transcription is increased transiently during the first few hours or days of treatment and that there is a delay before a sustained increase of HIV transcription, whose duration varies among study participants and may depend on the long term impact of vorinostat on host gene expression. Parameter estimation suggests that in latently infected cells, HIV transcription induced by vorinostat occurs at lower levels than in productively infected cells. Lastly, the estimated loss rate of transcriptionally induced cells remains close to baseline in most study participants, suggesting vorinostat treatment does not induce latently infected cell killing and thus reduce the latent reservoir in vivo.« less

  14. Appraisal of selected epidemiologic issues from studies of lung cancer among uranium and hard rock miners

    SciTech Connect (OSTI)

    Petersen, G R; Sever, L E

    1982-04-01

    An extensive body of published information about lung cancer among uranium miners was reviewed and diverse information, useful in identifying important issues but not in resolving them was found. Measuring exposure and response; thresholds of exposure; latency or the period from first mining experience to death; effort to predict excess risk of death, using a model; effects of smoking and radon daughter exposure on the histology of lung tumors; and the interplay of factors on the overall risk of death were all examined. The general concept of thresholds; that is, an exposure level below which risk does not increase was considered. The conclusion is that it should be possible to detect and estimate an epidemiologic threshold when the cohorts have been followed to the death of all members. Issues concerning latency in the studies of uranium miners published to date were examined. It is believed that the induction-latent period for lung cancer among uranium miners may be: as little as 10 to more than 40 years; dependent on age at which exposure begins; exposure rate; and ethnicity or smoking habits. Although suggested as factual, their existence is uncertain. An effect due to the exposure rate may exist although it has not been factual, their existence is uncertain. An effect due to the exposure rate may exist although it has not been confirmed. The median induction-latent period appears to be in excess of the 15 years frequently cited for US uranium miner. A distinct pattern of shorter induction-latent periods with increasing age at first mining exposure is reported. The evidence for and against an unusual histologic pattern of lung cancers among uranium miners was examined. The ratio of epidermoid to small cell types was close to 1:2; the ratio in the general population is nearer 2:1. The histologic pattern warrants closer attention of pathologists and epidemiologists. (ERB) (ERB)

  15. Regional CO2 and latent heat surface fluxes in the Southern Great Plains: Measurements, modeling, and scaling

    SciTech Connect (OSTI)

    Riley, W. J.; Biraud, S.C.; Torn, M.S.; Fischer, M.L.; Billesbach, D.P.; Berry, J.A.

    2009-08-15

    Characterizing net ecosystem exchanges (NEE) of CO{sub 2} and sensible and latent heat fluxes in heterogeneous landscapes is difficult, yet critical given expected changes in climate and land use. We report here a measurement and modeling study designed to improve our understanding of surface to atmosphere gas exchanges under very heterogeneous land cover in the mostly agricultural U.S. Southern Great Plains (SGP). We combined three years of site-level, eddy covariance measurements in several of the dominant land cover types with regional-scale climate data from the distributed Mesonet stations and Next Generation Weather Radar precipitation measurements to calibrate a land surface model of trace gas and energy exchanges (isotope-enabled land surface model (ISOLSM)). Yearly variations in vegetation cover distributions were estimated from Moderate Resolution Imaging Spectroradiometer normalized difference vegetation index and compared to regional and subregional vegetation cover type estimates from the U.S. Department of Agriculture census. We first applied ISOLSM at a 250 m spatial scale to account for vegetation cover type and leaf area variations that occur on hundred meter scales. Because of computational constraints, we developed a subsampling scheme within 10 km 'macrocells' to perform these high-resolution simulations. We estimate that the Atmospheric Radiation Measurement Climate Research Facility SGP region net CO{sub 2} exchange with the local atmosphere was -240, -340, and -270 gC m{sup -2} yr{sup -1} (positive toward the atmosphere) in 2003, 2004, and 2005, respectively, with large seasonal variations. We also performed simulations using two scaling approaches at resolutions of 10, 30, 60, and 90 km. The scaling approach applied in current land surface models led to regional NEE biases of up to 50 and 20% in weekly and annual estimates, respectively. An important factor in causing these biases was the complex leaf area index (LAI) distribution within cover types. Biases in predicted weekly average regional latent heat fluxes were smaller than for NEE, but larger than for either ecosystem respiration or assimilation alone. However, spatial and diurnal variations of hundreds of W m{sup -2} in latent heat fluxes were common. We conclude that, in this heterogeneous system, characterizing vegetation cover type and LAI at the scale of spatial variation are necessary for accurate estimates of bottom-up, regional NEE and surface energy fluxes.

  16. Targeting ILK and {beta}4 integrin abrogates the invasive potential of ovarian cancer

    SciTech Connect (OSTI)

    Choi, Yoon Pyo; Kim, Baek Gil; Department of Pathology, Yonsei University College of Medicine, Seoul ; Gao, Ming-Qing; Kang, Suki; Cho, Nam Hoon

    2012-10-26

    Highlights: Black-Right-Pointing-Pointer The potential of targeting ILK and integrins for highly aggressive ovarian cancer. Black-Right-Pointing-Pointer Unanticipated synergistic effect for the combination of ILK/{beta}4 integrin. Black-Right-Pointing-Pointer Combination of ILK/{beta}4 integrin effectively inhibited the PI3K/Akt/Rac1 cascade. Black-Right-Pointing-Pointer Targeting of {beta}4 integrin/ILK had potent inhibitory effects in ovarian cancer. -- Abstract: Integrins and integrin-linked kinase (ILK) are essential to cancerous invasion because they mediate physical interactions with the extracellular matrix, and regulate oncogenic signaling pathways. The purpose of our study is to determine whether deletion of {beta}1 and {beta}4 integrin and ILK, alone or in combination, has antitumoral effects in ovarian cancer. Expression of {beta}1 and {beta}4 integrin and ILK was analyzed by immunohistochemistry in 196 ovarian cancer tissue samples. We assessed the effects of depleting these molecules with shRNAs in ovarian cancer cells by Western blot, conventional RT-PCR, cell proliferation, migration, invasion, and in vitro Rac1 activity assays, and in vivo xenograft formation assays. Overexpression of {beta}4 integrin and ILK in human ovarian cancer specimens was found to correlate with tumor aggressiveness. Depletion of these targets efficiently suppresses ovarian cancer cell proliferation, migration, and invasion in vitro and xenograft tumor formation in vivo. We also demonstrated that single depletion of ILK or combination depletion of {beta}4 integrin/ILK inhibits phosphorylation of downstream signaling targets, p-Ser 473 Akt and p-Thr202/Tyr204 Erk1/2, and activation of Rac1, as well as reduce expression of MMP-2 and MMP-9 and increase expression of caspase-3 in vitro. In conclusion, targeting {beta}4 integrin combined with ILK can instigate the latent tumorigenic potential and abrogate the invasive potential in ovarian cancer.

  17. Fatal Flaw Analysis of Utility-Scale Wind Turbine Generators at the West Haymarket Joint Public Agency. A Study Prepared in Partnership with the Environmental Protection Agency for the RE-Powering America's Land Initiative: Siting Renewable Energy on Potentially Contaminated Land and Mine Sites

    SciTech Connect (OSTI)

    Roberts, J. O.; Mosey, G.

    2013-08-01

    Fatal flaw analysis of utility-scale wind turbines at the West Haymarket Joint Public Agency brownfields site in Lincoln, Nebraska, funded by EPA.

  18. cancer | National Nuclear Security Administration

    National Nuclear Security Administration (NNSA)

    cancer NNSA's work aids in fight against cancer World Cancer Day encourages citizens worldwide to take action, raise awareness, and garner support in the campaign to end cancer. Inherent in NNSA's missions are technological developments for detection, computation, and chemistry-with benefits for cancer research. Scientists at NNSA's laboratories

  19. Bismuth 213 Cancer Treatment

    ScienceCinema (OSTI)

    None

    2013-05-28

    See how INL scientists are increasing supplies of radioactive medical isotopes to treat cancer. For more information about INL research, visit http://www.facebook.com/idahonationallaboratory.

  20. Cancer Facts & Figures - 2010

    National Nuclear Security Administration (NNSA)

    ... among smokers), certain metals (chromium, cadmium, arsenic), 16 Cancer Facts & Figures 2010 some organic chemicals, radiation, air pollution, and a history of tuberculosis. ...

  1. Apple latent spherical virus vectors for reliable and effective virus-induced gene silencing among a broad range of plants including tobacco, tomato, Arabidopsis thaliana, cucurbits, and legumes

    SciTech Connect (OSTI)

    Igarashi, Aki; Yamagata, Kousuke; Sugai, Tomokazu; Takahashi, Yukari; Sugawara, Emiko; Tamura, Akihiro; Yaegashi, Hajime; Yamagishi, Noriko; Takahashi, Tsubasa; Isogai, Masamichi; Takahashi, Hideki; Yoshikawa, Nobuyuki

    2009-04-10

    Apple latent spherical virus (ALSV) vectors were evaluated for virus-induced gene silencing (VIGS) of endogenous genes among a broad range of plant species. ALSV vectors carrying partial sequences of a subunit of magnesium chelatase (SU) and phytoene desaturase (PDS) genes induced highly uniform knockout phenotypes typical of SU and PDS inhibition on model plants such as tobacco and Arabidopsis thaliana, and economically important crops such as tomato, legume, and cucurbit species. The silencing phenotypes persisted throughout plant growth in these plants. In addition, ALSV vectors could be successfully used to silence a meristem gene, proliferating cell nuclear antigen and disease resistant N gene in tobacco and RCY1 gene in A. thaliana. As ALSV infects most host plants symptomlessly and effectively induces stable VIGS for long periods, the ALSV vector is a valuable tool to determine the functions of interested genes among a broad range of plant species.

  2. Primary Radiation Therapy for Head-and-Neck Cancer in the Setting of Human Immunodeficiency Virus

    SciTech Connect (OSTI)

    Klein, Emily A.; Guiou, Michael; Farwell, D. Gregory; Luu, Quang; Lau, Derick H.; Stuart, Kerri; Vaughan, Andrew; Vijayakumar, Srinivasan; Chen, Allen M.

    2011-01-01

    Purpose: To analyze outcomes after radiation therapy for head-and-neck cancer among a cohort of patients with human immunodeficiency virus (HIV). Methods and Materials: The medical records of 12 patients with serologic evidence of HIV who subsequently underwent radiation therapy to a median dose of 68 Gy (range, 64-72 Gy) for newly diagnosed squamous cell carcinoma of the head and neck were reviewed. Six patients (50%) received concurrent chemotherapy. Intensity-modulated radiotherapy was used in 6 cases (50%). All patients had a Karnofsky performance status of 80 or 90. Nine patients (75%) were receiving antiretroviral therapies at the time of treatment, and the median CD4 count was 460 (range, 266-800). Toxicity was graded according to the Radiation Therapy Oncology Group / European Organization for the Treatment of Cancer toxicity criteria. Results: The 3-year estimates of overall survival and local-regional control were 78% and 92%, respectively. Acute Grade 3+ toxicity occurred in 7 patients (58%), the most common being confluent mucositis (5 patients) and moist skin desquamation (4 patients). Two patients experienced greater than 10% weight loss, and none experienced more than 15% weight loss from baseline. Five patients (42%) experienced treatment breaks in excess of 10 cumulative days, although none required hospitalization. There were no treatment-related fatalities. Conclusions: Radiation therapy for head-and-neck cancer seems to be relatively well tolerated among appropriately selected patients with HIV. The observed rates of toxicity were comparable to historical controls without HIV.

  3. Pre-clinical studies of toxin-specific Nanobodies: Evidence of in vivo efficacy to prevent fatal disturbances provoked by scorpion envenoming

    SciTech Connect (OSTI)

    Hmila, Issam; Cosyns, Bernard; Tounsi, Hayfa; Roosens, Bram; Caveliers, Vicky; Abderrazek, Rahma Ben; Boubaker, Samir; Muyldermans, Serge; Department of Structural Biology, VIB, Brussels ; El Ayeb, Mohamed; Bouhaouala-Zahar, Balkiss; Facult de Mdecine de Tunis, Universit de Tunis-El Manar ; Lahoutte, Tony

    2012-10-15

    Scorpions represent a significant threat to humans and animals in various countries throughout the world. Recently, we introduced Nanobodies (Nbs) to combat more efficiently scorpion envenoming and demonstrated the performance of NbAahIF12 and NbAahII10 to neutralize scorpion toxins of Androctonus australis hector venom. A bispecific Nb construct (NbF12-10) comprising these two Nbs is far more protective than the classic Fab?{sub 2} based therapy and is the most efficient antivenom therapy against scorpion sting in preclinical studies. Now we investigate the biodistribution and pharmacokinetics of {sup 99m}Tc labeled Nbs by in vivo imaging in rodents and compared these data with those of the Fab?{sub 2} product (PAS). The pharmacodynamics of the Nbs was investigated in rats by in vivo echocardiography and it is shown that NbF12-10 prevents effectively the hemodynamic disturbances induced by a lethal dose of venom. Moreover, even a late injection of NbF12-10 restores the heart rate and brings the blood pressure to baseline values. Histology confirms that NbF12-10 prevents lung and heart lesions of treated mice after envenoming. In conjunction, in this preclinical study, we provide proof of concept that NbF12-10 prevents effectively the fatal disturbances induced by Androctonus venom, and that the Nanobody based therapeutic has a potential to substitute the classic Fab?{sub 2} based product as immunotherapeutic in scorpion envenoming. Further clinical study using larger cohorts of animals should be considered to confirm the full protecting potential of our NbF12-10. -- Highlights: ? Nanobody therapy prevents the hemodynamic disturbances induced by a lethal dose. ? Late injection of Nanobody restores hemodynamic parameters to baseline values. ? Nanobody therapy prevents lung and heart lesions of treated mice after envenoming. ? Labeled Nanobody and Fab2 pharmacokinetics curves reach plateau in favour of Nanobody.

  4. Cell Senescence: Aging and Cancer

    ScienceCinema (OSTI)

    Campisi, Judith

    2013-05-29

    Scientists have identified a molecular cause behind the ravages of old age and in doing so have also shown how a natural process for fighting cancer in younger persons can actually promote cancer in older individuals.

  5. Role for a region of helically unstable DNA within the Epstein-Barr virus latent cycle origin of DNA replication oriP in origin function

    SciTech Connect (OSTI)

    Polonskaya, Zhanna; Benham, Craig J.; Hearing, Janet . E-mail: jhearing@ms.cc.sunysb.edu

    2004-10-25

    The minimal replicator of the Epstein-Barr virus (EBV) latent cycle origin of DNA replication oriP is composed of two binding sites for the Epstein-Barr virus nuclear antigen-1 (EBNA-1) and flanking inverted repeats that bind the telomere repeat binding factor TRF2. Although not required for minimal replicator activity, additional binding sites for EBNA-1 and TRF2 and one or more auxiliary elements located to the right of the EBNA-1/TRF2 sites are required for the efficient replication of oriP plasmids. Another region of oriP that is predicted to be destabilized by DNA supercoiling is shown here to be an important functional component of oriP. The ability of DNA fragments of unrelated sequence and possessing supercoiled-induced DNA duplex destabilized (SIDD) structures, but not fragments characterized by helically stable DNA, to substitute for this component of oriP demonstrates a role for the SIDD region in the initiation of oriP-plasmid DNA replication.

  6. Early Lung Cancer Detection Program

    Broader source: Energy.gov [DOE]

    Since 2000, DOE has made screening for occupational lung cancer with low-dose helical computed tomography (CT) scans available to workers at high risk for lung cancer. Because former workers undertook essential activities to fulfill the Department's mission, many of them were at risk for lung cancer.

  7. ch_5

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    HLW & FD EIS 5-73 DOE/EIS-0287 tion dose to the nonin- volved worker and maximally exposed offsite individual and the collective dose to the population residing within 50 miles of INTEC. The radiation dose values for the var- ious alternatives were then multiplied by the dose-to-risk conversion factors, which are based on the 1993 Limitations of Exposure to Ionizing Radiation (NCRP 1993). DOE has adopted these risk fac- tors of 0.0005 and 0.0004 latent cancer fatality (LCF) for each

  8. Reassessment of selected factors affecting siting of Nuclear Power Plants

    SciTech Connect (OSTI)

    Davis, R.E.; Hanson, A.L.; Mubayi, V.; Nourbakhsh, H.P.

    1997-02-01

    Brookhaven National Laboratory has performed a series of probabilistic consequence assessment calculations for nuclear reactor siting. This study takes into account recent insights into severe accident source terms and examines consequences in a risk based format consistent with the quantitative health objectives (QHOs) of the NRC`s Safety Goal Policy. Simplified severe accident source terms developed in this study are based on the risk insights of NUREG-1150. The results of the study indicate that both the quantity of radioactivity released in a severe accident as well as the likelihood of a release are lower than those predicted in earlier studies. The accident risks using the simplified source terms are examined at a series of generic plant sites, that vary in population distribution, meteorological conditions, and exclusion area boundary distances. Sensitivity calculations are performed to evaluate the effects of emergency protective action assumptions on the risk of prompt fatality and latent cancers fatality, and population relocation. The study finds that based on the new source terms the prompt and latent fatality risks at all generic sites meet the QHOs of the NRC`s Safety Goal Policy by margins ranging from one to more than three orders of magnitude. 4 refs., 17 figs., 24 tabs.

  9. Physics of Cancer | Princeton Plasma Physics Lab

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    MBG Auditorium Physics of Cancer Professor Wolfgang Losert, Associate Professor, and ... PDF icon Wolfgang Losert Bio.pdf Physics of Cancer Contact Information ...

  10. Laser research shows promise for cancer treatment

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    Cancer treatment Laser research shows promise for cancer treatment Scientists have observed for the first time how a laser penetrates dense, electron-rich plasma to generate ions. ...

  11. SQUID Instrumentation for Early Cancer Diagnostics: Combining...

    Office of Scientific and Technical Information (OSTI)

    Cancer Diagnostics: Combining SQUID-Based Ultra-Low Field MRI and Superparamagnetic Relaxometry Citation Details In-Document Search Title: SQUID Instrumentation for Early Cancer ...

  12. Breakthrough: Fighting Cancer with Nanoparticles

    ScienceCinema (OSTI)

    Rozhkova, Elena

    2013-04-19

    Argonne nanoscientist Elena Rozhkova is studying ways to enlist nanoparticles to treat brain cancer. This nano-bio technology may eventually provide an alternative form of therapy that targets only cancer cells and does not affect normal living tissue. Read more at http://1.usa.gov/JAXh7Q.

  13. Breakthrough: Fighting Cancer with Nanoparticles

    SciTech Connect (OSTI)

    Rozhkova, Elena

    2012-01-01

    Argonne nanoscientist Elena Rozhkova is studying ways to enlist nanoparticles to treat brain cancer. This nano-bio technology may eventually provide an alternative form of therapy that targets only cancer cells and does not affect normal living tissue. Read more at http://1.usa.gov/JAXh7Q.

  14. Accelerators for Cancer Therapy

    DOE R&D Accomplishments [OSTI]

    Lennox, Arlene J.

    2000-05-30

    The vast majority of radiation treatments for cancerous tumors are given using electron linacs that provide both electrons and photons at several energies. Design and construction of these linacs are based on mature technology that is rapidly becoming more and more standardized and sophisticated. The use of hadrons such as neutrons, protons, alphas, or carbon, oxygen and neon ions is relatively new. Accelerators for hadron therapy are far from standardized, but the use of hadron therapy as an alternative to conventional radiation has led to significant improvements and refinements in conventional treatment techniques. This paper presents the rationale for radiation therapy, describes the accelerators used in conventional and hadron therapy, and outlines the issues that must still be resolved in the emerging field of hadron therapy.

  15. Ancient Proteins Help Unravel a Modern Cancer Drug's Mechanism

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    Ancient Proteins Help Unravel a Modern Cancer Drug's Mechanism Print The cancer drug Gleevec is extremely specific, binding and inhibiting only the cancer-causing tyrosine protein...

  16. Safety assessment of spent-fuel transportation in extreme environments

    SciTech Connect (OSTI)

    Sandoval, R.P.; Weber, J.P.; Newton, G.J.

    1981-01-01

    Preliminary estimates of the health effects and/or consequences resulting from a malevolent attack on a spent fuel truck shipment in downtown New York City have been made. This estimate is based upon a measured quantity (0.78 +- 0.05 g) of respirable radioactive material released from a 1/4 scale event. A linear extrapolation from the 1/4 scale event to the generic full scale event has been made and an aerosolized release fraction (0.0023 percent) of the total heavy metal inventory of a three-PWR assembly truck cask has been calculated. Although scaling of the source term parameters is tentative at this point in the program, a full scale experiment is planned in 1981 to verify the scaling methodology used in these calculations. A preliminary correlation between spent fuel and surrogate fuel source terms has been shown to be feasible and that radionuclide size partitioning can be determined experimentally. Finally, it has been shown, based on our preliminary experimental source term data, that a maximum of 25 total latent cancer fatalities could occur, assuming a release in downtown New York City. This is 20 times smaller than the latent cancer fatalities predicted in the Urban Study.

  17. Cancer incidence in the Love Canal area

    SciTech Connect (OSTI)

    Janerich, D.T.; Burnett, W.S.; Feck, G.; Hoff, M.; Nasca, P.; Polednak, A.P.; Greenwald, P.; Vianna, N.

    1981-06-01

    Data from the New York Cancer Registry show no evidence for higher cancer rates associated with residence near the Love Canal toxic waste burial site in comparison with the entire state outside of New York City. Rates of liver cancer, lymphoma, and leukemia, which were selected for special attention, were not consistently elevated. Among the other cancers studied, a higher rate was noted only for respiratory cancer, but it was not consistent across age groups and appeared to be related to a high rate for the entire city of Niagara Falls. There was no evidence that the lung cancer rate was associated with the toxic wastes buried at the dump site.

  18. Microsoft PowerPoint - MBPCC CAMD Cancer Therapy Program, 12...

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    Bird Perkins Cancer Center's CAMD Cancer Therapy Research Program CAMD Cancer Therapy Research Program Kenneth R Hogstrom, PhD, PI Chief of Physics Mary Bird Perkins Cancer Center...

  19. Risk of Salivary Gland Cancer After Childhood Cancer: A Report From the Childhood Cancer Survivor Study

    SciTech Connect (OSTI)

    Boukheris, Houda; Stovall, Marilyn; Gilbert, Ethel S.; Stratton, Kayla L.; Smith, Susan A.; Weathers, Rita; Hammond, Sue; Mertens, Ann C.; Donaldson, Sarah S.; Armstrong, Gregory T.; Robison, Leslie L.; Neglia, Joseph P.; Inskip, Peter D.

    2013-03-01

    Purpose: To evaluate effects of radiation therapy, chemotherapy, cigarette smoking, and alcohol consumption on the risk of second primary salivary gland cancer (SGC) in the Childhood Cancer Survivor Study (CCSS). Methods and Materials: Standardized incidence ratios (SIR) and excess absolute risks (EAR) of SGC in the CCSS were calculated using incidence rates from Surveillance, Epidemiology, and End Results population-based cancer registries. Radiation dose to the salivary glands was estimated based on medical records. Poisson regression was used to assess risks with respect to radiation dose, chemotherapy, smoking, and alcohol consumption. Results: During the time period of the study, 23 cases of SGC were diagnosed among 14,135 childhood cancer survivors. The mean age at diagnosis of the first primary cancer was 8.3 years, and the mean age at SGC diagnosis was 24.8 years. The incidence of SGC was 39-fold higher in the cohort than in the general population (SIR = 39.4; 95% CI = 25.4-57.8). The EAR was 9.8 per 100,000 person-years. Risk increased linearly with radiation dose (excess relative risk = 0.36/Gy; 95% CI = 0.06-2.5) and remained elevated after 20 years. There was no significant trend of increasing risk with increasing dose of chemotherapeutic agents, pack-years of cigarette smoking, or alcohol intake. Conclusion: Although the cumulative incidence of SGC was low, childhood cancer survivors treated with radiation experienced significantly increased risk for at least 2 decades after exposure, and risk was positively associated with radiation dose. Results underscore the importance of long-term follow up of childhood cancer survivors for the development of new malignancies.

  20. Colon Cancer Mapping | GE Global Research

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    "With GE's cancer mapping technology, we're enabling cancer to be viewed in ways it ... of proteins and nucleic acids (RNA and DNA) without destroying the integrity of the ...

  1. Genetics and molecular biology of breast cancer

    SciTech Connect (OSTI)

    King, M.C.; Lippman, M.

    1992-12-31

    This volume contains the abstracts of oral presentations and poster sessions presented at the Cold Springs Harbor Meeting on Cancer Cells, this meeting entitled Genetics and Molecular Biology of Breast Cancer.

  2. Novel targeted therapy for stomach cancer

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    Novel targeted therapy for stomach cancer Novel targeted therapy for stomach cancer This finding has the potential to save thousand of lives a year by delivering a more effective, targeted treatment for cancer patients. November 1, 2015 New research at Los Alamos National Laboratory and the Wellcome Trust Sanger Institute shows a molecular fingerprint in stomach cancer that shows it can be treated with platinum drugs and/or molecular inhibitors known as PARP (poly ADP ribose polymerase). New

  3. HIV/Cancer DB Match Document

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    COLLECTION AND VERIFICATION OF DATA FOR MATCHED RECORDS FROM US CANCER AND HIV/AIDS REGISTRIES Janice Watkins, Oak Ridge Associated Universities, T. Borges, Robert Stafford, Oak Ridge National Laboratory Robert Biggar, James Goedert, National Cancer Institute Janice Watkins, ORAU, MS 45, P.O. Box 117, Oak Ridge, TN 37830 Key Words: AIDS, HIV/AIDS Registry, Cancer Registry, data verification, record matching BACKGROUND Data for investigating cancer rates, cofactors, and disease progression in HIV

  4. Spectroscopic Imaging of Bladder Cancer

    SciTech Connect (OSTI)

    Demos, S G; Gandour-Edwards, R; Ramsamooj, R; deVere White, R

    2003-01-01

    The feasibility of developing bladder cancer detection methods using intrinsic tissue optical properties is the focus of this investigation. In vitro experiments have been performed using polarized elastic light scattering in combination with tissue autofluorescence in the NIR spectral region under laser excitation in the green and red spectral regions. The experimental results obtained from a set of tissue specimens from 25 patients reveal the presence of optical fingerprint characteristics suitable for cancer detection with high contrast and accuracy. These photonic methods are compatible with existing endoscopic imaging modalities which make them suitable for in-vivo application.

  5. Use of ARM observations and numerical models to determine radiative and latent heating profiles of mesoscale convective systems for general circulation models

    SciTech Connect (OSTI)

    Tao, Wei-Kuo; Houze, Robert, A., Jr.; Zeng, Xiping

    2013-03-14

    This three-year project, in cooperation with Professor Bob Houze at University of Washington, has been successfully finished as planned. Both ARM (the Atmospheric Radiation Measurement Program) data and cloud-resolving model (CRM) simulations were used to identify the water budgets of clouds observed in two international field campaigns. The research results achieved shed light on several key processes of clouds in climate change (or general circulation models), which are summarized below. 1. Revealed the effect of mineral dust on mesoscale convective systems (MCSs) Two international field campaigns near a desert and a tropical coast provided unique data to drive and evaluate CRM simulations, which are TWP-ICE (the Tropical Warm Pool International Cloud Experiment) and AMMA (the African Monsoon Multidisciplinary Analysis). Studies of the two campaign data were contrasted, revealing that much mineral dust can bring about large MCSs via ice nucleation and clouds. This result was reported as a PI presentation in the 3rd ASR Science Team meeting held in Arlington, Virginia in March 2012. A paper on the studies was published in the Journal of the Atmospheric Sciences (Zeng et al. 2013). 2. Identified the effect of convective downdrafts on ice crystal concentration Using the large-scale forcing data from TWP-ICE, ARM-SGP (the Southern Great Plains) and other field campaigns, Goddard CRM simulations were carried out in comparison with radar and satellite observations. The comparison between model and observations revealed that convective downdrafts could increase ice crystal concentration by up to three or four orders, which is a key to quantitatively represent the indirect effects of ice nuclei, a kind of aerosol, on clouds and radiation in the Tropics. This result was published in the Journal of the Atmospheric Sciences (Zeng et al. 2011) and summarized in the DOE/ASR Research Highlights Summaries (see http://www.arm.gov/science/highlights/RMjY5/view). 3. Used radar observations to evaluate model simulations In cooperation with Profs. Bob Houze at University of Washington and Steven Rutledge at Colorado State University, numerical model results were evaluated with observations from W- and C-band radars and CloudSat/TRMM satellites. These studies exhibited some shortcomings of current numerical models, such as too little of thin anvil clouds, directing the future improvement of cloud microphysics parameterization in CRMs. Two papers of Powell et al (2012) and Zeng et al. (2013), summarizing these studies, were published in the Journal of the Atmospheric Sciences. 4. Analyzed the water budgets of MCSs Using ARM data from TWP-ICE, ARM-SGP and other field campaigns, the Goddard CRM simulations were carried out to analyze the water budgets of clouds from TWP-ICE and AMMA. The simulations generated a set of datasets on clouds and radiation, which are available http://cloud.gsfc.nasa.gov/. The cloud datasets were available for modelers and other researchers aiming to improve the representation of cloud processes in multi-scale modeling frameworks, GCMs and climate models. Special datasets, such as 3D cloud distributions every six minutes for TWP-ICE, were requested and generated for ARM/ASR investigators. Data server records show that 86,206 datasets were downloaded by 120 users between April of 2010 and January of 2012. 5. MMF simulations The Goddard MMF (multi-scale modeling framework) has been improved by coupling with the Goddard Land Information System (LIS) and the Goddard Earth Observing System Model, Version 5 (GOES5). It has also been optimized on NASA HEC supercomputers and can be run over 4000 CPUs. The improved MMF with high horizontal resolution (1 x 1 degree) is currently being applied to cases covering 2005 and 2006. The results show that the spatial distribution pattern of precipitation rate is well simulated by the MMF through comparisons with satellite retrievals from the CMOPRH and GPCP data sets. In addition, the MMF results were compared with three reanalyses (MERRA, ERA-Interim and CFSR). Although the MMF tends to produce a higher precipitation rate over some topical regions, it actually well captures the variations in the zonal and meridional means. Among the three reanalyses, ERA-Interim seems to have values close to those of the satellite retrievals especially for GPCP. It is interesting to note that the MMF obtained the best results in the rain forest of Africa even better than those of CFSR and ERA-Interim, when compared to CMORPH. MERRA fails to capture the precipitation in this region. We are now collaborating with Steve Rutledge (CSU) to validate the model results for AMMA 6. MC3E and the diurnal variation of precipitation processes The Midlatitude Continental Convective Clouds Experiment (MC3E) was a joint field campaign between the U.S. Department of Energy (DOE) Atmospheric Radiation Measurement (ARM) Climate Research Facility and the NASA Global Precipitation Measurement (GPM) mission Ground Validation (GV) program. It took place in central Oklahoma during the period April 22 _ June 6, 2011. Some of its major objectives involve the use of CRMs in precipitation science such as: (1) testing the fidelity of CRM simulations via intensive statistical comparisons between simulated and observed cloud properties and latent heating fields for a variety of case types, (2) establishing the limits of CRM space-time integration capabilities for quantitative precipitation estimates, and (3) supporting the development and refinement of physically-based GMI, DPR, and DPR-GMI combined retrieval algorithms using ground-based GPM GV Ku-Ka band radar and CRM simulations. The NASA unified WRF model (nu-WRF) was used for real time forecasts during the field campaign, and ten precipitation events were selected for post mission simulations. These events include well-organized squall lines, scattered storms and quasi-linear storms. A paper focused on the diurnal variation of precipitation will be submitted in September 2012. The major highlights are as follows: a. The results indicate that NU-WRF model could capture observed diurnal variation of rainfall (composite not individual); b. NU-WRF model could simulate two different types (propagating and local type) of the diurnal variation of rainfall; c. NU-WRF model simulation show very good agreement with observation in terms of precipitation pattern (linear MCS), radar reflectivity (a second low peak – shallow convection); d. NU-WRF model simulation indicates that the cool-pool dynamic is the main physical process for MCS propagation speed; e. Surface heat fluxes (including land surface model and initial surface condition) do not play a major role in phase of diurnal variation (change rainfall amount slightly); f. Terrain effect is important for initial stage of MCS (rainfall is increased and close to observation by increasing the terrain height that is also close to observed); g. Diurnal variation of radiation is not important for the simulated variation of rainfall. Publications: Zeng, X., W.-K. Tao, S. Powell, R. Houze, Jr., P. Ciesielski, N. Guy, H. Pierce and T. Matsui, 2012: A comparison of the water budgets between clouds from AMMA and TWP-ICE. J. Atmos. Sci., 70, 487-503. Powell, S. W., R. A. Houze, Jr., A. Kumar, and S. A. McFarlane, 2012: Comparison of simulated and observed continental tropical anvil clouds and their radiative heating profiles. J. Atmos. Sci., 69, 2662-2681. Zeng, X., W.-K. Tao, T. Matsui, S. Xie, S. Lang, M. Zhang, D. Starr, and X. Li, 2011: Estimating the Ice Crystal Enhancement Factor in the Tropics. J. Atmos. Sci., 68, 1424-1434. Conferences: Zeng, X., W.-K. Tao, S. Powell, R. Houze, Jr., P. Ciesielski, N. Guy, H. Pierce and T. Matsui, 2012: Comparison of water budget between AMMA and TWP-ICE clouds. The 3rd Annual ASR Science Team Meeting. Arlington, Virginia, Mar. 12-16, 2012. Zeng, X., W.-K. Tao, S. Powell, R. A. Houze Jr., and P. Ciesielski, 2011: Comparing the water budgets between AMMA and TWP-ICE clouds. Fall 2011 ASR Working Group Meeting. Annapolis, September 12-16, 2011. Zeng, X. et al., 2011: Introducing ice nuclei into turbulence parameterizations in CRMs. Fall 2011 ASR Working Group Meeting. Annapolis, September 12-16, 2011.

  6. Predictive and therapeutic markers in ovarian cancer

    DOE Patents [OSTI]

    Gray, Joe W.; Guan, Yinghui; Kuo, Wen-Lin; Fridlyand, Jane; Mills, Gordon B.

    2013-03-26

    Cancer markers may be developed to detect diseases characterized by increased expression of apoptosis-suppressing genes, such as aggressive cancers. Genes in the human chromosomal regions, 8q24, 11q13, 20q11-q13, were found to be amplified indicating in vivo drug resistance in diseases such as ovarian cancer. Diagnosis and assessment of amplification levels certain genes shown to be amplified, including PVT1, can be useful in prediction of poor outcome of patient's response and drug resistance in ovarian cancer patients with low survival rates. Certain genes were found to be high priority therapeutic targets by the identification of recurrent aberrations involving genome sequence, copy number and/or gene expression are associated with reduced survival duration in certain diseases and cancers, specifically ovarian cancer. Therapeutics to inhibit amplification and inhibitors of one of these genes, PVT1, target drug resistance in ovarian cancer patients with low survival rates is described.

  7. Pancreatic cancer: Pathogenesis, prevention and treatment

    SciTech Connect (OSTI)

    Sarkar, Fazlul H. Banerjee, Sanjeev; Li, Yiwei

    2007-11-01

    Pancreatic cancer is the fourth leading cause of cancer death in the United States with a very low survival rate of 5 years. To better design new preventive and/or therapeutic strategies for the fight against pancreatic cancer, the knowledge of the pathogenesis of pancreatic cancer at the molecular level is very important. It has been known that the development and the progression of pancreatic cancer are caused by the activation of oncogenes, the inactivation of tumor suppressor genes, and the deregulation of many signaling pathways among which the EGFR, Akt, and NF-{kappa}B pathways appear to be most relevant. Therefore, the strategies targeting EGFR, Akt, NF-{kappa}B, and their downstream signaling could be promising for the prevention and/or treatment of pancreatic cancer. In this brief review, we will summarize the current knowledge regarding the pathogenesis, prevention, and treatment of pancreatic cancer.

  8. Nanoparticles and amyloid systems: A fatal encounter?

    SciTech Connect (OSTI)

    Abel, Bernd

    2014-10-06

    Nanoparticles (NPs) are used in many products of our daily life, however, there has been concern that they may also be harmful to human health. Recently NPs have been found to accelerate the fibrillation kinetics of amyloid systems. In the past this has been preliminarily attributed to a nucleation effect. Nanoparticle surfaces and interfaces appear to limit the degrees of freedom of amyloid systems (i.e., peptides and proteins) due to a phase space constraint such that rapid cross-beta structures are formed faster than without interface interactions and in turn fibril formation is enhanced significantly. Here we explore if lipid bilayers in the form of liposomes (140nm) also accelerate fibril formation for amyloid systems. We have investigated a fragment NNFGAIL of the Human islet amyloid polypeptide (hIAPP) in contact with 1,2-diphytanoyl-sn-glycero-3-phosphocholine (DPhPC) liposomes in aqueous solution. We found that the lipid bilayer vesicles do accelerate fibril formation in time-resolved off-line detected atomic force microscopy experiments. Characteristic Thioflavine-T fluorescence on the same structures verify that the structures consist of aggregated peptides in a typical cross-?-structure arrangement.

  9. A RE-LOOK AT THE US NRC SAFETY GOALS

    SciTech Connect (OSTI)

    mubayi v.

    2013-09-22

    Since they were adopted in 1986, the US NRC’s Safety Goals have played a valuable role as a de facto risk acceptance criterion against which the predicted performance of a commercial nuclear power reactor can be evaluated and assessed. The current safety goals are cast in terms of risk metrics called quantitative health objectives (QHOs), limiting numerical values of the risks of the early and latent health effects of accidental releases of radioactivity to the offsite population. However, while demonstrating compliance with current safety goals has been an important step in assessing the acceptance of the risk posed by LWRs, new or somewhat different goals may be needed that go beyond the current early fatality and latent cancer fatality QHOs in assessing reactor risk. Natural phenomena such as hurricanes seem to be suitable candidates for establishing a background rate to derive a risk goal as their order of magnitude cost of damages is similar to those estimated in severe accident Level 3 PRAs done for nuclear power plants. This paper obtains a risk goal that could have a wider applicability, compared to the current QHOs, as a technology-neutral goal applicable to future reactors and multi-unit sites.

  10. Isotopes for cancer and cardiac care

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    Isotopes for cancer Isotopes for cancer and cardiac care Eva Birnbaum is interviewed on KSFR radio on the Lab's Isotope Program February 4, 2016 hot cell facility A worker uses remote manipulator arms to handle a highly radioactive target inside the Lab's radiochemistry hot cell facility. Isotopes from Los Alamos are used for the diagnosis of cardiac disease, for the calibration of PET scanners which in turn diagnose cancer, neurological disease, inflammatory diseases, trauma, and other

  11. Genome Science and Personalized Cancer Treatment

    SciTech Connect (OSTI)

    Gray, Joe

    2009-08-07

    August 4, 2009 Berkeley Lab lecture: Results from the Human Genome Project are enabling scientists to understand how individual cancers form and progress. This information, when combined with newly developed drugs, can optimize the treatment of individual cancers. Joe Gray, director of Berkeley Labs Life Sciences Division and Associate Laboratory Director for Life and Environmental Sciences, will focus on this approach, its promise, and its current roadblocks particularly with regard to breast cancer.

  12. Genome Science and Personalized Cancer Treatment

    SciTech Connect (OSTI)

    Gray, Joe

    2009-08-04

    Summer Lecture Series 2009: Results from the Human Genome Project are enabling scientists to understand how individual cancers form and progress. This information, when combined with newly developed drugs, can optimize the treatment of individual cancers. Joe Gray, director of Berkeley Labs Life Sciences Division and Associate Laboratory Director for Life and Environmental Sciences, will focus on this approach, its promise, and its current roadblocks particularly with regard to breast cancer.

  13. Genome Science and Personalized Cancer Treatment

    ScienceCinema (OSTI)

    Gray, Joe

    2010-01-08

    August 4, 2009 Berkeley Lab lecture: Results from the Human Genome Project are enabling scientists to understand how individual cancers form and progress. This information, when combined with newly developed drugs, can optimize the treatment of individual cancers. Joe Gray, director of Berkeley Labs Life Sciences Division and Associate Laboratory Director for Life and Environmental Sciences, will focus on this approach, its promise, and its current roadblocks ? particularly with regard to breast cancer.

  14. Risk evaluation of the alternate-3A modification to the ATWS prevention/mitigation system in a BWR-4, Mark-II power plant

    SciTech Connect (OSTI)

    Papazoglou, I.A.; Karol, R.; Shiu, K.; Bari, R.A.

    1983-01-01

    Purpose of this paper is to present a risk evaluation of the ATWS Alternate 3A modification (ATWS-3A) proposed by NRC staff in NUREG-0460 to the ATWS prevention/mitigation system in a BWR nuclear power plant. The evaluation is done relative to three risk indices: the frequency of core damage, the expected early fatalities, and the expected latent fatalities.

  15. SQUID Instrumentation for Early Cancer Diagnostics: Combining...

    Office of Scientific and Technical Information (OSTI)

    Conference: SQUID Instrumentation for Early Cancer Diagnostics: Combining SQUID-Based ... Research Org: Los Alamos National Laboratory (LANL) Sponsoring Org: LDRD Country of ...

  16. Breast Density and Cancer | GE Global Research

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    Home > Innovation > Breast Cancer Awareness Series: Understanding Breast Density Click to email this to a friend (Opens in new window) Share on Facebook (Opens in new window) Click...

  17. Ancient Proteins Help Unravel a Modern Cancer Drug's Mechanism

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    Ancient Proteins Help Unravel a Modern Cancer Drug's Mechanism Ancient Proteins Help Unravel a Modern Cancer Drug's Mechanism Print Tuesday, 23 June 2015 13:00 The cancer drug...

  18. Ancient Proteins Help Unravel a Modern Cancer Drug's Mechanism

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    Print The cancer drug Gleevec is extremely specific, binding and inhibiting only the cancer-causing tyrosine protein kinase Blc-Abl, while not targeting homologous protein...

  19. Locally Advanced Prostate Cancer: Three-Dimensional Magnetic...

    Office of Scientific and Technical Information (OSTI)

    Cancer: Three-Dimensional Magnetic Resonance Spectroscopy to Monitor Prostate Response to Therapy Citation Details In-Document Search Title: Locally Advanced Prostate Cancer: ...

  20. Structures of Lung Cancer-Derived EGFR Mutants and Inhibitor...

    Office of Scientific and Technical Information (OSTI)

    Structures of Lung Cancer-Derived EGFR Mutants and Inhibitor Complexes: Mechanism of ... Citation Details In-Document Search Title: Structures of Lung Cancer-Derived EGFR Mutants ...

  1. DOE Research Contributions to Radiation and Cancer Therapy

    Office of Scientific and Technical Information (OSTI)

    DOE Research Contributions to Radiation and Cancer Therapy Resources with Additional ... made many contributions to radiation and cancer therapy, including PEREGRINE and Boron ...

  2. Cornell dots research collaboration leads to $10M cancer center...

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    at MSKCC in New York City - will focus on melanoma (skin) and malignant brain cancers. ... Assessment of particles in brain tumors for cancer therapy. C dots successfully have ...

  3. Designer Proteins Target Epstein-Barr-Virus-Associated Cancer

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    Designer Proteins Target Epstein-Barr-Virus-Associated Cancer Designer Proteins Target Epstein-Barr-Virus-Associated Cancer Print Wednesday, 03 December 2014 00:00 Immortality is...

  4. Los Alamos researcher pens prizewinning essay on cancer

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    Researcher pens prizewinning essay on cancer Los Alamos researcher pens prizewinning essay on cancer Ludmil Alexandrov made strong points this week in the journal Science winning a...

  5. Restoration of normal phenotype in cancer cells

    DOE Patents [OSTI]

    Bissell, M.J.; Weaver, V.M.

    1998-12-08

    A method for reversing expression of malignant phenotype in cancer cells is described. The method comprises applying {beta}{sub 1} integrin function-blocking antibody to the cells. The method can be used to assess the progress of cancer therapy. Human breast epithelial cells were shown to be particularly responsive. 14 figs.

  6. Restoration of normal phenotype in cancer cells

    DOE Patents [OSTI]

    Bissell, Mina J.; Weaver, Valerie M.

    1998-01-01

    A method for reversing expression of malignant phenotype in cancer cells is described. The method comprises applying .beta..sub.1 integrin function-blocking antibody to the cells. The method can be used to assess the progress of cancer therapy. Human breast epithelial cells were shown to be particularly responsive.

  7. Diet and Cancer Are Cooked Meats Involved

    ScienceCinema (OSTI)

    LLNL - University of California Television

    2009-09-01

    Diet has been associated with differences in cancer rates in human populations for many years. Mark Knize presents the latest research on cancer causes including work performed at Lawrence Livermore National Laboratory investigating some interesting chemical products created when meat is cooked and how to reduce them. Series: Science on Saturday [10/2006] [Health and Medicine] [Science] [Show ID: 11542

  8. Understanding the origins of human cancer

    SciTech Connect (OSTI)

    Alexandrov, L. B.

    2015-12-04

    All cancers originate from a single cell that starts to behave abnormally, to divide uncontrollably, and, eventually, to invade adjacent tissues (1). The aberrant behavior of this single cell is due to somatic mutations—changes in the genomic DNA produced by the activity of different mutational processes (1). These various mutational processes include exposure to exogenous or endogenous mutagens, abnormal DNA editing, the incomplete fidelity of DNA polymerases, and failure of DNA repair mechanisms (2). Early studies that sequenced TP53, the most commonly mutated gene in human cancer, provided evidence that mutational processes leave distinct imprints of somatic mutations on the genome of a cancer cell (3). For example, C:G>A:T transversions predominate in smoking-associated lung cancer, whereas C:G>T:A transitions occurring mainly at dipyrimidines and CC:GG>TT:AA double-nucleotide substitutions are common in ultraviolet light–associated skin cancers. Moreover, these patterns of mutations matched the ones induced experimentally by tobacco mutagens and ultraviolet light, respectively, the major, known, exogenous carcinogenic influences in these cancer types, and demonstrated that examining patterns of mutations in cancer genomes can yield information about the mutational processes that cause human cancer (4).

  9. Understanding the origins of human cancer

    DOE Public Access Gateway for Energy & Science Beta (PAGES Beta)

    Alexandrov, L. B.

    2015-12-04

    All cancers originate from a single cell that starts to behave abnormally, to divide uncontrollably, and, eventually, to invade adjacent tissues (1). The aberrant behavior of this single cell is due to somatic mutations—changes in the genomic DNA produced by the activity of different mutational processes (1). These various mutational processes include exposure to exogenous or endogenous mutagens, abnormal DNA editing, the incomplete fidelity of DNA polymerases, and failure of DNA repair mechanisms (2). Early studies that sequenced TP53, the most commonly mutated gene in human cancer, provided evidence that mutational processes leave distinct imprints of somatic mutations on themore » genome of a cancer cell (3). For example, C:G>A:T transversions predominate in smoking-associated lung cancer, whereas C:G>T:A transitions occurring mainly at dipyrimidines and CC:GG>TT:AA double-nucleotide substitutions are common in ultraviolet light–associated skin cancers. Moreover, these patterns of mutations matched the ones induced experimentally by tobacco mutagens and ultraviolet light, respectively, the major, known, exogenous carcinogenic influences in these cancer types, and demonstrated that examining patterns of mutations in cancer genomes can yield information about the mutational processes that cause human cancer (4).« less

  10. Prevalence and contribution of BRCA1 mutations in breast cancer and ovarian cancer: Results from three US population-based case-control studies of ovarian cancer

    SciTech Connect (OSTI)

    Whittemore, A.S.; Gong, G.; Itnyre, J.

    1997-03-01

    We investigate the familial risks of cancers of the breast and ovary, using data pooled from three population-based case-control studies of ovarian cancer that were conducted in the United States. We base estimates of the frequency of mutations of BRCA1 (and possibly other genes) on the reported occurrence of breast cancer and ovarian cancer in the mothers and sisters of 922 women with incident ovarian cancer (cases) and in 922 women with no history of ovarian cancer (controls). Segregation analysis and goodness-of-fit testing of genetic models suggest that rare mutations (frequency .0014; 95% confidence interval .0002-.011) account for all the observed aggregation of breast cancer and ovarian cancer in these families. The estimated risk of breast cancer by age 80 years is 73.5% in mutation carriers and 6.8% in noncarriers. The corresponding estimates for ovarian cancer are 27.8% in carriers and 1.8% in noncarriers. For cancer risk in carriers, these estimates are lower than those obtained from families selected for high cancer prevalence. The estimated proportion of all U.S. cancer diagnoses, by age 80 years, that are due to germ-line BRCA1 mutations is 3.0% for breast cancer and 4.4% for ovarian cancer. Aggregation of breast cancer and ovarian cancer was less evident in the families of 169 cases with borderline ovarian cancers than in the families of cases with invasive cancers. Familial aggregation did not differ by the ethnicity of the probands, although the number of non-White and Hispanic cases (N = 99) was sparse. 14 refs., 3 figs., 6 tabs.

  11. Endoscopic Electron-Beam Cancer Therapy | Argonne National Laboratory

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    Endoscopic Electron-Beam Cancer Therapy Technology available for licensing: A successful and cost-effective means of treating cancer in previously inoperable or radiation-sensitive areas of the body. Cost-effective Can treat cancer in inoperable or radiation-sensitive areas PDF icon e-beam_cancer_therapy

  12. Ancient Proteins Help Unravel a Modern Cancer Drug's Mechanism

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    Ancient Proteins Help Unravel a Modern Cancer Drug's Mechanism Print The cancer drug Gleevec is extremely specific, binding and inhibiting only the cancer-causing tyrosine protein kinase Blc-Abl, while not targeting homologous protein kinases found in normal, healthy cells. It has been widely used to fight colon cancers and chronic myeloid leukemia. The protein kinase Abl is involved in regulating cell growth. Protein kinases have in general been the target of many cancer drug designs, since

  13. Genetic heterogeneity of breast-ovarian cancer revisited

    SciTech Connect (OSTI)

    Narod, S.; Ford, D.; Easton, D.

    1995-10-01

    We have recently reported the results of a linkage analysis of 145 breast-ovarian cancer families. Each family has three or more cases of early-onset breast cancer (age {le}60) or of ovarian cancer, and all families have at least one case of ovarian cancer (there were nine site-specific ovarian cancer families). Overall, we estimated that 76% of the families were linked to the BRCA1 locus. 5 refs., 1 tab.

  14. Ancient Proteins Help Unravel a Modern Cancer Drug's Mechanism

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    Ancient Proteins Help Unravel a Modern Cancer Drug's Mechanism Print The cancer drug Gleevec is extremely specific, binding and inhibiting only the cancer-causing tyrosine protein kinase Blc-Abl, while not targeting homologous protein kinases found in normal, healthy cells. It has been widely used to fight colon cancers and chronic myeloid leukemia. The protein kinase Abl is involved in regulating cell growth. Protein kinases have in general been the target of many cancer drug designs, since

  15. Ancient Proteins Help Unravel a Modern Cancer Drug's Mechanism

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    Ancient Proteins Help Unravel a Modern Cancer Drug's Mechanism Print The cancer drug Gleevec is extremely specific, binding and inhibiting only the cancer-causing tyrosine protein kinase Blc-Abl, while not targeting homologous protein kinases found in normal, healthy cells. It has been widely used to fight colon cancers and chronic myeloid leukemia. The protein kinase Abl is involved in regulating cell growth. Protein kinases have in general been the target of many cancer drug designs, since

  16. Ancient Proteins Help Unravel a Modern Cancer Drug's Mechanism

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    Ancient Proteins Help Unravel a Modern Cancer Drug's Mechanism Print The cancer drug Gleevec is extremely specific, binding and inhibiting only the cancer-causing tyrosine protein kinase Blc-Abl, while not targeting homologous protein kinases found in normal, healthy cells. It has been widely used to fight colon cancers and chronic myeloid leukemia. The protein kinase Abl is involved in regulating cell growth. Protein kinases have in general been the target of many cancer drug designs, since

  17. Ancient Proteins Help Unravel a Modern Cancer Drug's Mechanism

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    Ancient Proteins Help Unravel a Modern Cancer Drug's Mechanism Ancient Proteins Help Unravel a Modern Cancer Drug's Mechanism Print Tuesday, 23 June 2015 13:00 The cancer drug Gleevec is extremely specific, binding and inhibiting only the cancer-causing tyrosine protein kinase Blc-Abl, while not targeting homologous protein kinases found in normal, healthy cells. It has been widely used to fight colon cancers and chronic myeloid leukemia. The protein kinase Abl is involved in regulating cell

  18. WE-E-BRE-10: Level of Breast Cancer Stem Cell Correlated with...

    Office of Scientific and Technical Information (OSTI)

    WE-E-BRE-10: Level of Breast Cancer Stem Cell Correlated with Tumor Radioresistence: An Indication for Individualized Breast Cancer Therapy Adapted to Cancer Stem Cell Fractions ...

  19. GE Cancer Research | GE Global Research

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    Technology "Relay Race" Against Cancer Click to email this to a friend (Opens in new window) Share on Facebook (Opens in new window) Click to share (Opens in new window) Click to...

  20. Functional Promoter Variant rs2868371 of HSPB1 Is Associated With Risk of Radiation Pneumonitis After Chemoradiation for Non-Small Cell Lung Cancer

    SciTech Connect (OSTI)

    Pang, Qingsong; Department of Radiation Oncology and Lung Cancer Center, Tianjin Medical University Cancer Institute and Hospital, Key Laboratory of Cancer Prevention and Therapy, Tianjin ; Wei, Qingyi; Xu, Ting; Yuan, Xianglin; Lopez Guerra, Jose Luis; Levy, Lawrence B.; Liu, Zhensheng; Gomez, Daniel R.; Zhuang, Yan; Wang, Li-E.; Mohan, Radhe; Komaki, Ritsuko; Liao, Zhongxing

    2013-04-01

    Purpose: To date, no biomarkers have been found to predict, before treatment, which patients will develop radiation pneumonitis (RP), a potentially fatal toxicity, after chemoradiation for lung cancer. We investigated potential associations between single nucleotide polymorphisms (SNPs) in HSPB1 and risk of RP after chemoradiation for non-small cell lung cancer (NSCLC). Methods and Materials: Subjects were patients with NSCLC treated with chemoradiation at 1 institution. The training data set comprised 146 patients treated from 1999 to July 2004; the validation data set was 125 patients treated from August 2004 to March 2010. We genotyped 2 functional SNPs of HSPB1 (rs2868370 and rs2868371) from all patients. We used Kaplan-Meier analysis to assess the risk of grade ≥2 or ≥3 RP in both data sets and a parametric log-logistic survival model to evaluate the association of HSPB1 genotypes with that risk. Results: Grade ≥3 RP was experienced by 13% of those with CG/GG and 29% of those with CC genotype of HSPB1 rs2868371 in the training data set (P=.028); corresponding rates in the validation data set were 2% CG/GG and 14% CC (P=.02). Univariate and multivariate analysis confirmed the association of CC of HSPB1 rs2868371 with higher risk of grade ≥3 RP than CG/GG after adjustment for sex, age, performance status, and lung mean dose. This association was validated both in the validation data set and with Harrell's C statistic. Conclusions: The CC genotype of HSPB1 rs2868371 was associated with severe RP after chemoradiation for NSCLC.

  1. Prospective Trial of High-Dose Reirradiation Using Daily Image Guidance With Intensity-Modulated Radiotherapy for Recurrent and Second Primary Head-and-Neck Cancer

    SciTech Connect (OSTI)

    Chen, Allen M.; Farwell, D. Gregory; Luu, Quang; Cheng, Suzan; Donald, Paul J.; Purdy, James A.

    2011-07-01

    Purpose: To report a single-institutional experience using intensity-modulated radiotherapy with daily image-guided radiotherapy for the reirradiation of recurrent and second cancers of the head and neck. Methods and Materials: Twenty-one consecutive patients were prospectively treated with intensity-modulated radiotherapy from February 2006 to March 2009 to a median dose of 66 Gy (range, 60-70 Gy). None of these patients received concurrent chemotherapy. Daily helical megavoltage CT scans were obtained before each fraction as part of an image-guided radiotherapy registration protocol for patient alignment. Results: The 1- and 2-year estimates of in-field control were 72% and 65%, respectively. A total of 651 daily megavoltage CT scans were obtained. The mean systematic shift to account for interfraction motion was 1.38 {+-} 1.25 mm, 1.79 {+-} 1.45 mm, and 1.98 {+-} 1.75 mm for the medial-lateral, superior-inferior, and anterior-posterior directions, respectively. Pretreatment shifts of >3 mm occurred in 19% of setups in the medial-lateral, 27% in the superior-inferior, and 33% in the anterior-posterior directions, respectively. There were no treatment-related fatalities or hospitalizations. Complications included skin desquamation, odynophagia, otitis externa, keratitis, naso-lacrimal duct stenosis, and brachial plexopathy. Conclusions: Intensity-modulated radiotherapy with daily image guidance results in effective disease control with relatively low morbidity and should be considered for selected patients with recurrent and second primary cancers of the head and neck.

  2. Chapter 27 -- Breast Cancer Genomics, Section VI, Pathology and Biological Markers of Invasive Breast Cancer

    SciTech Connect (OSTI)

    Spellman, Paul T.; Heiser, Laura; Gray, Joe W.

    2009-06-18

    Breast cancer is predominantly a disease of the genome with cancers arising and progressing through accumulation of aberrations that alter the genome - by changing DNA sequence, copy number, and structure in ways that that contribute to diverse aspects of cancer pathophysiology. Classic examples of genomic events that contribute to breast cancer pathophysiology include inherited mutations in BRCA1, BRCA2, TP53, and CHK2 that contribute to the initiation of breast cancer, amplification of ERBB2 (formerly HER2) and mutations of elements of the PI3-kinase pathway that activate aspects of epidermal growth factor receptor (EGFR) signaling and deletion of CDKN2A/B that contributes to cell cycle deregulation and genome instability. It is now apparent that accumulation of these aberrations is a time-dependent process that accelerates with age. Although American women living to an age of 85 have a 1 in 8 chance of developing breast cancer, the incidence of cancer in women younger than 30 years is uncommon. This is consistent with a multistep cancer progression model whereby mutation and selection drive the tumor's development, analogous to traditional Darwinian evolution. In the case of cancer, the driving events are changes in sequence, copy number, and structure of DNA and alterations in chromatin structure or other epigenetic marks. Our understanding of the genetic, genomic, and epigenomic events that influence the development and progression of breast cancer is increasing at a remarkable rate through application of powerful analysis tools that enable genome-wide analysis of DNA sequence and structure, copy number, allelic loss, and epigenomic modification. Application of these techniques to elucidation of the nature and timing of these events is enriching our understanding of mechanisms that increase breast cancer susceptibility, enable tumor initiation and progression to metastatic disease, and determine therapeutic response or resistance. These studies also reveal the molecular differences between cancer and normal that may be exploited to therapeutic benefit or that provide targets for molecular assays that may enable early cancer detection, and predict individual disease progression or response to treatment. This chapter reviews current and future directions in genome analysis and summarizes studies that provide insights into breast cancer pathophysiology or that suggest strategies to improve breast cancer management.

  3. Radiation Dose and Subsequent Risk for Stomach Cancer in Long-term Survivors of Cervical Cancer

    SciTech Connect (OSTI)

    Kleinerman, Ruth A.; Smith, Susan A.; Holowaty, Eric; Hall, Per; Pukkala, Eero; Vaalavirta, Leila; Stovall, Marilyn; Weathers, Rita; Gilbert, Ethel; Aleman, Berthe M.P.; Kaijser, Magnus; Andersson, Michael; Storm, Hans; Joensuu, Heikki; Lynch, Charles F.; and others

    2013-08-01

    Purpose: To assess the doseresponse relationship for stomach cancer after radiation therapy for cervical cancer. Methods and Materials: We conducted a nested, matched casecontrol study of 201 cases and 378 controls among 53,547 5-year survivors of cervical cancer diagnosed from 1943 to 1995, from 5 international, population-based cancer registries. We estimated individual radiation doses to the site of the stomach cancer for all cases and to corresponding sites for the matched controls (overall mean stomach tumor dose, 2.56 Gy, range 0.03-46.1 and after parallel opposed pelvic fields, 1.63 Gy, range 0.12-6.3). Results: More than 90% of women received radiation therapy, mostly with external beam therapy in combination with brachytherapy. Stomach cancer risk was nonsignificantly increased (odds ratio 1.27-2.28) for women receiving between 0.5 and 4.9 Gy to the stomach cancer site and significantly increased at doses ?5 Gy (odds ratio 4.20, 95% confidence interval 1.41-13.4, P{sub trend}=.047) compared with nonirradiated women. A highly significant radiation doseresponse relationship was evident when analyses were restricted to the 131 cases (251 controls) whose stomach cancer was located in the middle and lower portions of the stomach (P{sub trend}=.003), whereas there was no indication of increasing risk with increasing dose for 30 cases (57 controls) whose cancer was located in the upper stomach (P{sub trend}=.23). Conclusions: Our findings show for the first time a significant linear doseresponse relationship for risk of stomach cancer in long-term survivors of cervical cancer.

  4. Cold atmospheric plasma in cancer therapy

    SciTech Connect (OSTI)

    Keidar, Michael; Shashurin, Alex; Volotskova, Olga; Ann Stepp, Mary; Srinivasan, Priya; Sandler, Anthony; Trink, Barry

    2013-05-15

    Recent progress in atmospheric plasmas has led to the creation of cold plasmas with ion temperature close to room temperature. This paper outlines recent progress in understanding of cold plasma physics as well as application of cold atmospheric plasma (CAP) in cancer therapy. Varieties of novel plasma diagnostic techniques were developed recently in a quest to understand physics of CAP. It was established that the streamer head charge is about 10{sup 8} electrons, the electrical field in the head vicinity is about 10{sup 7} V/m, and the electron density of the streamer column is about 10{sup 19} m{sup ?3}. Both in-vitro and in-vivo studies of CAP action on cancer were performed. It was shown that the cold plasma application selectively eradicates cancer cells in-vitro without damaging normal cells and significantly reduces tumor size in-vivo. Studies indicate that the mechanism of action of cold plasma on cancer cells is related to generation of reactive oxygen species with possible induction of the apoptosis pathway. It is also shown that the cancer cells are more susceptible to the effects of CAP because a greater percentage of cells are in the S phase of the cell cycle.

  5. Occult Breast Cancer: Scintimammography with High-Resolution...

    Office of Scientific and Technical Information (OSTI)

    Occult Breast Cancer: Scintimammography with High-Resolution Breast-specific Gamma Camera in Women at High Risk for Breast Cancer Citation Details In-Document Search Title: Occult ...

  6. Enzyme Structure Provides Insights into Cancer and Aging

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    Enzyme Structure Provides Insights into Cancer and Aging Enzyme Structure Provides Insights into Cancer and Aging Print Wednesday, 25 February 2009 00:00 XPD helicase is an enzyme...

  7. Breaking a Pocket of Resistance in the Fight Against Cancer

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    Breaking a Pocket of Resistance in the Fight Against Cancer Breaking a Pocket of Resistance in the Fight Against Cancer Print Thursday, 12 December 2013 11:55 ras protein The new...

  8. Lab Breakthrough: Nanomaterials Discoveries Lead to Possible Cancer

    Office of Energy Efficiency and Renewable Energy (EERE) Indexed Site

    Treatment | Department of Energy Nanomaterials Discoveries Lead to Possible Cancer Treatment Lab Breakthrough: Nanomaterials Discoveries Lead to Possible Cancer Treatment June 4, 2012 - 3:05pm Addthis Argonne nanoscientist Elena Rozhkova is studying ways to enlist nanoparticles to treat brain cancer. This nano-bio technology may eventually provide an alternative form of therapy that targets only cancer cells and does not affect normal living tissue. View the entire Lab Breakthrough playlist.

  9. DNA damage checkpoint recovery and cancer development

    SciTech Connect (OSTI)

    Wang, Haiyong; Zhang, Xiaoshan; Teng, Lisong; Legerski, Randy J.

    2015-06-10

    Cell cycle checkpoints were initially presumed to function as a regulator of cell cycle machinery in response to different genotoxic stresses, and later found to play an important role in the process of tumorigenesis by acting as a guard against DNA over-replication. As a counterpart of checkpoint activation, the checkpoint recovery machinery is working in opposition, aiming to reverse the checkpoint activation and resume the normal cell cycle. The DNA damage response (DDR) and oncogene induced senescence (OIS) are frequently found in precancerous lesions, and believed to constitute a barrier to tumorigenesis, however, the DDR and OIS have been observed to be diminished in advanced cancers of most tissue origins. These findings suggest that when progressing from pre-neoplastic lesions to cancer, DNA damage checkpoint barriers are overridden. How the DDR checkpoint is bypassed in this process remains largely unknown. Activated cytokine and growth factor-signaling pathways were very recently shown to suppress the DDR and to promote uncontrolled cell proliferation in the context of oncovirus infection. In recent decades, data from cell line and tumor models showed that a group of checkpoint recovery proteins function in promoting tumor progression; data from patient samples also showed overexpression of checkpoint recovery proteins in human cancer tissues and a correlation with patients' poor prognosis. In this review, the known cell cycle checkpoint recovery proteins and their roles in DNA damage checkpoint recovery are reviewed, as well as their implications in cancer development. This review also provides insight into the mechanism by which the DDR suppresses oncogene-driven tumorigenesis and tumor progression. - Highlights: • DNA damage checkpoint works as a barrier to cancer initiation. • DDR machinary response to genotoxic and oncogenic stress in similar way. • Checkpoint recovery pathways provide active signaling in cell cycle control. • Checkpoint recovery pathway plays a role in overriding tumor barrier in tumorigenesis. • Recovery protein dysregulation and human cancer development is correlated.

  10. Detecting and treating breast cancer resistance to EGFR inhibitors

    DOE Patents [OSTI]

    Moonlee, Sun-Young; Bissell, Mina J.; Furuta, Saori; Meier, Roland; Kenny, Paraic A.

    2016-04-05

    The application describes therapeutic compositions and methods for treating cancer. For example, therapeutic compositions and methods related to inhibition of FAM83A (family with sequence similarity 83) are provided. The application also describes methods for diagnosing cancer resistance to EGFR inhibitors. For example, a method of diagnosing cancer resistance to EGFR inhibitors by detecting increased FAM83A levels is described.

  11. Blood Vessel Normalization in the Hamster Oral Cancer Model for Experimental Cancer Therapy Studies

    SciTech Connect (OSTI)

    Ana J. Molinari; Romina F. Aromando; Maria E. Itoiz; Marcela A. Garabalino; Andrea Monti Hughes; Elisa M. Heber; Emiliano C. C. Pozzi; David W. Nigg; Veronica A. Trivillin; Amanda E. Schwint

    2012-07-01

    Normalization of tumor blood vessels improves drug and oxygen delivery to cancer cells. The aim of this study was to develop a technique to normalize blood vessels in the hamster cheek pouch model of oral cancer. Materials and Methods: Tumor-bearing hamsters were treated with thalidomide and were compared with controls. Results: Twenty eight hours after treatment with thalidomide, the blood vessels of premalignant tissue observable in vivo became narrower and less tortuous than those of controls; Evans Blue Dye extravasation in tumor was significantly reduced (indicating a reduction in aberrant tumor vascular hyperpermeability that compromises blood flow), and tumor blood vessel morphology in histological sections, labeled for Factor VIII, revealed a significant reduction in compressive forces. These findings indicated blood vessel normalization with a window of 48 h. Conclusion: The technique developed herein has rendered the hamster oral cancer model amenable to research, with the potential benefit of vascular normalization in head and neck cancer therapy.

  12. Isotope Cancer Treatment Research at LANL

    ScienceCinema (OSTI)

    Weidner, John; Nortier, Meiring

    2014-06-02

    Los Alamos National Laboratory has produced medical isotopes for diagnostic and imaging purposes for more than 30 years. Now LANL researchers have branched out into isotope cancer treatment studies. New results show that an accelerator-based approach can produce clinical trial quantities of actinium-225, an isotope that has promise as a way to kill tumors without damaging surrounding healthy cells.

  13. Downregulation of tumor suppressor QKI in gastric cancer and its implication in cancer prognosis

    SciTech Connect (OSTI)

    Bian, Yongqian [The State Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, The Fourth Military Medical University, Xi'an 710032 (China)] [The State Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, The Fourth Military Medical University, Xi'an 710032 (China); Wang, Li; Lu, Huanyu; Yang, Guodong [The State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, Xi'an 710032 (China)] [The State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, Xi'an 710032 (China); Zhang, Zhang [The State Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, The Fourth Military Medical University, Xi'an 710032 (China)] [The State Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, The Fourth Military Medical University, Xi'an 710032 (China); Fu, Haiyan; Lu, Xiaozhao; Wei, Mengying [The State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, Xi'an 710032 (China)] [The State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, Xi'an 710032 (China); Sun, Jianyong; Zhao, Qingchuan [The State Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, The Fourth Military Medical University, Xi'an 710032 (China)] [The State Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, The Fourth Military Medical University, Xi'an 710032 (China); Dong, Guanglong, E-mail: gldong301@gmail.com [The State Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, The Fourth Military Medical University, Xi'an 710032 (China) [The State Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, The Fourth Military Medical University, Xi'an 710032 (China); Department of General Surgery, The General Hospital of the PLA, Beijing 100853 (China); Lu, Zifan, E-mail: luzfliuq@fmmu.edu.cn [The State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, Xi'an 710032 (China)] [The State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, Xi'an 710032 (China)

    2012-05-25

    Highlights: Black-Right-Pointing-Pointer QKI expression is decreased in gastric cancer samples. Black-Right-Pointing-Pointer Promoter hyper methylation contributes to the downregulation of QKI. Black-Right-Pointing-Pointer QKI inhibits the growth of gastric cancer cells. Black-Right-Pointing-Pointer Decreased QKI expression predicts poor survival. -- Abstract: Gastric cancer (GC) is the fourth most common cancer and second leading cause of cancer-related death worldwide. RNA-binding protein Quaking (QKI) is a newly identified tumor suppressor in multiple cancers, while its role in GC is largely unknown. Our study here aimed to clarify the relationship between QKI expression with the clinicopathologic characteristics and the prognosis of GC. In the 222 GC patients' specimens, QKI expression was found to be significantly decreased in most of the GC tissues, which was largely due to promoter hypermethylation. QKI overexpression reduced the proliferation ability of GC cell line in vitro study. In addition, the reduced QKI expression correlated well with poor differentiation status, depth of invasion, gastric lymph node metastasis, distant metastasis, advanced TNM stage, and poor survival. Multivariate analysis showed QKI expression was an independent prognostic factor for patient survival.

  14. Finding of No Significant Impact for the Construction and Operation...

    Energy Savers [EERE]

    (NCRP, 1997), the maximally exposed worker would have an annual probability of fatal cancer induced by radiation of approximately 4 x 10 -6 . The average exposed worker would...

  15. Compositions and methods for cancer treatment using targeted carbon nanotubes

    DOE Patents [OSTI]

    Harrison, Jr., Roger G; Resasco, Daniel E; Neves, Luis Filipe Ferreira

    2013-08-27

    The present invention is a method for detecting and destroying cancer tumors. The method is based on the concept of associating a linking protein or linking peptide such as, but not limited to, annexin V or other annexins to carbon nanotubes such as single-walled carbon nanotubes (SWNTs) to form a protein-CNT complex. Said linking protein or peptide can selectively bind to cancerous cells, especially tumor vasculature endothelial cells, rather than to healthy ones by binding to cancer-specific external receptors such as anionic phospholipids including phosphatidylserine expressed on the outer surfaces of cancer cells only. Irradiation of bound CNTs with one or more specific electromagnetic wavelengths is then used to detect and destroy those cells to which the CNTs are bound via the linking protein or peptide thereby destroying the tumor or cancer cells and preferably an immunostimulant is provided to the patient to enhance the immune response against antigens released from the tumor or cancer cells.

  16. Translating the cancer genome: Going beyond p values

    SciTech Connect (OSTI)

    Chin, Lynda; Chin, Lynda; Gray, Joe W.

    2008-04-03

    Cancer cells are endowed with diverse biological capabilities driven by myriad inherited and somatic genetic and epigenetic aberrations that commandeer key cancer-relevant pathways. Efforts to elucidate these aberrations began with Boveri's hypothesis of aberrant mitoses causing cancer and continue today with a suite of powerful high-resolution technologies that enable detailed catalogues of genomic aberrations and epigenomic modifications. Tomorrow will likely bring the complete atlas of reversible and irreversible alteration in individual cancers. The challenge now is to discern causal molecular abnormalities from genomic and epigenomic 'noise', to understand how the ensemble of these aberrations collaborate to drive cancer pathophysiology. Here, we highlight lessons learned from now classical examples of successful translation of genomic discoveries into clinical practice, lessons that may be used to guide and accelerate translation of emerging genomic insights into practical clinical endpoints that can impact on practice of cancer medicine.

  17. Genome Science and Personalized Cancer Treatment (LBNL Summer Lecture Series)

    ScienceCinema (OSTI)

    Gray, Joe

    2011-04-28

    Summer Lecture Series 2009: Results from the Human Genome Project are enabling scientists to understand how individual cancers form and progress. This information, when combined with newly developed drugs, can optimize the treatment of individual cancers. Joe Gray, director of Berkeley Labs Life Sciences Division and Associate Laboratory Director for Life and Environmental Sciences, will focus on this approach, its promise, and its current roadblocks ? particularly with regard to breast cancer.

  18. New nanotech invention improves effectiveness of the 'penicillin of cancer'

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    | Argonne National Laboratory nanotech invention improves effectiveness of the 'penicillin of cancer' By Jared Sagoff * August 13, 2014 Tweet EmailPrint ARGONNE, Ill. - Scientists at the U.S. Department of Energy's Argonne National Laboratory have added a new weapon to oncologists' arsenal of anti-cancer therapies. By combining magnetic nanoparticles with one of the most common and effective chemotherapy drugs, Argonne researchers have created a way to deliver anti-cancer drugs directly into

  19. Jefferson Lab Medical Imager Spots Breast Cancer | Jefferson Lab

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    Medical Imager Spots Breast Cancer PEM This PEM image shows two cancerous lesions. The one on the right was depicted by conventional mammography, but the one on the left was only identified by the PEM unit. Image courtesy: Eric Rosen, Duke University Medical Center Jefferson Lab Medical Imager Spots Breast Cancer March 3, 2005 Newport News, VA - A study published in the February issue of the journal Radiology shows that a positron emission mammography (PEM) device designed and built by Jefferson

  20. Genome Science and Personalized Cancer Treatment (LBNL Summer Lecture Series)

    SciTech Connect (OSTI)

    Gray, Joe

    2009-08-04

    Summer Lecture Series 2009: Results from the Human Genome Project are enabling scientists to understand how individual cancers form and progress. This information, when combined with newly developed drugs, can optimize the treatment of individual cancers. Joe Gray, director of Berkeley Labs Life Sciences Division and Associate Laboratory Director for Life and Environmental Sciences, will focus on this approach, its promise, and its current roadblocks particularly with regard to breast cancer.

  1. Receipt of Guideline-Concordant Treatment in Elderly Prostate Cancer

    Office of Scientific and Technical Information (OSTI)

    Patients (Journal Article) | SciTech Connect Receipt of Guideline-Concordant Treatment in Elderly Prostate Cancer Patients Citation Details In-Document Search Title: Receipt of Guideline-Concordant Treatment in Elderly Prostate Cancer Patients Purpose: To examine the proportion of elderly prostate cancer patients receiving guideline-concordant treatment, using the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database. Methods and Materials: A total of 29,001 men

  2. COLLOQUIUM: Proton Therapy for Cancer: Current Status, Promise and

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    Challenges | Princeton Plasma Physics Lab 25, 2016, 4:15pm to 5:30pm Colloquia MBG Auditorium, PPPL (284 cap.) COLLOQUIUM: Proton Therapy for Cancer: Current Status, Promise and Challenges Dr. Dennis Mah ProCure Proton Therapy Center This presentation will provide a physicist's perspective on a proton therapy for cancer treatment. It will include a context of how radiation therapy fits into cancer management overall with an emphasis on the differences between proton and conventional

  3. Los Alamos researcher pens prizewinning essay on cancer

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    Researcher pens prizewinning essay on cancer Los Alamos researcher pens prizewinning essay on cancer Ludmil Alexandrov made strong points this week in the journal Science winning a 2015 Science & SciLifeLab Prize, on "Understanding the Origins of Human Cancer." December 6, 2015 The international prize is awarded annually to four young scientists for outstanding life science research for which he or she earned a doctoral degree in the previous two years. The international prize is

  4. Enzyme Structure Provides Insights into Cancer and Aging

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    protein are responsible for three different human diseases: in xeroderma pigmentosum (XP), extreme sensitivity to sunlight promotes cancer; Cockayne syndrome (CS) involves...

  5. Occult Breast Cancer: Scintimammography with High-Resolution...

    Office of Scientific and Technical Information (OSTI)

    cancer but with normal mammographic and physical examination findings. MATERIALS AND METHODS: Institutional Review ... Resource Type: Journal Article Resource Relation: Journal ...

  6. Feeding Arteries of Primary Tongue Cancers on Intra-arterial...

    Office of Scientific and Technical Information (OSTI)

    on Intra-arterial Infusion Chemotherapy Citation Details In-Document Search Title: Feeding Arteries of Primary Tongue Cancers on Intra-arterial Infusion Chemotherapy PurposeTo ...

  7. World Cancer Day 2015: Not Beyond Us | GE Global Research

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    World Cancer Day 2015: Not Beyond Us Click to email this to a friend (Opens in new window) Share on Facebook (Opens in new window) Click to share (Opens in new window) Click to share on LinkedIn (Opens in new window) Click to share on Tumblr (Opens in new window) World Cancer Day 2015: Not Beyond Us Mark Frontera 2015.02.05 Yesterday, Feb. 4, marked World Cancer Day, a day set aside each year to raise awareness about cancer worldwide. This year's theme, "not beyond us," speaks to the

  8. NNSA's work aids in fight against cancer | National Nuclear Security...

    National Nuclear Security Administration (NNSA)

    NNSA retrained nuclear weapons scientists internationally to work in cancer treatment. A recently developed laser plasma accelerator can be used in scanning devices to spot hidden ...

  9. Radioisotopes for Medical Diagnostics and Cancer Therapy at BNL...

    Office of Science (SC) Website

    Radioisotopes for Medical Diagnostics and Cancer Therapy at BNL Nuclear Physics (NP) NP Home About Research Facilities Science Highlights Benefits of NP Applications of Nuclear ...

  10. Identification of cancer protein biomarkers using proteomic techniques

    DOE Patents [OSTI]

    Mor, Gil G.; Ward, David C.; Bray-Ward, Patricia

    2010-02-23

    The claimed invention describes methods to diagnose or aid in the diagnosis of cancer. The claimed methods are based on the identification of biomarkers which are particularly well suited to discriminate between cancer subjects and healthy subjects. These biomarkers were identified using a unique and novel screening method described herein. The biomarkers identified herein can also be used in the prognosis and monitoring of cancer. The invention comprises the use of leptin, prolactin, OPN and IGF-II for diagnosing, prognosis and monitoring of ovarian cancer.

  11. Identification of cancer protein biomarkers using proteomic techniques

    DOE Patents [OSTI]

    Mor, Gil G; Ward, David C; Bray-Ward, Patricia

    2015-03-10

    The claimed invention describes methods to diagnose or aid in the diagnosis of cancer. The claimed methods are based on the identification of biomarkers which are particularly well suited to discriminate between cancer subjects and healthy subjects. These biomarkers were identified using a unique and novel screening method described herein. The biomarkers identified herein can also be used in the prognosis and monitoring of cancer. The invention comprises the use of leptin, prolactin, OPN and IGF-II for diagnosing, prognosis and monitoring of ovarian cancer.

  12. Cancer-fighting treatment gets boost from Isotope Production...

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    Medical Isotope Work Moves Cancer Treatment Agent Forward - Los Alamos scientist Meiring Nortier holds a thorium foil test target for the proof-of-concept production experiments. ...

  13. Software speeds detection of diseases and cancer-treatment targets

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    Software speeds detection of diseases and cancer-treatment targets Alumni Link: Opportunities, News and Resources for Former Employees Latest Issue:September 2015 all issues All...

  14. Insight into Alzheimer's, cancer, anemia gleaned from ribosome...

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    Insights from ribosome research Insight into Alzheimer's, cancer, anemia gleaned from ribosome research Groundbreaking study of the human ribosome reveals tiny molecular machine is...

  15. Three-Dimensional Thermal Tomography Advances Cancer Treatment...

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    Three-Dimensional Thermal Tomography Advances Cancer Treatment Technology available for licensing: A 3D technique to detect early skin changes due to radiation treatment in breast...

  16. Protocadherin-7 induces bone metastasis of breast cancer

    SciTech Connect (OSTI)

    Li, Ai-Min; Tian, Ai-Xian; Zhang, Rui-Xue; Ge, Jie; Key Laboratory of Breast Cancer Prevention and Treatment of the Ministry of Education, Tianjin Medical University Cancer Institute and Hospital, Tianjin ; Sun, Xuan; Cao, Xu-Chen; Key Laboratory of Breast Cancer Prevention and Treatment of the Ministry of Education, Tianjin Medical University Cancer Institute and Hospital, Tianjin

    2013-07-05

    Highlights: PCDH7 is overexpression in high bone metastatic MDA-MB-231 cells. PCDH7 is up-regulation in bone metastatic breast cancer tissues. Suppression of PCDH7 inhibits cell proliferation, migration, and invasion in vitro. PCDH7 induces breast cancer bone metastasis in vivo. -- Abstract: Breast cancer had a propensity to metastasize to bone, resulting in serious skeletal complications associated with poor outcome. Previous study showed that Protocadherin-7 (PCDH7) play an important role in brain metastatic breast cancer, however, the role of PCDH7 in bone metastatic breast cancer has never been explored. In the present study, we found that PCDH7 expression was up-regulation in bone metastatic breast cancer tissues by real-time PCR and immunohistochemistry assays. Furthermore, suppression of PCDH7 inhibits breast cancer cell proliferation, migration, and invasion in vitro by MTT, scratch, and transwell assays. Most importantly, overexpression of PCDH7 promotes breast cancer cell proliferation and invasion in vitro, and formation of bone metastasis in vivo. These data provide an important insight into the role of PCDH7 in bone metastasis of breast cancer.

  17. Phase II Study of Accelerated High-Dose Radiotherapy With Concurrent Chemotherapy for Patients With Limited Small-Cell Lung Cancer: Radiation Therapy Oncology Group Protocol 0239

    SciTech Connect (OSTI)

    Komaki, Ritsuko; Paulus, Rebecca; Ettinger, David S.; Videtic, Gregory M.M.; Bradley, Jeffrey D.; Glisson, Bonnie S.; Sause, William T.; Curran, Walter J.; Choy, Hak

    2012-07-15

    Purpose: To investigate whether high-dose thoracic radiation given twice daily during cisplatin-etoposide chemotherapy for limited small-cell lung cancer (LSCLC) improves survival, acute esophagitis, and local control rates relative to findings from Intergroup trial 0096 (47%, 27%, and 64%). Patients and Methods: Patients were accrued over a 3-year period from 22 US and Canadian institutions. Patients with LSCLC and good performance status were given thoracic radiation to 61.2 Gy over 5 weeks (daily 1.8-Gy fractions on days 1-22, then twice-daily 1.8-Gy fractions on days 23-33). Cisplatin (60 mg/m{sup 2} IV) was given on day 1 and etoposide (120 mg/m{sup 2} IV) on days 1-3 and days 22-24, followed by 2 cycles of cisplatin plus etoposide alone. Patients who achieved complete response were offered prophylactic cranial irradiation. Endpoints included overall and progression-free survival; severe esophagitis (Common Toxicity Criteria v 2.0) and treatment-related fatalities; response (Response Evaluation Criteria in Solid Tumors); and local control. Results: Seventy-two patients were accrued from June 2003 through May 2006; 71 were evaluable (median age 63 years; 52% female; 58% Zubrod 0). Median survival time was 19 months; at 2 years, the overall survival rate was 36.6% (95% confidence interval [CI] 25.6%-47.7%), and progression-free survival 19.7% (95% CI 11.4%-29.6%). Thirteen patients (18%) experienced severe acute esophagitis, and 2 (3%) died of treatment-related causes; 41% achieved complete response, 39% partial response, 10% stable disease, and 6% progressive disease. The local control rate was 73%. Forty-three patients (61%) received prophylactic cranial irradiation. Conclusions: The overall survival rate did not reach the projected goal; however, rates of esophagitis were lower, and local control higher, than projected. This treatment strategy is now one of three arms of a prospective trial of chemoradiation for LSCLC (Radiation Therapy Oncology Group 0538/Cancer and Leukemia Group B 30610).

  18. Targeting NRF2 signaling for cancer chemoprevention

    SciTech Connect (OSTI)

    Kwak, Mi-Kyoung; Kensler, Thomas W.

    2010-04-01

    Modulation of the metabolism and disposition of carcinogens through induction of cytoprotective enzymes is one of several promising strategies to prevent cancer. Chemopreventive efficacies of inducers such as dithiolethiones and sulforaphane have been extensively studied in animals as well as in humans. The KEAP1-NRF2 system is a key, but not unilateral, molecular target for these chemopreventive agents. The transcription factor NRF2 (NF-E2-related factor 2) is a master regulator of the expression of a subset of genes, which produce proteins responsible for the detoxication of electrophiles and reactive oxygen species as well as the removal or repair of some of their damage products. It is believed that chemopreventive enzyme inducers affect the interaction between KEAP1 and NRF2 through either mediating conformational changes of the KEAP1 protein or activating phosphorylation cascades targeting the KEAP1-NRF2 complex. These events in turn affect NRF2 stability and trafficking. Recent advances elucidating the underlying structural biology of KEAP1-NRF2 signaling and identification of the gene clusters under the transcriptional control of NRF2 are facilitating understanding of the potential pleiotropic effects of NRF2 activators and discovery of novel classes of potent chemopreventive agents such as the triterpenoids. Although there is appropriately a concern regarding a deleterious role of the KEAP1-NRF2 system in cancer cell biology, especially as the pathway affects cell survival and drug resistance, the development and the use of NRF2 activators as chemopreventive agents still holds a great promise for protection of normal cells from a diversity of environmental stresses that contribute to the burden of cancer and other chronic, degenerative diseases.

  19. Endoscopic Radiation Revolutionizes Cancer Treatment - Energy Innovation

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    Portal Endoscopic Radiation Revolutionizes Cancer Treatment Argonne National Laboratory Contact ANL About This Technology <p> <em>Conventional X-ray radiation and electron beam therapy: a comparison</em></p> <p> <em>Left: Conventional treatment depositing energy into tissue as a function of distance for three 250-kV X-ray beams; Right: Electron beam treatment depositing energy into tissue for a 3-MeV electron beam as a function of distance, with the zero

  20. Liposome-encapsulated actinomycin for cancer chemotherapy

    DOE Patents [OSTI]

    Rahman, Yueh-Erh; Cerny, Elizabeth A.

    1976-01-01

    An improved method is provided for chemotherapy of malignant tumors by injection of antitumor drugs. The antitumor drug is encapsulated within liposomes and the liposomes containing the encapsulated drug are injected into the body. The encapsulated drug penetrates into the tumor cells where the drug is slowly released and induces degeneration and death of the tumor cells, while any toxicity to the host body is reduced. Liposome encapsulation of actinomycin D has been found to be particularly effective in treating cancerous abdominal tumors, while drastically reducing the toxicity of actinomycin D to the host.

  1. Using HEP Technology to Fight Cancer

    SciTech Connect (OSTI)

    Le Du, Patrick

    2004-06-30

    Many engineering and physics HEP groups are now collaborating with medical doctors and biomedical scientists to develop new modern and 'state of the art' radiation instruments for cancer diagnostics and treatment. This presentation will review some of these studies, oriented towards the imaging fields for diagnostic (Positron Emission Tomography and Computed Tomography) and particle therapy for tumor treatment (from proton to light ions). I will try, using appropriate examples, to show what are the challenges and where the development of HEP concepts, tools and techniques can be used.

  2. Three-Dimensional Thermal Tomography Advances Cancer Treatment | Argonne

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    National Laboratory Three-Dimensional Thermal Tomography Advances Cancer Treatment Technology available for licensing: A 3D technique to detect early skin changes due to radiation treatment in breast cancer patients. Lowers medical costs due to lessened side effects Noninvasive, enhances healing and detects other conditions PDF icon thermal_tomography

  3. Berkeley Lab Scientist Co-Leads Breast Cancer Dream Team

    SciTech Connect (OSTI)

    Gray, Joe

    2009-01-01

    An $16.5 million, three-year grant to develop new and more effective therapies to fight breast cancer was awarded today to a multi-institutional Dream Team of scientists and clinicians that is co-led by Joe Gray, a renowned cancer researcher with the U.S. Department of Energys Lawrence Berkeley National Laboratory. http://newscenter.lbl.gov/

  4. Method for detecting the presence of prostate cancer

    DOE Patents [OSTI]

    Karin, Michael; Luo, Jun-Li; Tan, Wei

    2010-04-13

    The present invention relates to compositions and methods for cancer diagnosis, treatment and drug screening. In particular, the present invention provides compositions and methods for targeting the nuclear translocation of IkB kinase-.alpha. (IKK.alpha.) and the IKK.alpha.-mediated suppression of Maspin expression observed in metastatic prostate cancer cells.

  5. Berkeley Lab Scientist Co-Leads Breast Cancer Dream Team

    ScienceCinema (OSTI)

    Gray, Joe

    2013-05-29

    An $16.5 million, three-year grant to develop new and more effective therapies to fight breast cancer was awarded today to a multi-institutional Dream Team of scientists and clinicians that is co-led by Joe Gray, a renowned cancer researcher with the U.S. Department of Energys Lawrence Berkeley National Laboratory. http://newscenter.lbl.gov/

  6. Method for restoration of normal phenotype in cancer cells

    DOE Patents [OSTI]

    Bissell, Mina J.; Weaver, Valerie M.

    2000-01-01

    A method for reversing expression of malignant phenotype in cancer cells is described. The method comprises applying .beta..sub.1 integrin function-blocking antibody to the cells. The method can be used to assess the progress of cancer therapy. Human breast epithelial cells were shown to be particularly responsive.

  7. A mutational signature in gastric cancer suggests therapeutic strategies

    SciTech Connect (OSTI)

    Alexandrov, Ludmil B.; Nik-Zainal, Serena; Siu, Hoi Cheong; Leung, Suet Yi; Stratton, Michael R.

    2015-10-29

    Targeting defects in the DNA repair machinery of neoplastic cells, for example, those due to inactivating BRCA1 and/or BRCA2 mutations, has been used for developing new therapies in certain types of breast, ovarian and pancreatic cancers. Recently, a mutational signature was associated with failure of double-strand DNA break repair by homologous recombination based on its high mutational burden in samples harbouring BRCA1 or BRCA2 mutations. In pancreatic cancer, all responders to platinum therapy exhibit this mutational signature including a sample that lacked any defects in BRCA1 or BRCA2. Here, we examine 10,250 cancer genomes across 36 types of cancer and demonstrate that, in addition to breast, ovarian and pancreatic cancers, gastric cancer is another cancer type that exhibits this mutational signature. Furthermore, our results suggest that 7–12% of gastric cancers have defective double-strand DNA break repair by homologous recombination and may benefit from either platinum therapy or PARP inhibitors.

  8. A mutational signature in gastric cancer suggests therapeutic strategies

    DOE Public Access Gateway for Energy & Science Beta (PAGES Beta)

    Alexandrov, Ludmil B.; Nik-Zainal, Serena; Siu, Hoi Cheong; Leung, Suet Yi; Stratton, Michael R.

    2015-10-29

    Targeting defects in the DNA repair machinery of neoplastic cells, for example, those due to inactivating BRCA1 and/or BRCA2 mutations, has been used for developing new therapies in certain types of breast, ovarian and pancreatic cancers. Recently, a mutational signature was associated with failure of double-strand DNA break repair by homologous recombination based on its high mutational burden in samples harbouring BRCA1 or BRCA2 mutations. In pancreatic cancer, all responders to platinum therapy exhibit this mutational signature including a sample that lacked any defects in BRCA1 or BRCA2. Here, we examine 10,250 cancer genomes across 36 types of cancer andmore » demonstrate that, in addition to breast, ovarian and pancreatic cancers, gastric cancer is another cancer type that exhibits this mutational signature. Furthermore, our results suggest that 7–12% of gastric cancers have defective double-strand DNA break repair by homologous recombination and may benefit from either platinum therapy or PARP inhibitors.« less

  9. SOARCA Peach Bottom Atomic Power Station Long-Term Station Blackout Uncertainty Analysis: Convergence of the Uncertainty Results

    SciTech Connect (OSTI)

    Bixler, Nathan E.; Osborn, Douglas M.; Sallaberry, Cedric Jean-Marie; Eckert-Gallup, Aubrey Celia; Mattie, Patrick D.; Ghosh, S. Tina

    2014-02-01

    This paper describes the convergence of MELCOR Accident Consequence Code System, Version 2 (MACCS2) probabilistic results of offsite consequences for the uncertainty analysis of the State-of-the-Art Reactor Consequence Analyses (SOARCA) unmitigated long-term station blackout scenario at the Peach Bottom Atomic Power Station. The consequence metrics evaluated are individual latent-cancer fatality (LCF) risk and individual early fatality risk. Consequence results are presented as conditional risk (i.e., assuming the accident occurs, risk per event) to individuals of the public as a result of the accident. In order to verify convergence for this uncertainty analysis, as recommended by the Nuclear Regulatory Commission’s Advisory Committee on Reactor Safeguards, a ‘high’ source term from the original population of Monte Carlo runs has been selected to be used for: (1) a study of the distribution of consequence results stemming solely from epistemic uncertainty in the MACCS2 parameters (i.e., separating the effect from the source term uncertainty), and (2) a comparison between Simple Random Sampling (SRS) and Latin Hypercube Sampling (LHS) in order to validate the original results obtained with LHS. Three replicates (each using a different random seed) of size 1,000 each using LHS and another set of three replicates of size 1,000 using SRS are analyzed. The results show that the LCF risk results are well converged with either LHS or SRS sampling. The early fatality risk results are less well converged at radial distances beyond 2 miles, and this is expected due to the sparse data (predominance of “zero” results).

  10. BRCA1-linked marker in postmenopausal breast cancer families

    SciTech Connect (OSTI)

    Folsom, A.R.; Chen, P.L.; Sellers, T.A.

    1994-09-01

    A majority of breast and ovarian cancer families and half of the early-onset breast cancer families are linked to markers on 17q (BRCA1). While linkage has been demonstrated in families with premenopausal disease, few studies have tested these markers in families with postmenopausal breast cancer. In the Iowa Women`s Health Study, a population-based study of over 42,000 women, an association of waist-to-hip ratio (WHR) with the risk of postmenopausal breast cancer was found predominantly in women with a positive family history -- this interaction was associated with a 3.2-fold elevated risk. This effect was even more pronounced when the definition of family history included breast and ovarian cancer, known to be linked to 17q markers. We evaluated evidence for linkage with D17S579, a BRCA-1-linked marker, in 13 families in which the index case had postmenopausal breast cancer. Genotyping for alleles at D17S579 was performed on 84 blood samples. Linkage analysis assumed that the breast cancer trait had an autosomal dominant mode of inheritance with a penetrance of 80%. For the 13 families studied, the maximum lod score was 0.29 at a theta of 0.27. There was significant evidence against tight linkage of breast cancer with D17S579 (theta<0.4). Heterogeneity analysis suggested evidence for the presence of both linked and unlinked families. Partitioning informative families on WHR of the index case suggested heterogeneity. These data suggest that, in a subset of families identified by a postmenopausal breast cancer proband, risk of breast cancer may be mediated by BRCA1, with heterogeneity defined by WHR.

  11. Fermilab | Newsroom | Press Releases | 2010 | Fatality at Fermilab

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    Fermi National Accelerator Laboratory. Around 10:50 a.m. employees investigating a noise found a young female lying in the atrium of Wilson Hall. Batavia paramedics pronounced...

  12. Accident Investigation of the September 20, 2012 Fatal Fall from...

    Office of Environmental Management (EM)

    Power Marketing Administration Accident Investigation of the September 20, 2012 ... (BPA) Chief Safety Officer, a Level I Accident Investigation was convened to ...

  13. Monitoring bat and bird fatalities at the Casselman Wind Energy...

    Office of Energy Efficiency and Renewable Energy (EERE) Indexed Site

    We are indebted to Holly McCready, Jeff Miller, Erica LaMore, Mario Desilva, Brian ... Austin, Texas, USA. Arnett, E. B., K. Brown, W. P. Erickson, J. Fiedler, T. H. Henry, G. ...

  14. Aging Impacts Transcriptome but not Genome of Hormone-dependentBreast Cancers

    SciTech Connect (OSTI)

    Yau, Christina; Fedele, Vita; Roydasgupta, Ritu; Fridlyand, Jane; Hubbard, Alan; Gray, Joe W.; Chew, Karen; Dairkee, Shanaz H.; Moore, DanH.; Schittulli, Francesco; Tommasi, Stefania; Paradiso, Angelo; Albertson, Donna G.; Benz, Christopher C.

    2007-10-09

    Age is one of the most important risk factors for human malignancies, including breast cancer; in addition, age-at-diagnosis has been shown to be an independent indicator of breast cancer prognosis. However, except for inherited forms of breast cancer, there is little genetic or epigenetic understanding of the biological basis linking aging with sporadic breast cancer incidence and its clinical behavior.

  15. Geranylgeranylacetone inhibits ovarian cancer progression in vitro and in vivo

    SciTech Connect (OSTI)

    Hashimoto, Kae; Morishige, Ken-ichirou . E-mail: mken@gyne.med.osaka-u.ac.jp; Sawada, Kenjiro; Ogata, Seiji; Tahara, Masahiro; Shimizu, Shoko; Sakata, Masahiro; Tasaka, Keiichi; Kimura, Tadashi

    2007-04-27

    Geranylgeranylacetone (GGA), an isoprenoid compound, is an anti-ulcer drug developed in Japan. In our previous study, GGA was shown to inhibit ovarian cancer invasion by attenuating Rho activation [K. Hashimoto, K. Morishige, K. Sawada, M. Tahara, S. Shimizu, M. Sakata, K. Tasaka, Y. Murata, Geranylgeranylacetone inhibits lysophosphatidic acid-induced invasion of human ovarian carcinoma cells in vitro. Cancer 103 (2005) 1529-1536.]. In the present study, GGA treatment inhibited ovarian cancer progression in vitro and suppressed the tumor growth and ascites in the in vivo ovarian cancer model. In vitro analysis, treatment of cancer cells by GGA resulted in the inhibition of cancer cell proliferation, the inactivation of Ras, and the suppression of tyrosine phosphorylation of mitogen-activated protein kinase (MAPK). In conclusion, this is the first report that GGA inhibited ovarian cancer progression and the anti-tumor effect by GGA is, at least in part, derived not only from the suppression of Rho activation but also Ras-MAPK activation.

  16. Practice Patterns of Radiotherapy in Cervical Cancer Among Member Groups of the Gynecologic Cancer Intergroup (GCIG)

    SciTech Connect (OSTI)

    Gaffney, David K. . E-mail: david.gaffney@hci.utah.edu; Du Bois, Andreas; Narayan, Kailash; Reed, Nick; Toita, Takafumi; Pignata, Sandro; Blake, Peter; Portelance, Lorraine; Sadoyze, Azmat; Poetter, Richard; Colombo, Alessandro; Randall, Marcus; Mirza, Mansoor R.; Trimble, Edward L.

    2007-06-01

    Purpose: The aim of this study was to describe radiotherapeutic practice of the treatment of cervical cancer in member groups of the Gynecologic Cancer Intergroup (GCIG). Methods and Materials: A survey was developed and distributed to the members of the GCIG focusing on details of radiotherapy practice. Different scenarios were queried including advanced cervical cancer, postoperative patients, and para-aortic-positive lymph node cases. Items focused on indications for radiation therapy, radiation fields, dose, use of chemotherapy, brachytherapy and others. The cooperative groups from North America were compared with the other groups to evaluate potential differences in radiotherapy doses. Results: A total of 39 surveys were returned from 13 different cooperative groups. For the treatment of advanced cervical cancer, external beam pelvic doses and total doses to point A were 47 + 3.5 Gy (mean + SD) and 79.1 + 7.9 Gy, respectively. Point A doses were not different between the North American cooperative groups compared with the others (p = 0.103). All groups used concomitant chemotherapy, with 30 of 36 respondents using weekly cisplatin. Of 33 respondents, 31 intervened for a low hemoglobin level. For a para-aortic field, the upper border was most commonly (15 of 24) at the T12-L1 interspace. Maintenance chemotherapy (after radiotherapy) was not performed by 68% of respondents. For vaginal brachytherapy after hysterectomy, 23 groups performed HDR brachytherapy and four groups used LDR brachytherapy. In the use of brachytherapy, there was no uniformity in dose prescription. Conclusions: Radiotherapy practices among member groups of the GCIG are similar in terms of both doses and use of chemotherapy.

  17. Radiotherapy in the management of early breast cancer

    SciTech Connect (OSTI)

    Wang, Wei

    2013-03-15

    Radiotherapy is an indispensible part of the management of all stages of breast cancer. In this article, the common indications for radiotherapy in the management of early breast cancer (stages 0, I, and II) are reviewed, including whole-breast radiotherapy as part of breast-conserving treatment for early invasive breast cancer and pre-invasive disease of ductal carcinoma in situ, post-mastectomy radiotherapy, locoregional radiotherapy, and partial breast irradiation. Key clinical studies that underpin our current practice are discussed briefly.

  18. Protein Modifications as Potential Biomarkers in Breast Cancer

    SciTech Connect (OSTI)

    Jin, Hongjun; Zangar, Richard C.

    2009-11-30

    A variety of post-translational protein modifications (PTMs) are known to be altered as a result of cancer development. Thus, these PTMs are potentially useful biomarkers for breast cancer. Mass spectrometry, antibody microarrays and immunohistochemistry techniques have shown promise for identifying changes in PTMs. In this review, we summarize the current literature on PTMs identified in the plasma and tumor tissue of breast-cancer patients or in breast cell lines. We also discuss some of the analytical techniques currently being used to evaluate PTMs.

  19. The Kauai Skin Cancer Study--1983 to 1992

    SciTech Connect (OSTI)

    Reizner, G.T. )

    1993-05-01

    The Kauai Skin Cancer Study began as a modest effort in 1983 to look at this island's skin cancer incidence. David Elpern MD, Kauai's only dermatologist at the time, was interested in the large number of these tumors in his practice. He first enlisted his office staff to help keep track of the numbers and type of these skin cancers. Along with this information, the basic demographic data on each patient was collected. These records became the first entries into what has become a decade-long project.

  20. Gene expression profiles in irradiated cancer cells

    SciTech Connect (OSTI)

    Minafra, L.; Bravat, V.; Russo, G.; Ripamonti, M.; Gilardi, M. C.

    2013-07-26

    Knowledge of the molecular and genetic mechanisms underlying cellular response to radiation may provide new avenues to develop innovative predictive tests of radiosensitivity of tumours and normal tissues and to improve individual therapy. Nowadays very few studies describe molecular changes induced by hadrontherapy treatments, therefore this field has to be explored and clarified. High-throughput methodologies, such as DNA microarray, allow us to analyse mRNA expression of thousands of genes simultaneously in order to discover new genes and pathways as targets of response to hadrontherapy. Our aim is to elucidate the molecular networks involved in the sensitivity/resistance of cancer cell lines subjected to hadrontherapy treatments with a genomewide approach by using cDNA microarray technology to identify gene expression profiles and candidate genes responsible of differential cellular responses.

  1. Detection of eight BRCA1 mutations in 10 breast/ovarian cancer families, including 1 family with male breast cancer

    SciTech Connect (OSTI)

    Sruewing, J.P.; Brody, L.C.; Erdos, M.R.

    1995-07-01

    Genetic epidemiological evidence suggests that mutations in BRCA1 may be responsible for approximately one half of early onset familial breast cancer and the majority of familial breast/ovarian cancer. The recent cloning of BRCA1 allows for the direct detection of mutations, but the feasibility of presymptomatic screening for cancer susceptibility is unknown. We analyzed genomic DNA from one affected individual from each of 24 families with at least three cases of ovarian or breast cancer, using SSCP assays. Variant SSCP bands were subcloned and sequenced. Allele-specific oligonucleotide hybridization was used to verify sequence changes and to screen DNA from control individuals. Six frameshift and two missense mutations were detected in 10 different families. A frameshift mutation was detected in a male proband affected with both breast and prostate cancer. A 40-bp deletion was detected in a patient who developed intra-abdominal carcinomatosis 1 year after prophylactic oophorectomy. Mutations were detected throughout the gene, and only one was detected in more than a single family. These results provide further evidence that inherited breast and ovarian cancer can occur as a consequence of a wide array of BRCA1 mutations. These results suggests that development of a screening test for BRCA1 mutations will be technically challenging. The finding of a mutation in a family with male breast cancer, not previously thought to be related to BRCA1, also illustrates the potential difficulties of genetic counseling for individuals known to carry mutations. 37 refs., 1 fig., 1 tab.

  2. Intraoperative radiation therapy in recurrent ovarian cancer

    SciTech Connect (OSTI)

    Yap, O.W. Stephanie . E-mail: stbeast@stanford.edu; Kapp, Daniel S.; Teng, Nelson N.H.; Husain, Amreen

    2005-11-15

    Purpose: To evaluate disease outcomes and complications in patients with recurrent ovarian cancer treated with cytoreductive surgery and intraoperative radiation therapy (IORT). Methods and Materials: A retrospective study of 24 consecutive patients with ovarian carcinoma who underwent secondary cytoreduction and intraoperative radiation therapy at our institution between 1994 and 2002 was conducted. After optimal cytoreductive surgery, IORT was delivered with orthovoltage X-rays (200 kVp) using individually sized and beveled cone applications. Outcomes measures were local control of disease, progression-free interval, overall survival, and treatment-related complications. Results: Of these 24 patients, 22 were available for follow-up analysis. Additional treatment at the time of and after IORT included whole abdominopelvic radiation, 9; pelvic or locoregional radiation, 5; chemotherapy, 6; and no adjuvant treatment, 2. IORT doses ranged from 9-14 Gy (median, 12 Gy). The anatomic sites treated were pelvis (sidewalls, vaginal cuff, presacral area, anterior pubis), para-aortic and paracaval lymph node beds, inguinal region, or porta hepatitis. At a median follow-up of 24 months, 5 patients remain free of disease, whereas 17 patients have recurred, of whom 4 are alive with disease and 13 died from disease. Five patients recurred within the radiation fields for a locoregional relapse rate of 32% and 12 patients recurred at distant sites with a median time to recurrence of 13.7 months. Five-year overall survival was 22% with a median survival of 26 months from time of IORT. Nine patients (41%) experienced Grade 3 toxicities from their treatments. Conclusion: In carefully selected patients with locally recurrent ovarian cancer, combined IORT and tumor reductive surgery is reasonably tolerated and may contribute to achieving local control and disease palliation.

  3. Genomics at the Ontario Institute for Cancer Research

    SciTech Connect (OSTI)

    Ali, Johar

    2010-06-02

    Johar Ali of the Ontario Institute for Cancer Research discusses genomics and next-gen applications at the OICR on June 2, 2010 at the "Sequencing, Finishing, Analysis in the Future" meeting in Santa Fe, NM

  4. Nested methylation-specific polymerase chain reaction cancer detection method

    DOE Patents [OSTI]

    Belinsky, Steven A.; Palmisano, William A.

    2007-05-08

    A molecular marker-based method for monitoring and detecting cancer in humans. Aberrant methylation of gene promoters is a marker for cancer risk in humans. A two-stage, or "nested" polymerase chain reaction method is disclosed for detecting methylated DNA sequences at sufficiently high levels of sensitivity to permit cancer screening in biological fluid samples, such as sputum, obtained non-invasively. The method is for detecting the aberrant methylation of the p16 gene, O 6-methylguanine-DNA methyltransferase gene, Death-associated protein kinase gene, RAS-associated family 1 gene, or other gene promoters. The method offers a potentially powerful approach to population-based screening for the detection of lung and other cancers.

  5. Our Role in the War on Cancer | GE Global Research

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    Our Role in the War on Cancer Click to email this to a friend (Opens in new window) Share on Facebook (Opens in new window) Click to share (Opens in new window) Click to share on...

  6. Cancer mortality and residence near petrochemical industries in Taiwan

    SciTech Connect (OSTI)

    Yang, Chun-Yuh; Chiu, Hui-Fen; Chiu, Jeng-Fen

    1997-02-21

    An ecologic study design was used to investigate the relationship between cancer risks and residence in communities adjacent to petrochemical industrial counties (PICs). Directly age-adjusted mortality rates for cancer during 1982-1991 among 16 counties characterized by a heavy concentration of petrochemical industries were compared to rates among 16 matched counties with similar concentration of nonpetrochemical manufacturing industries, urbanization level, and demographic characteristics. An excess rate for liver cancer among males was found in the so-called PICs. The correlation could not be explained by confounding variables such as urbanization, socioeconomic class, or employment in nonpetrochemical industries. No other increased cancer risks were found to be associated with residence near petrochemical industries. 30 refs., 3 tabs.

  7. Research Sheds Light on Workings of Anti-cancer Drug

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    to be effective in the treatment of Wilson disease, a disease caused by an overload ... For patients with Wilson disease and certain cancers whose initial growth is helped by ...

  8. Enzyme Structure Provides Insights into Cancer and Aging

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    Provides Insights into Cancer and Aging Print XPD helicase is an enzyme that unwinds the DNA double helix; it is one component of an essential repair mechanism that maintains the...

  9. Doctor Patient Conversation Around Breast Cancer | GE Global...

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    Doctor Patient Conversation Around Breast Cancer Click to email this to a friend (Opens in new window) Share on Facebook (Opens in new window) Click to share (Opens in new window)...

  10. Technology Relay Race in Cancer Prevention Research | GE Global...

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    Technology Relay Race in Cancer Prevention Research Click to email this to a friend (Opens in new window) Share on Facebook (Opens in new window) Click to share (Opens in new...

  11. New screening process for potentially cancer causing chemicals

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    New screening process for potentially cancer causing chemicals Click to share on Facebook (Opens in new window) Click to share on Twitter (Opens in new window) Click to share on ...

  12. Topo II: An Enzyme Target for Antibacterial and Cancer Drugs

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    Topo II: An Enzyme Target for Antibacterial and Cancer Drugs Print The veil has finally been lifted on an enzyme that is critical to the process of DNA transcription and...

  13. Iran Thomas Auditorium, 8600 Fighting Cancer with Nanoparticle...

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    October 13, 2011 4:00 pm Iran Thomas Auditorium, 8600 Fighting Cancer with Nanoparticle Medicines Mark E. Davis Chemical Engineering California Institute of Technology CNMS D D I I...

  14. Enzyme Structure Provides Insights into Cancer and Aging

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    Enzyme Structure Provides Insights into Cancer and Aging Print XPD helicase is an enzyme that unwinds the DNA double helix; it is one component of an essential repair mechanism...

  15. Designer Proteins Target Epstein-Barr-Virus-Associated Cancer

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    Designer Proteins Target Epstein-Barr-Virus-Associated Cancer Print Immortality is not a good thing for cells, and in fact, cells will destroy themselves in a process called...

  16. Proton Therapy for Cancer: Current Status, Promise and Challenges...

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    March 9, 2016, 4:15pm to 5:30pm Colloquia MBG Auditorium Proton Therapy for Cancer: Current Status, Promise and Challenges Dr. Dennis Mah ProCure Proton Therapy Center Colloquium...

  17. Software speeds detection of diseases and cancer-treatment targets

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    Software speeds detection of diseases Software speeds detection of diseases and cancer-treatment targets The Lab has released an updated version of software that is now capable of...

  18. Scanxiety: Waiting anxiously for childhood cancer test results...

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    results that could change your life Mark Frontera 2015.09.18 September is Childhood Cancer Awareness Month and we are publishing a series of blog posts to share stories about...

  19. Enzyme Structure Provides Insights into Cancer and Aging

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    Enzyme Structure Provides Insights into Cancer and Aging Print XPD helicase is an enzyme that unwinds the DNA double helix; it is one component of an essential repair mechanism that maintains the integrity of DNA. XPD is unique, however, in that pinpoint mutations of this single protein are responsible for three different human diseases: in xeroderma pigmentosum (XP), extreme sensitivity to sunlight promotes cancer; Cockayne syndrome (CS) involves stunted growth and premature aging;

  20. Enzyme Structure Provides Insights into Cancer and Aging

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    Enzyme Structure Provides Insights into Cancer and Aging Print XPD helicase is an enzyme that unwinds the DNA double helix; it is one component of an essential repair mechanism that maintains the integrity of DNA. XPD is unique, however, in that pinpoint mutations of this single protein are responsible for three different human diseases: in xeroderma pigmentosum (XP), extreme sensitivity to sunlight promotes cancer; Cockayne syndrome (CS) involves stunted growth and premature aging;

  1. Enzyme Structure Provides Insights into Cancer and Aging

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    Enzyme Structure Provides Insights into Cancer and Aging Print XPD helicase is an enzyme that unwinds the DNA double helix; it is one component of an essential repair mechanism that maintains the integrity of DNA. XPD is unique, however, in that pinpoint mutations of this single protein are responsible for three different human diseases: in xeroderma pigmentosum (XP), extreme sensitivity to sunlight promotes cancer; Cockayne syndrome (CS) involves stunted growth and premature aging;

  2. Enzyme Structure Provides Insights into Cancer and Aging

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    Enzyme Structure Provides Insights into Cancer and Aging Print XPD helicase is an enzyme that unwinds the DNA double helix; it is one component of an essential repair mechanism that maintains the integrity of DNA. XPD is unique, however, in that pinpoint mutations of this single protein are responsible for three different human diseases: in xeroderma pigmentosum (XP), extreme sensitivity to sunlight promotes cancer; Cockayne syndrome (CS) involves stunted growth and premature aging;

  3. Enzyme Structure Provides Insights into Cancer and Aging

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    Enzyme Structure Provides Insights into Cancer and Aging Enzyme Structure Provides Insights into Cancer and Aging Print Wednesday, 25 February 2009 00:00 XPD helicase is an enzyme that unwinds the DNA double helix; it is one component of an essential repair mechanism that maintains the integrity of DNA. XPD is unique, however, in that pinpoint mutations of this single protein are responsible for three different human diseases: in xeroderma pigmentosum (XP), extreme sensitivity to sunlight

  4. Is Primary Prostate Cancer Treatment Influenced by Likelihood of

    Office of Scientific and Technical Information (OSTI)

    Extraprostatic Disease? A Surveillance, Epidemiology and End Results Patterns of Care Study (Journal Article) | SciTech Connect Is Primary Prostate Cancer Treatment Influenced by Likelihood of Extraprostatic Disease? A Surveillance, Epidemiology and End Results Patterns of Care Study Citation Details In-Document Search Title: Is Primary Prostate Cancer Treatment Influenced by Likelihood of Extraprostatic Disease? A Surveillance, Epidemiology and End Results Patterns of Care Study Purpose: To

  5. Locally Advanced Prostate Cancer: Three-Dimensional Magnetic Resonance

    Office of Scientific and Technical Information (OSTI)

    Spectroscopy to Monitor Prostate Response to Therapy (Journal Article) | SciTech Connect Locally Advanced Prostate Cancer: Three-Dimensional Magnetic Resonance Spectroscopy to Monitor Prostate Response to Therapy Citation Details In-Document Search Title: Locally Advanced Prostate Cancer: Three-Dimensional Magnetic Resonance Spectroscopy to Monitor Prostate Response to Therapy Purpose: To correlate results of three-dimensional magnetic resonance spectroscopic imaging (MRSI) with

  6. New screening process for potentially cancer causing chemicals

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    New screening process for potentially cancer causing chemicals Click to share on Facebook (Opens in new window) Click to share on Twitter (Opens in new window) Click to share on Reddit (Opens in new window) Click to share on Pinterest (Opens in new window) A better way to screen chemicals that may cause cancer is under development. This image shows in two dimensions what Berkeley lab scientists are working to achieve in three dimensions: cultures containing diverse cell types (seen here using

  7. DOE Laboratories Help Develop Promising New Cancer Fighting Drug,

    Office of Energy Efficiency and Renewable Energy (EERE) Indexed Site

    Vemurafenib | Department of Energy Laboratories Help Develop Promising New Cancer Fighting Drug, Vemurafenib DOE Laboratories Help Develop Promising New Cancer Fighting Drug, Vemurafenib August 18, 2011 - 1:03pm Addthis Powerful X-Rays Enable Development of Successful Treatment for Melanoma and Other Life-Threatening Diseases WASHINGTON, DC - Powerful X-ray technology developed at the U.S. Department of Energy's (DOE's) national laboratories is revealing new insights into diseases ranging

  8. Enzyme Structure Provides Insights into Cancer and Aging

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    Enzyme Structure Provides Insights into Cancer and Aging Print XPD helicase is an enzyme that unwinds the DNA double helix; it is one component of an essential repair mechanism that maintains the integrity of DNA. XPD is unique, however, in that pinpoint mutations of this single protein are responsible for three different human diseases: in xeroderma pigmentosum (XP), extreme sensitivity to sunlight promotes cancer; Cockayne syndrome (CS) involves stunted growth and premature aging;

  9. Enzyme Structure Provides Insights into Cancer and Aging

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    Enzyme Structure Provides Insights into Cancer and Aging Print XPD helicase is an enzyme that unwinds the DNA double helix; it is one component of an essential repair mechanism that maintains the integrity of DNA. XPD is unique, however, in that pinpoint mutations of this single protein are responsible for three different human diseases: in xeroderma pigmentosum (XP), extreme sensitivity to sunlight promotes cancer; Cockayne syndrome (CS) involves stunted growth and premature aging;

  10. Prospective Longitudinal Assessment of Quality of Life for Liver Cancer

    Office of Scientific and Technical Information (OSTI)

    Patients Treated With Stereotactic Body Radiation Therapy (Journal Article) | SciTech Connect Prospective Longitudinal Assessment of Quality of Life for Liver Cancer Patients Treated With Stereotactic Body Radiation Therapy Citation Details In-Document Search Title: Prospective Longitudinal Assessment of Quality of Life for Liver Cancer Patients Treated With Stereotactic Body Radiation Therapy Purpose: To evaluate quality of life (QoL), an important outcome owing to poor long-term survival,

  11. Ribosome research in atomic detail offers potential insights into cancer,

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    anemia, Alzheimer's Ribosome research offers potential insights into cancer Ribosome research in atomic detail offers potential insights into cancer, anemia, Alzheimer's A groundbreaking study of the human ribosome is revealing that the tiny molecular machine is more versatile than previously understood. July 3, 2014 Figure 3. The newly discovered rolling movement shown in (A) three-dimensional cryo-electron microscopy image of ribosome, and (B) computer-generated atomic-resolution model of

  12. Preoperative chemoradiation of locally advanced T3 rectal cancer combined

    Office of Scientific and Technical Information (OSTI)

    with an endorectal boost (Journal Article) | SciTech Connect SciTech Connect Search Results Journal Article: Preoperative chemoradiation of locally advanced T3 rectal cancer combined with an endorectal boost Citation Details In-Document Search Title: Preoperative chemoradiation of locally advanced T3 rectal cancer combined with an endorectal boost Purpose: To investigate the effect and feasibility of concurrent radiation and chemotherapy combined with endorectal brachytherapy in T3 rectal

  13. Mathematical Models Shed New Light on Cancer Mutations

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    Mathematical Models Shed New Light on Cancer Mutations Mathematical Models Shed New Light on Cancer Mutations Calculations Run at NERSC Pinpoint Rare Mutants More Quickly November 3, 2014 Contact: David Cameron, 617.432.0441, david_cameron@hms.harvard.edu cancermutations3 Heat map of the average magnitude of interaction energies projected onto a structural representation of SH2 domains (white) in complex with phosphopeptide (green). SH2 (Src Homology 2) is a protein domain found in many

  14. Residential radon and lung cancer incidence in a Danish cohort

    SciTech Connect (OSTI)

    Braeuner, Elvira V.; Andersen, Claus E.; Sorensen, Mette; Jovanovic Andersen, Zorana; Center for Epidemiology Screening, Department of Public Health, University of Copenhagen ; Gravesen, Peter; Ulbak, Kaare; Hertel, Ole; Pedersen, Camilla; Overvad, Kim; Tjonneland, Anne; Raaschou-Nielsen, Ole

    2012-10-15

    High-level occupational radon exposure is an established risk factor for lung cancer. We assessed the long-term association between residential radon and lung cancer risk using a prospective Danish cohort using 57,053 persons recruited during 1993-1997. We followed each cohort member for cancer occurrence until 27 June 2006, identifying 589 lung cancer cases. We traced residential addresses from 1 January 1971 until 27 June 2006 and calculated radon at each of these addresses using information from central databases regarding geology and house construction. Cox proportional hazards models were used to estimate incidence rate ratios (IRR) and 95% confidence intervals (CI) for lung cancer risk associated with residential radon exposure with and without adjustment for sex, smoking variables, education, socio-economic status, occupation, body mass index, air pollution and consumption of fruit and alcohol. Potential effect modification by sex, traffic-related air pollution and environmental tobacco smoke was assessed. Median estimated radon was 35.8 Bq/m{sup 3}. The adjusted IRR for lung cancer was 1.04 (95% CI: 0.69-1.56) in association with a 100 Bq/m{sup 3} higher radon concentration and 1.67 (95% CI: 0.69-4.04) among non-smokers. We found no evidence of effect modification. We find a positive association between radon and lung cancer risk consistent with previous studies but the role of chance cannot be excluded as these associations were not statistically significant. Our results provide valuable information at the low-level radon dose range.

  15. Microsatellite instability is rare in sporadic ovarian cancer

    SciTech Connect (OSTI)

    Chen, S.S.; Han, H.; Schwartz, P.E.

    1994-09-01

    Microsatellite instability was first demonstrated to be a common underlying mechanism in hereditary nonpolyposis colorectal cancer (HNPCC) and has recently been implicated in the development of several other human cancers. Although numerous genetic changes have been documented in ovarian cancer, their molecular bases are poorly understood. In investigating the molecular genetics of ovarian cancer, we analyzed twelve short tandem repeats that were amplified by PCR from DNA of 48 tumors and their corresponding lymphocyte samples. All of the 48 cases studied have no noticeable family history and, of them, 42 are epithelial (benign/borderline, 5; grade I, 4; GII, 4; GIII, 29) and 6 are nonepithelial. A microsatellite instability has been shown to be inversely correlated with the occurrence of allelic losses, half of those cases chosen have a fractional allele loss of {le}15 (median = .18 of 50 tumors tested for 86 loci from every chromosomal arm). The loci examined included eight dinucleotide repeats (D2S123, D9S104, D10S197, D11S904, D16S408, D16S421, D17S250, and D17S579), two trinucleotide repeats (DM and AR) and two tetranucleotide repeats (DXS981 and VWF). Despite the fact that HNPCC phenotype includes ovarian cancer and that microsatellite instability has been shown in one ovarian cancer from an HNPCC family, the allele sizes of 12 loci were found to be identical in all paired tumor and normal samples we studied except for one tumor at a single locus. The band shift displayed on polyacrylamide gel representing an additional allele of VWF was only observed in one grade III tumor. Our results are thus a strong indication that the alteration of microsatellite repeats may not play a major role in the development of sporadic ovarian cancer.

  16. Pancreatic stellate cells enhance stem cell-like phenotypes in pancreatic cancer cells

    SciTech Connect (OSTI)

    Hamada, Shin [Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai (Japan)] [Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai (Japan); Masamune, Atsushi, E-mail: amasamune@med.tohoku.ac.jp [Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai (Japan)] [Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai (Japan); Takikawa, Tetsuya; Suzuki, Noriaki; Kikuta, Kazuhiro; Hirota, Morihisa [Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai (Japan)] [Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai (Japan); Hamada, Hirofumi [Laboratory of Oncology, Department of Life Sciences, Tokyo University of Pharmacy and Life Sciences, Hachioji (Japan)] [Laboratory of Oncology, Department of Life Sciences, Tokyo University of Pharmacy and Life Sciences, Hachioji (Japan); Kobune, Masayoshi [Fourth Department of Internal Medicine, Sapporo Medical University School of Medicine, Sapporo (Japan)] [Fourth Department of Internal Medicine, Sapporo Medical University School of Medicine, Sapporo (Japan); Satoh, Kennichi [Division of Cancer Stem Cell, Miyagi Cancer Center Research Institute, Natori (Japan)] [Division of Cancer Stem Cell, Miyagi Cancer Center Research Institute, Natori (Japan); Shimosegawa, Tooru [Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai (Japan)] [Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai (Japan)

    2012-05-04

    Highlights: Black-Right-Pointing-Pointer Pancreatic stellate cells (PSCs) promote the progression of pancreatic cancer. Black-Right-Pointing-Pointer Pancreatic cancer cells co-cultured with PSCs showed enhanced spheroid formation. Black-Right-Pointing-Pointer Expression of stem cell-related genes ABCG2, Nestin and LIN28 was increased. Black-Right-Pointing-Pointer Co-injection of PSCs enhanced tumorigenicity of pancreatic cancer cells in vivo. Black-Right-Pointing-Pointer This study suggested a novel role of PSCs as a part of the cancer stem cell niche. -- Abstract: The interaction between pancreatic cancer cells and pancreatic stellate cells (PSCs), a major profibrogenic cell type in the pancreas, is receiving increasing attention. There is accumulating evidence that PSCs promote the progression of pancreatic cancer by increasing cancer cell proliferation and invasion as well as by protecting them from radiation- and gemcitabine-induced apoptosis. Recent studies have identified that a portion of cancer cells, called 'cancer stem cells', within the entire cancer tissue harbor highly tumorigenic and chemo-resistant phenotypes, which lead to the recurrence after surgery or re-growth of the tumor. The mechanisms that maintain the 'stemness' of these cells remain largely unknown. We hypothesized that PSCs might enhance the cancer stem cell-like phenotypes in pancreatic cancer cells. Indirect co-culture of pancreatic cancer cells with PSCs enhanced the spheroid-forming ability of cancer cells and induced the expression of cancer stem cell-related genes ABCG2, Nestin and LIN28. In addition, co-injection of PSCs enhanced tumorigenicity of pancreatic cancer cells in vivo. These results suggested a novel role of PSCs as a part of the cancer stem cell niche.

  17. cAMP-response-element-binding protein positively regulates breast cancer metastasis and subsequent bone destruction

    SciTech Connect (OSTI)

    Son, Jieun; Lee, Jong-Ho; Kim, Ha-Neui; Ha, Hyunil Lee, Zang Hee

    2010-07-23

    Research highlights: {yields} CREB is highly expressed in advanced breast cancer cells. {yields} Tumor-related factors such as TGF-{beta} further elevate CREB expression. {yields} CREB upregulation stimulates metastatic potential of breast cancer cells. {yields} CREB signaling is required for breast cancer-induced bone destruction. -- Abstract: cAMP-response-element-binding protein (CREB) signaling has been reported to be associated with cancer development and poor clinical outcome in various types of cancer. However, it remains to be elucidated whether CREB is involved in breast cancer development and osteotropism. Here, we found that metastatic MDA-MB-231 breast cancer cells exhibited higher CREB expression than did non-metastatic MCF-7 cells and that CREB expression was further increased by several soluble factors linked to cancer progression, such as IL-1, IGF-1, and TGF-{beta}. Using wild-type CREB and a dominant-negative form (K-CREB), we found that CREB signaling positively regulated the proliferation, migration, and invasion of MDA-MB-231 cells. In addition, K-CREB prevented MDA-MB-231 cell-induced osteolytic lesions in a mouse model of cancer metastasis. Furthermore, CREB signaling in cancer cells regulated the gene expression of PTHrP, MMPs, and OPG, which are closely involved in cancer metastasis and bone destruction. These results indicate that breast cancer cells acquire CREB overexpression during their development and that this CREB upregulation plays an important role in multiple steps of breast cancer bone metastasis.

  18. An evaluation of genetic heterogeneity in 145 breast-ovarian cancer families

    SciTech Connect (OSTI)

    Narod, S.A.; Ford, D.; Devilee, P.; Barkardottir, R.B.; Lynch, H.T.; Smith, S.A.; Ponder, B.A.J.; Weber, B.L.; Garber, J.E.; Birch, J.M.

    1995-01-01

    The breast-ovary cancer-family syndrome is a dominant predisposition to cancer of the breast and ovaries which has been mapped to chromosome region 17q12-q21. The majority, but not all, of breast-ovary cancer families show linkage to this susceptibility locus, designated BRCA1. We report the results of a linkage analysis of 145 families with both breast and ovarian cancer. These families contain either a total of three or more cases of early-onset (before age 60 years) breast cancer or ovarian cancer. All families contained at least one case of ovarian cancer. Overall, an estimated 76% of the 145 families are linked to the BRCA1 locus. None of the 13 families with cases of male breast cancer appear to be linked, but it is estimated that 92% (95% confidence interval 76%-100%) of families with no male breast cancer and with two or more ovarian cancers are linked to BRCA1. These data suggest that the breast-ovarian cancer-family syndrome is genetically heterogeneous. However, the large majority of families with early-onset breast cancer and with two or more cases of ovarian cancer are likely to be due to BRCA1 mutations. 39 refs., 6 figs., 3 tabs.

  19. Subclonal diversification of primary breast cancer revealed by multiregion sequencing

    DOE Public Access Gateway for Energy & Science Beta (PAGES Beta)

    Yates, Lucy R.; Gerstung, Moritz; Knappskog, Stian; Desmedt, Christine; Gundem, Gunes; Van Loo, Peter; Aas, Turid; Alexandrov, Ludmil B.; Larsimont, Denis; Davies, Helen; et al

    2015-06-22

    Sequencing cancer genomes may enable tailoring of therapeutics to the underlying biological abnormalities driving a particular patient's tumor. However, sequencing-based strategies rely heavily on representative sampling of tumors. To understand the subclonal structure of primary breast cancer, we applied whole-genome and targeted sequencing to multiple samples from each of 50 patients' tumors (303 samples in total). The extent of subclonal diversification varied among cases and followed spatial patterns. No strict temporal order was evident, with point mutations and rearrangements affecting the most common breast cancer genes, including PIK3CA, TP53, PTEN, BRCA2 and MYC, occurring early in some tumors and latemore » in others. In 13 out of 50 cancers, potentially targetable mutations were subclonal. Landmarks of disease progression, such as resistance to chemotherapy and the acquisition of invasive or metastatic potential, arose within detectable subclones of antecedent lesions. These findings highlight the importance of including analyses of subclonal structure and tumor evolution in clinical trials of primary breast cancer.« less

  20. Sexual Function in Males After Radiotherapy for Rectal Cancer

    SciTech Connect (OSTI)

    Bruheim, Kjersti, E-mail: Kjersti.bruheim@medisin.uio.n [Oslo University Hospital, Ulleval Cancer Centre, Oslo (Norway); Guren, Marianne G. [Oslo University Hospital, Ulleval Cancer Centre, Oslo (Norway); Dahl, Alv A. [Oslo University Hospital, Department of Clinical Cancer Research, the Norwegian Radium Hospital, Oslo (Norway); Faculty of Medicine, University of Oslo, Oslo (Norway); Skovlund, Eva [School of Pharmacy, University of Oslo, Oslo (Norway); Balteskard, Lise [University Hospital of Northern Norway, Tromso (Norway); Carlsen, Erik [Oslo University Hospital, Department of Gastrointestinal Surgery, Ulleval, Oslo (Norway); Fossa, Sophie D. [Oslo University Hospital, Department of Clinical Cancer Research, the Norwegian Radium Hospital, Oslo (Norway); Faculty of Medicine, University of Oslo, Oslo (Norway); Tveit, Kjell Magne [Oslo University Hospital, Ulleval Cancer Centre, Oslo (Norway); Faculty of Medicine, University of Oslo, Oslo (Norway)

    2010-03-15

    Purpose: Knowledge of sexual problems after pre- or postoperative radiotherapy (RT) with 50 Gy for rectal cancer is limited. In this study, we aimed to compare self-rated sexual functioning in irradiated (RT+) and nonirradiated (RT-) male patients at least 2 years after surgery for rectal cancer. Methods and Materials: Patients diagnosed with rectal cancer from 1993 to 2003 were identified from the Norwegian Rectal Cancer Registry. Male patients without recurrence at the time of the study. The International Index of Erectile Function, a self-rated instrument, was used to assess sexual functioning, and serum levels of serum testosterone were measured. Results: Questionnaires were returned from 241 patients a median of 4.5 years after surgery. The median age was 67 years at survey. RT+ patients (n = 108) had significantly poorer scores for erectile function, orgasmic function, intercourse satisfaction, and overall satisfaction with sex life compared with RT- patients (n = 133). In multiple age-adjusted analysis, the odds ratio for moderate-severe erectile dysfunction in RT+ patients was 7.3 compared with RT- patients (p <0.001). Furthermore, erectile dysfunction of this degree was associated with low serum testosterone (p = 0.01). Conclusion: RT for rectal cancer is associated with significant long-term effects on sexual function in males.

  1. Subclonal diversification of primary breast cancer revealed by multiregion sequencing

    SciTech Connect (OSTI)

    Yates, Lucy R.; Gerstung, Moritz; Knappskog, Stian; Desmedt, Christine; Gundem, Gunes; Van Loo, Peter; Aas, Turid; Alexandrov, Ludmil B.; Larsimont, Denis; Davies, Helen; Li, Yilong; Ju, Young Seok; Ramakrishna, Manasa; Haugland, Hans Kristian; Lilleng, Peer Kaare; Nik-Zainal, Serena; McLaren, Stuart; Butler, Adam; Martin, Sancha; Glodzik, Dominic; Menzies, Andrew; Raine, Keiran; Hinton, Jonathan; Jones, David; Mudie, Laura J.; Jiang, Bing; Vincent, Delphine; Greene-Colozzi, April; Adnet, Pierre -Yves; Fatima, Aquila; Maetens, Marion; Ignatiadis, Michail; Stratton, Michael R.; Sotiriou, Christos; Richardson, Andrea L.; Lønning, Per Eystein; Wedge, David C.; Campbell, Peter J.

    2015-06-22

    Sequencing cancer genomes may enable tailoring of therapeutics to the underlying biological abnormalities driving a particular patient's tumor. However, sequencing-based strategies rely heavily on representative sampling of tumors. To understand the subclonal structure of primary breast cancer, we applied whole-genome and targeted sequencing to multiple samples from each of 50 patients' tumors (303 samples in total). The extent of subclonal diversification varied among cases and followed spatial patterns. No strict temporal order was evident, with point mutations and rearrangements affecting the most common breast cancer genes, including PIK3CA, TP53, PTEN, BRCA2 and MYC, occurring early in some tumors and late in others. In 13 out of 50 cancers, potentially targetable mutations were subclonal. Landmarks of disease progression, such as resistance to chemotherapy and the acquisition of invasive or metastatic potential, arose within detectable subclones of antecedent lesions. These findings highlight the importance of including analyses of subclonal structure and tumor evolution in clinical trials of primary breast cancer.

  2. Chromosome abnormalities in primary ovarian cancer

    SciTech Connect (OSTI)

    Yonescu, R.; Currie, J.; Griffin, C.A.

    1994-09-01

    Chromosome abnormalities that are specific and recurrent may occur in regions of the genome that are involved in the conversion of normal cells to those with tumorigenic potential. Ovarian cancer is the primary cause of death among patients with gynecological malignancies. We have performed cytogenetic analysis of 16 ovarian tumors from women age 28-82. Three tumors of low malignant potential and three granulosa cell tumors had normal karyotypes. To look for the presence of trisomy 12, which has been suggested to be a common aberration in this group of tumors, interphase fluorescence in situ hybridization was performed on direct preparations from three of these tumors using a probe for alpha satellite sequences of chromosome 12. In the 3 preparations, 92-98 percent of the cells contained two copies of chromosome 12, indicating that trisomy 12 is not a universal finding in low grade ovarian tumors. Endometrioid carcinoma of the ovary is histologically indistinguishable from endometial carcinoma of the uterus. We studied 10 endometrioid tumors to determine the degree of genetic similarity between these two carcinomas. Six out of ten endometrioid tumors showed a near-triploid modal number, and one presented with a tetraploid modal number. Eight of the ten contained structural chromosome abnormalities, of which the most frequent were 1p- (5 tumors), 19q+ (3 tumors), 6q- or ins(6) (4 tumors), 3q- or 3q+ (4 tumors). These cytogenetic results resemble those reported for papillary ovarian tumors and differ from those of endometrial carcinoma of the uterus. We conclude that despite the histologic similarities between the endometrioid and endometrial carcinomas, the genetic abnormalities in the genesis of these tumors differ significantly.

  3. Los Alamos turns its nuclear weapons power to war on cancer

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    Los Alamos turns its nuclear weapons power to war on cancer Los Alamos turns its nuclear weapons power to war on cancer Los Alamos Physicist Eva Birnbaum shows how the laboratory ...

  4. Magnetic relaxometry as applied to sensitive cancer detection and localization

    DOE Public Access Gateway for Energy & Science Beta (PAGES Beta)

    De Haro, Leyma P.; Karaulanov, Todor; Vreeland, Erika C.; Anderson, Bill; Hathaway, Helen J.; Huber, Dale L.; Matlashov, Andrei N.; Nettles, Christopher P.; Price, Andrew D.; Monson, Todd C.; et al

    2015-06-02

    Here we describe superparamagnetic relaxometry (SPMR), a technology that utilizes highly sensitive magnetic sensors and superparamagnetic nanoparticles for cancer detection. Using SPMR, we sensitively and specifically detect nanoparticles conjugated to biomarkers for various types of cancer. SPMR offers high contrast In SPMR measurements, a brief magnetizing pulse is used to align superparamagnetic nanoparticles of a discrete size. Following the pulse, an array of superconducting quantum interference detectors (SQUID) sensors detect the decaying magnetization field. NP size is chosen so that, when bound, the induced field decays in seconds. They are functionalized with specific biomarkers and incubated with cancer cellsmore » As a result, superparamagnetic NPs developed here have small size dispersion. Cell incubation studies measure specificity for different cell lines and antibodies with very high contrast.« less

  5. Magnetic relaxometry as applied to sensitive cancer detection and localization

    SciTech Connect (OSTI)

    De Haro, Leyma P.; Karaulanov, Todor; Vreeland, Erika C.; Anderson, Bill; Hathaway, Helen J.; Huber, Dale L.; Matlashov, Andrei N.; Nettles, Christopher P.; Price, Andrew D.; Monson, Todd C.; Flynn, Edward R.

    2015-06-02

    Abstract

    Here we describe superparamagnetic relaxometry (SPMR), a technology that utilizes highly sensitive magnetic sensors and superparamagnetic nanoparticles for cancer detection. Using SPMR, we sensitively and specifically detect nanoparticles conjugated to biomarkers for various types of cancer. SPMR offers high contrast

    In SPMR measurements, a brief magnetizing pulse is used to align superparamagnetic nanoparticles of a discrete size. Following the pulse, an array of superconducting quantum interference detectors (SQUID) sensors detect the decaying magnetization field. NP size is chosen so that, when bound, the induced field decays in seconds. They are functionalized with specific biomarkers and incubated with cancer cells

    As a result, superparamagnetic NPs developed here have small size dispersion. Cell incubation studies measure specificity for different cell lines and antibodies with very high contrast.

  6. Biofunctionalized magnetic vortex microdisks for targeted cancer cell destruction.

    SciTech Connect (OSTI)

    Kim, D.-H.; Rozhkova, E. A.; Ulasov, I. V.; Bader, S. D.; Rajh, T.; Lesniak, M. S.; Novosad, V.; Univ. of Chicago Pritzker School of Medicine

    2010-01-01

    Nanomagnetic materials offer exciting avenues for probing cell mechanics and activating mechanosensitive ion channels, as well as for advancing cancer therapies. Most experimental works so far have used superparamagnetic materials. This report describes a first approach based on interfacing cells with lithographically defined microdiscs that possess a spin-vortex ground state. When an alternating magnetic field is applied the microdisc vortices shift, creating an oscillation, which transmits a mechanical force to the cell. Because reduced sensitivity of cancer cells toward apoptosis leads to inappropriate cell survival and malignant progression, selective induction of apoptosis is of great importance for the anticancer therapeutic strategies. We show that the spin-vortex-mediated stimulus creates two dramatic effects: compromised integrity of the cellular membrane, and initiation of programmed cell death. A low-frequency field of a few tens of hertz applied for only ten minutes was sufficient to achieve {approx}90% cancer-cell destruction in vitro.

  7. Searching for a system: The quest for ovarian cancer biomarkers

    SciTech Connect (OSTI)

    Rodland, Karin D.; Maihle, Nita J.

    2011-11-01

    The stark difference in clinical outcome for patients with ovarian cancer diagnosed at early stages (95% at 5 years) versus late stages (27.6% at 5 years) has driven a decades-long quest for effective biomarkers that will enable earlier detection of ovarian cancer. Yet despite intense efforts, including the application of modern high throughput technologies such as transcriptomics and proteomics, there has been little improvement in performance compared to the gold standard of quantifying serum CA125 immunoreactivity paired with transvaginal ultrasound. This review describes the strategies that have been used for identification of ovarian cancer biomarkers, including the recent introduction of novel bioinformatic approaches. Results obtained using high throughput-based vs. biologically rational approaches for the discovery of diagnostic early detection biomarkers are compared and analyzed for functional enrichment.

  8. Linkage analysis of 19 French breast cancer families, with five chromosome 17q markers

    SciTech Connect (OSTI)

    Mazoyer, S.; Jamot, B.; Sobol, H. ); Lalle, P.; Bignon, Y.J.; Courjal, F. ); Narod, S.A. ); Dutrillaux, B.; Stoppa-Lyonnet, D. )

    1993-04-01

    Nineteen French breast and breast-ovarian cancer families were tested for linkage with five chromosome 17q markers. The five breast-ovarian cancer families as a group give positive evidence for linkage, whereas the 14 breast cancer-only families do not. Heterogeneity of linkage of breast and breast-ovarian cancers is significant in France and supports the existence of more than one susceptibility gene. 15 refs., 2 figs., 3 tabs.

  9. Ell3 stimulates proliferation, drug resistance, and cancer stem cell properties of breast cancer cells via a MEK/ERK-dependent signaling pathway

    SciTech Connect (OSTI)

    Ahn, Hee-Jin; Kim, Gwangil; Park, Kyung-Soon

    2013-08-09

    Highlights: Ell3 enhances proliferation and drug resistance of breast cancer cell lines. Ell3 is related to the cancer stem cell characteristics of breast cancer cell lines. Ell3 enhances oncogenicity of breast cancer through the ERK1/2 signaling pathway. -- Abstract: Ell3 is a RNA polymerase II transcription elongation factor that is enriched in testis. The C-terminal domain of Ell3 shows strong similarities to that of Ell (eleven?nineteen lysine-rich leukemia gene), which acts as a negative regulator of p53 and regulates cell proliferation and survival. Recent studies in our laboratory showed that Ell3 induces the differentiation of mouse embryonic stem cells by protecting differentiating cells from apoptosis via the promotion of p53 degradation. In this study, we evaluated the function of Ell3 in breast cancer cell lines. MCF-7 cell lines overexpressing Ell3 were used to examine cell proliferation and cancer stem cell properties. Ectopic expression of Ell3 in breast cancer cell lines induces proliferation and 5-FU resistance. In addition, Ell3 expression increases the cancer stem cell population, which is characterized by CD44 (+) or ALDH1 (+) cells. Mammosphere-forming potential and migration ability were also increased upon Ell3 expression in breast cancer cell lines. Through biochemical and molecular biological analyses, we showed that Ell3 regulates proliferation, cancer stem cell properties and drug resistance in breast cancer cell lines partly through the MEK?extracellular signal-regulated kinase signaling pathway. Murine xenograft experiments showed that Ell3 expression promotes tumorigenesis in vivo. These results suggest that Ell3 may play a critical role in promoting oncogenesis in breast cancer by regulating cell proliferation and cancer stem cell properties via the ERK1/2 signaling pathway.

  10. Topo II: An Enzyme Target for Antibacterial and Cancer Drugs

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    Topo II: An Enzyme Target for Antibacterial and Cancer Drugs Topo II: An Enzyme Target for Antibacterial and Cancer Drugs Print Wednesday, 27 February 2008 00:00 The veil has finally been lifted on an enzyme that is critical to the process of DNA transcription and replication and is a prime target of antibacterial and anticancer drugs. Researchers at Berkeley Lab and the University of California, Berkeley, have produced the first three-dimensional structural images of a DNA-bound type II

  11. High performance nanobio photocatalyst for targeted brain cancer therapy.

    SciTech Connect (OSTI)

    Rozhkova, E.; Ulasov, I.; Dimitrijevic, N. M.; Lesniak, M.; Rajh, T.; Lai, B.; Center for Nanoscale Materials

    2009-09-01

    We report pronounced and specific antiglioblastoma cell phototoxicity of 5 nm TiO{sub 2} particles covalently tethered to an antibody via a dihydroxybenzene bivalent linker. The linker application enables absorption of a visible part of the solar spectrum by the nanobio hybrid. The phototoxicity is mediated by reactive oxygen species (ROS) that initiate programmed death of the cancer cell. Synchrotron X-ray fluorescence microscopy (XFM) was applied for direct visualization of the nanobioconjugate distribution through a single brain cancer cell at the submicrometer scale.

  12. Mutator gene and hereditary non-polyposis colorectal cancer

    DOE Patents [OSTI]

    de la Chapelle, Albert; Vogelstein, Bert; Kinzler, Kenneth W.

    2008-02-05

    The human MSH2 gene, responsible for hereditary non-polyposis colorectal cancer, was identified by virtue of its homology to the MutS class of genes, which are involved in DNA mismatch repair. The sequence of cDNA clones of the human gene are provided, and the sequence of the gene can be used to demonstrate the existence of germ line mutations in hereditary non-polyposis colorectal cancer (HNPCC) kindreds, as well as in replication error.sup.+ (RER.sup.+) tumor cells.

  13. The role of general nuclear medicine in breast cancer

    SciTech Connect (OSTI)

    Greene, Lacey R; Wilkinson, Deborah

    2015-03-15

    The rising incidence of breast cancer worldwide has prompted many improvements to current care. Routine nuclear medicine is a major contributor to a full gamut of clinical studies such as early lesion detection and stratification; guiding, monitoring, and predicting response to therapy; and monitoring progression, recurrence or metastases. Developments in instrumentation such as the high-resolution dedicated breast device coupled with the diagnostic versatility of conventional cameras have reinserted nuclear medicine as a valuable tool in the broader clinical setting. This review outlines the role of general nuclear medicine, concluding that targeted radiopharmaceuticals and versatile instrumentation position nuclear medicine as a powerful modality for patients with breast cancer.

  14. Designer Proteins Target Epstein-Barr-Virus-Associated Cancer

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    Designer Proteins Target Epstein-Barr-Virus-Associated Cancer Designer Proteins Target Epstein-Barr-Virus-Associated Cancer Print Wednesday, 03 December 2014 00:00 Immortality is not a good thing for cells, and in fact, cells will destroy themselves in a process called apoptosis when they are a danger to other cells. For instance, when a cell is infected by a virus it becomes an unwilling factory for the virus, which uses the cell machinery to produce ever more copies of itself. Eventually, if

  15. YY1 modulates taxane response in epithelial ovarian cancer

    SciTech Connect (OSTI)

    Matsumura, Noriomi; Huang, Zhiqing; Baba, Tsukasa; Lee, Paula S.; Barnett, Jason C.; Mori, Seiichi; Chang, Jeffrey T.; Kuo, Wen-Lin; Gusberg, Alison H.; Whitaker, Regina S.; Gray, JoeW.; Fujii, Shingo; Berchuck, Andrew; Murphy, Susan K.

    2008-10-10

    The results of this study show that a high YY1 gene signature (characterized by coordinate elevated expression of transcription factor YY1 and putative YY1 target genes) within serous epithelial ovarian cancers is associated with enhanced response to taxane-based chemotherapy and improved survival. If confirmed in a prospective study, these results have important implications for the potential future use of individualized therapy in treating patients with ovarian cancer. Identification of the YY1 gene signature profile within a tumor prior to initiation of chemotherapy may provide valuable information about the anticipated response of these tumors to taxane-based drugs, leading to better informed decisions regarding chemotherapeutic choice. Survival of ovarian cancer patients is largely dictated by their response to chemotherapy, which depends on underlying molecular features of the malignancy. We previously identified YIN YANG 1 (YY1) as a gene whose expression is positively correlated with ovarian cancer survival. Herein we investigated the mechanistic basis of this association. Epigenetic and genetic characteristics of YY1 in serous epithelial ovarian cancer (SEOC) were analyzed along with YY1 mRNA and protein. Patterns of gene expression in primary SEOC and in the NCI60 database were investigated using computational methods. YY1 function and modulation of chemotherapeutic response in vitro was studied using siRNA knockdown. Microarray analysis showed strong positive correlation between expression of YY1 and genes with YY1 and transcription factor E2F binding motifs in SEOC and in the NCI60 cancer cell lines. Clustering of microarray data for these genes revealed that high YY1/E2F3 activity positively correlates with survival of patients treated with the microtubule stabilizing drug paclitaxel. Increased sensitivity to taxanes, but not to DNA crosslinking platinum agents, was also characteristic of NCI60 cancer cell lines with a high YY1/E2F signature. YY1 knockdown in ovarian cancer cell lines results in inhibition of anchorage-independent growth, motility and proliferation, but also increases resistance to taxanes, with no effect on cisplatin sensitivity. These results, together with the prior demonstration of augmentation of microtubule-related genes by E2F3, suggest that enhanced taxane sensitivity in tumors with high YY1/E2F activity may be mediated by modulation of putative target genes with microtubule function.

  16. Assessment of Latent Heat Reservoirs for Thermal Management of...

    Office of Scientific and Technical Information (OSTI)

    For the pulsed, quasi-continuous wave (QCW) operating mode employed for LIFE and certain ... reliability - which improves the diode costs as measured in W. We have proposed the ...

  17. Assessment of Latent Heat Reservoirs for Thermal Management of...

    Office of Scientific and Technical Information (OSTI)

    and also results in reliability limits due to catastrophic failure at diode mirror facets. ... output power without compromised reliability - which improves the diode costs as ...

  18. Spatially Distributed CO2, Sensible, and Latent Heat Fluxes Over...

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    forcing data from Mesonet facilities; (3) the USGS soil database; (4) MODIS NDVI data at 250 meters resolution; and (5) a tested carbon and isotope land-surface model...

  19. Diffracted light from latent images in photoresist for exposure control

    DOE Patents [OSTI]

    Bishop, Kenneth P.; Brueck, Steven R. J.; Gaspar, Susan M.; Hickman, Kirt C.; McNeil, John R.; Naqvi, S. Sohail H.; Stallard, Brian R.; Tipton, Gary D.

    1997-01-01

    In microelectronics manufacturing, an arrangement for monitoring and control of exposure of an undeveloped photosensitive layer on a structure susceptible to variations in optical properties in order to attain the desired critical dimension for the pattern to be developed in the photosensitive layer. This is done by ascertaining the intensities for one or more respective orders of diffracted power for an incident beam of radiation corresponding to the desired critical dimension for the photosensitive layer as a function of exposure time and optical properties of the structure, illuminating the photosensitive layer with a beam of radiation of one or more frequencies to which the photosensitive layer is not exposure-sensitive, and monitoring the intensities of the orders of diffracted radiation due to said illumination including at least the first order of diffracted radiation thereof, such that when said predetermined intensities for the diffracted orders are reached during said illumination of photosensitive layer, it is known that a pattern having at least approximately the desired critical dimension can be developed on the photosensitive layer.

  20. Molecular Markers of Lung Cancer in MAYAK Workers

    SciTech Connect (OSTI)

    Steven A. Belinsky, PhD

    2007-02-15

    The molecular mechanisms that result in the elevated risk for lung cancer associated with exposure to radiation have not been well characterized. Workers from the MAYAK nuclear enterprise are an ideal cohort in which to study the molecular epidemiology of cancer associated with radiation exposure and to identify the genes targeted for inactivation that in turn affect individual risk for radiation-induced lung cancer. Epidemiology studies of the MAYAK cohort indicate a significantly higher frequency for adenocarcinoma and squamous cell carcinoma (SCC) in workers than in a control population and a strong correlation between these tumor types and plutonium exposure. Two hypotheses will be evaluated through the proposed studies. First, radiation exposure targets specific genes for inactivation by promoter methylation. This hypothesis is supported by our recent studies with the MAYAK population that demonstrated the targeting of the p16 gene for inactivation by promoter methylation in adenocarcinomas from workers (1). Second, genes inactivated in tumors can serve as biomarkers for lung cancer risk in a cancer-free population of workers exposed to plutonium. Support for this hypothesis is based on exciting preliminary results of our nested, case-control study of persons from the Colorado cohort. In that study, a panel of methylation markers for predicting lung cancer risk is being evaluated in sputum samples from incident lung cancer cases and controls. The first hypothesis will be tested by determining the prevalence for promoter hypermethylation of a panel of genes shown to play a critical role in the development of either adenocarcinoma and/or SCC associated with tobacco. Our initial studies on adenocarcinoma in MAYAK workers will be extended to evaluate methylation of the PAX5 {alpha}, PAX5 {beta}, H-cadherin, GATA5, and bone morphogenesis 3B (BMP3B) genes in the original sample set described under Preliminary studies. In addition, studies will be initiated in SCC from workers and controls to identify genes targeted for inactivation by plutonium in this other common histologic form of lung cancer. We will examine methylation of the p16, O{sup 6}-methylguanine-DNA methyl-transferase (MGMT), and death associated protein kinase genes ([DAP-K], evaluated previously in adenocarcinomas) as well as the new genes being assessed in the adenocarcinomas. The second hypothesis will be tested in a cross-sectional study of cancer-free workers exposed to plutonium and an unexposed population. A cohort of 700 cancer-free workers and 700 unexposed persons is being assembled, exposures are being defined, and induced sputum collected at initial entry into the study and approximately 1-year later. Exposed and unexposed persons will be matched by 5-year age intervals and smoking status (current and former). The frequency for methylation of four genes that show the greatest difference in prevalence in tumors from workers and controls will be determined in exfoliated cells within sputum. These studies will extend those in primary tumors to determine whether difference in prevalence for individual or multiple genes are detected in sputum samples from high-risk subjects exposed to plutonium. Follow-up of this cohort offers the opportunity to validate these endpoints and future biomarkers as true markers for lung cancer risk.

  1. Frizzled-8 as a putative therapeutic target in human lung cancer

    SciTech Connect (OSTI)

    Wang, Hua-qing; Department of Medical Oncology, Tianjin Medical University Cancer Hospital, Tianjin 300060 ; Xu, Mei-lin; Ma, Jie; Zhang, Yi; Xie, Cong-hua

    2012-01-06

    Highlights: Black-Right-Pointing-Pointer Fzd-8 is over-expressed in human lung cancer. Black-Right-Pointing-Pointer shRNA knock-down of Fzd-8 inhibits proliferation and Wnt pathway in lung cancer cells. Black-Right-Pointing-Pointer shRNA knock-down of Fzd-8 suppresses tumor growth in vivo. Black-Right-Pointing-Pointer shRNA knock-down Fzd-8 sensitizes lung cancer cells to chemotherapy Taxotere. -- Abstract: Lung cancer is the leading cause of cancer related deaths worldwide. It is necessary to better understand the molecular mechanisms involved in lung cancer in order to develop more effective therapeutics for the treatment of this disease. Recent reports have shown that Wnt signaling pathway is important in a number of cancer types including lung cancer. However, the role of Frizzled-8 (Fzd-8), one of the Frizzled family of receptors for the Wnt ligands, in lung cancer still remains to be elucidated. Here in this study we showed that Fzd-8 was over-expressed in human lung cancer tissue samples and cell lines. To investigate the functional importance of the Fzd-8 over-expression in lung cancer, we used shRNA to knock down Fzd-8 mRNA in lung cancer cells expressing the gene. We observed that Fzd-8 shRNA inhibited cell proliferation along with decreased activity of Wnt pathway in vitro, and also significantly suppressed A549 xenograft model in vivo (p < 0.05). Furthermore, we found that knocking down Fzd-8 by shRNA sensitized the lung cancer cells to chemotherapy Taxotere. These data suggest that Fzd-8 is a putative therapeutic target for human lung cancer and over-expression of Fzd-8 may be important for aberrant Wnt activation in lung cancer.

  2. Selective killing of ovarian cancer cells through induction of apoptosis by nonequilibrium atmospheric pressure plasma

    SciTech Connect (OSTI)

    Iseki, Sachiko; Tanaka, Hiromasa; Kondo, Hiroki; Hori, Masaru; Nakamura, Kae; Hayashi, Moemi; Kajiyama, Hiroaki; Kikkawa, Fumitaka; Kano, Hiroyuki

    2012-03-12

    Two independent ovarian cancer cell lines and fibroblast controls were treated with nonequilibrium atmospheric pressure plasma (NEAPP). Most ovarian cancer cells were detached from the culture dish by continuous plasma treatment to a single spot on the dish. Next, the plasma source was applied over the whole dish using a robot arm. In vitro cell proliferation assays showed that plasma treatments significantly decreased proliferation rates of ovarian cancer cells compared to fibroblast cells. Flow cytometry and western blot analysis showed that plasma treatment of ovarian cancer cells induced apoptosis. NEAPP could be a promising tool for therapy for ovarian cancers.

  3. Radiation-Induced Notch Signaling in Breast Cancer Stem Cells

    SciTech Connect (OSTI)

    Lagadec, Chann; Vlashi, Erina; Alhiyari, Yazeed; Phillips, Tiffany M.; Bochkur Dratver, Milana; Pajonk, Frank

    2013-11-01

    Purpose: To explore patterns of Notch receptor and ligand expression in response to radiation that could be crucial in defining optimal dosing schemes for ?-secretase inhibitors if combined with radiation. Methods and Materials: Using MCF-7 and T47D breast cancer cell lines, we used real-time reverse transcriptionpolymerase chain reaction to study the Notch pathway in response to radiation. Results: We show that Notch receptor and ligand expression during the first 48 hours after irradiation followed a complex radiation dosedependent pattern and was most pronounced in mammospheres, enriched for breast cancer stem cells. Additionally, radiation activated the Notch pathway. Treatment with a ?-secretase inhibitor prevented radiation-induced Notch family gene expression and led to a significant reduction in the size of the breast cancer stem cell pool. Conclusions: Our results indicate that, if combined with radiation, ?-secretase inhibitors may prevent up-regulation of Notch receptor and ligand family members and thus reduce the number of surviving breast cancer stem cells.

  4. ProxiScan?: A Novel Camera for Imaging Prostate Cancer

    ScienceCinema (OSTI)

    Ralph James

    2010-01-08

    ProxiScan is a compact gamma camera suited for high-resolution imaging of prostate cancer. Developed by Brookhaven National Laboratory and Hybridyne Imaging Technologies, Inc., ProxiScan won a 2009 R&D 100 Award, sponsored by R&D Magazine to recognize t

  5. Comprehensive Quantitative Analysis of Ovarian and Breast Cancer Tumor Peptidomes

    SciTech Connect (OSTI)

    Xu, Zhe; Wu, Chaochao; Xie, Fang; Slysz, Gordon W.; Tolic, Nikola; Monroe, Matthew E.; Petyuk, Vladislav A.; Payne, Samuel H.; Fujimoto, Grant M.; Moore, Ronald J.; Fillmore, Thomas L.; Schepmoes, Athena A.; Levine, Douglas; Townsend, Reid; Davies, Sherri; Li, Shunqiang; Ellis, Matthew; Boja, Emily; Rodriguez, Henry; Rodland, Karin D.; Liu, Tao; Smith, Richard D.

    2015-01-01

    Aberrant degradation of proteins is associated with many pathological states, including cancers. Mass spectrometric analysis of tumor peptidomes, the intracellular and intercellular products of protein degradation, has the potential to provide biological insights on proteolytic processing in cancer. However, attempts to use the information on these smaller protein degradation products from tumors for biomarker discovery and cancer biology studies have been fairly limited to date, largely due to the lack of effective approaches for robust peptidomics identification and quantification, and the prevalence of confounding factors and biases associated with sample handling and processing. Herein, we have developed an effective and robust analytical platform for comprehensive analyses of tissue peptidomes, and which is suitable for high throughput quantitative studies. The reproducibility and coverage of the platform, as well as the suitability of clinical ovarian tumor and patient-derived breast tumor xenograft samples with post-excision delay of up to 60 min before freezing for peptidomics analysis, have been demonstrated. Moreover, our data also show that the peptidomics profiles can effectively separate breast cancer subtypes, reflecting tumor-associated protease activities. Peptidomics complements results obtainable from conventional bottom-up proteomics, and provides insights not readily obtainable from such approaches.

  6. Investigation of excess thyroid cancer incidence in Los Alamos County

    SciTech Connect (OSTI)

    Athas, W.F.

    1996-04-01

    Los Alamos County (LAC) is home to the Los Alamos National Laboratory, a U.S. Department of Energy (DOE) nuclear research and design facility. In 1991, the DOE funded the New Mexico Department of Health to conduct a review of cancer incidence rates in LAC in response to citizen concerns over what was perceived as a large excess of brain tumors and a possible relationship to radiological contaminants from the Laboratory. The study found no unusual or alarming pattern in the incidence of brain cancer, however, a fourfold excess of thyroid cancer was observed during the late-1980`s. A rapid review of the medical records for cases diagnosed between 1986 and 1990 failed to demonstrate that the thyroid cancer excess had resulted from enhanced detection. Surveillance activities subsequently undertaken to monitor the trend revealed that the excess persisted into 1993. A feasibility assessment of further studies was made, and ultimately, an investigation was conducted to document the epidemiologic characteristics of the excess in detail and to explore possible causes through a case-series records review. Findings from the investigation are the subject of this report.

  7. Multiclass cancer diagnosis using tumor gene expression signatures

    DOE Public Access Gateway for Energy & Science Beta (PAGES Beta)

    Ramaswamy, S.; Tamayo, P.; Rifkin, R.; Mukherjee, S.; Yeang, C. -H.; Angelo, M.; Ladd, C.; Reich, M.; Latulippe, E.; Mesirov, J. P.; et al

    2001-12-11

    The optimal treatment of patients with cancer depends on establishing accurate diagnoses by using a complex combination of clinical and histopathological data. In some instances, this task is difficult or impossible because of atypical clinical presentation or histopathology. To determine whether the diagnosis of multiple common adult malignancies could be achieved purely by molecular classification, we subjected 218 tumor samples, spanning 14 common tumor types, and 90 normal tissue samples to oligonucleotide microarray gene expression analysis. The expression levels of 16,063 genes and expressed sequence tags were used to evaluate the accuracy of a multiclass classifier based on a supportmore » vector machine algorithm. Overall classification accuracy was 78%, far exceeding the accuracy of random classification (9%). Poorly differentiated cancers resulted in low-confidence predictions and could not be accurately classified according to their tissue of origin, indicating that they are molecularly distinct entities with dramatically different gene expression patterns compared with their well differentiated counterparts. Taken together, these results demonstrate the feasibility of accurate, multiclass molecular cancer classification and suggest a strategy for future clinical implementation of molecular cancer diagnostics.« less

  8. Inhibition of HAS2 induction enhances the radiosensitivity of cancer cells via persistent DNA damage

    SciTech Connect (OSTI)

    Shen, Yan Nan; Shin, Hyun-Jin; Joo, Hyun-Yoo; Park, Eun-Ran; Kim, Su-Hyeon; Hwang, Sang-Gu; Park, Sang Jun; Kim, Chun-Ho; Lee, Kee-Ho

    2014-01-17

    Highlights: •HAS2 may be a promising target for the radiosensitization of human cancer. •HAS2 is elevated (up to ∼10-fold) in irradiated radioresistant and -sensitive cancer cells. •HAS2 knockdown sensitizes cancer cells to radiation. •HAS2 knockdown potentiates irradiation-induced DNA damage and apoptotic death. •Thus, the irradiation-induced up-regulation of HAS2 contributes to the radioresistance of cancer cells. -- Abstract: Hyaluronan synthase 2 (HAS2), a synthetic enzyme for hyaluronan, regulates various aspects of cancer progression, including migration, invasion and angiogenesis. However, the possible association of HAS2 with the response of cancer cells to anticancer radiotherapy, has not yet been elucidated. Here, we show that HAS2 knockdown potentiates irradiation-induced DNA damage and apoptosis in cancer cells. Upon exposure to radiation, all of the tested human cancer cell lines exhibited marked (up to 10-fold) up-regulation of HAS2 within 24 h. Inhibition of HAS2 induction significantly reduced the survival of irradiated radioresistant and -sensitive cells. Interestingly, HAS2 depletion rendered the cells to sustain irradiation-induced DNA damage, thereby leading to an increase of apoptotic death. These findings indicate that HAS2 knockdown sensitizes cancer cells to radiation via persistent DNA damage, further suggesting that the irradiation-induced up-regulation of HAS2 contributes to the radioresistance of cancer cells. Thus, HAS2 could potentially be targeted for therapeutic interventions aimed at radiosensitizing cancer cells.

  9. Low Dose Radiation Cancer Risks: Epidemiological and Toxicological Models

    SciTech Connect (OSTI)

    David G. Hoel, PhD

    2012-04-19

    The basic purpose of this one year research grant was to extend the two stage clonal expansion model (TSCE) of carcinogenesis to exposures other than the usual single acute exposure. The two-stage clonal expansion model of carcinogenesis incorporates the biological process of carcinogenesis, which involves two mutations and the clonal proliferation of the intermediate cells, in a stochastic, mathematical way. The current TSCE model serves a general purpose of acute exposure models but requires numerical computation of both the survival and hazard functions. The primary objective of this research project was to develop the analytical expressions for the survival function and the hazard function of the occurrence of the first cancer cell for acute, continuous and multiple exposure cases within the framework of the piece-wise constant parameter two-stage clonal expansion model of carcinogenesis. For acute exposure and multiple exposures of acute series, it is either only allowed to have the first mutation rate vary with the dose, or to have all the parameters be dose dependent; for multiple exposures of continuous exposures, all the parameters are allowed to vary with the dose. With these analytical functions, it becomes easy to evaluate the risks of cancer and allows one to deal with the various exposure patterns in cancer risk assessment. A second objective was to apply the TSCE model with varing continuous exposures from the cancer studies of inhaled plutonium in beagle dogs. Using step functions to estimate the retention functions of the pulmonary exposure of plutonium the multiple exposure versions of the TSCE model was to be used to estimate the beagle dog lung cancer risks. The mathematical equations of the multiple exposure versions of the TSCE model were developed. A draft manuscript which is attached provides the results of this mathematical work. The application work using the beagle dog data from plutonium exposure has not been completed due to the fact that the research project did not continue beyond its first year.

  10. Nonbreast Second Malignancies After Treatment of Primary Breast Cancer

    SciTech Connect (OSTI)

    Yadav, Budhi S. Sharma, Suresh C.; Patel, Firuza D.; Ghoshal, Sushmita; Kapoor, Rakesh; Kumar, Rajinder

    2009-04-01

    Purpose: To determine the incidence and risk factors for nonbreast second malignancies (NBSMs) in women after treatment for primary breast cancer. Methods and Materials: Between January 1985 and December 1995, a total of 1,084 breast cancer patients were analyzed for NBSMs. Detailed analysis was carried out for age, family history, disease stage, radiation therapy, chemotherapy, hormone therapy, other clinical/pathologic characteristics, and site of NBSMs. The Cox proportional hazard regression model was used to estimate the relative risk of NBSMs. Results: Median follow-up was 12 years. In total, 33 cases of NBSMs were noted in 29 patients. The overall incidence of NBSM was 3%, and the median time for NBSMs was 7 years. The most common NBSMs were gynecologic (22 patients), gastrointestinal (4 patients), head and neck (3 patients), hematologic (2 patients), lung (1 patient), and thyroid (1 patient). The NBSMs rate at 12 years was 2.4% for both mastectomy and radiation therapy groups. In the subset of patients less than 45 years of age at the time of treatment, the NBSMs rate was 0.7% as compared with 4.6% in patients more than 45 years of age (p = 0.001). Statistically significant higher incidences of endometrial and ovarian cancer were seen in patients with hormonal therapy (5.2%) as compared with patients without hormonal therapy (1.8%, p = 0.002). Women with a family history of breast cancer had a higher incidence (6%) of endometrial and ovarian malignancy compared with women without such a history (2.1%, p = 0.003). Chemotherapy did not affect the risk of second malignancy. Conclusion: The most common NBSMs in this study were gynecologic. Family history of breast cancer was a high risk factor for NBSMs. No risk of NBSMs with radiotherapy was observed.

  11. Linkage heterogeneity among 59 Dutch hereditary breast cancer families

    SciTech Connect (OSTI)

    Cornelis, R.S.; Vliet, M. van; Leeuwen, I. van

    1994-09-01

    We have investigated 59 Dutch kindreds with at least three first-degree relatives with breast and/or ovarian cancer for linkage to BRCA1 on 17q12-q21, using at least 4 microsatellite markers flanking BRCA1 on either side. Assuming no heterogeneity, the overall multipoint lod score in this group of families was -7.59. A marked clustering of lod scores >0.5 was observed among the 13 families with a mean age of onset lower than 45 (total lod score: +3.36). Among the 8 kindreds with a mean age of onset lower than 45 and {ge}3 cases diagnosed under 45, the lod score was +4.43. Interestingly, most of the evidence against linkage was found in 17 families with a mean age of onset between 45 and 54 (total lod score of -8.72). It was estimated that 28% of the breast-only families might be caused by BRCA1. Over the 16 breast-ovarian cancer families a lod score of -3.78 was obtained under homogeneity. The highest lod score was +0.57, assuming heterogeneity with 33% of the families being linked to BRCA1. One family gave a multipoint lod score of -2.01 and thereby satisfies the conventional criterion of an unlinked family. Our results support the conclusions from earlier work by others, namely that BRCA1 predisposes particularly to early-onset breast cancer. The proportion of breast-ovarian cancer families we found linked to BRCA1 is much lower than that found by the Breast Cancer Linkage Consortium. This might be caused by the single unlinked family against an insufficient number of families able to give conclusive positive lod scores.

  12. Interaction of celecoxib with different anti-cancer drugs is antagonistic in breast but not in other cancer cells

    SciTech Connect (OSTI)

    El-Awady, Raafat A.; Saleh, Ekram M.; Ezz, Marwa; Elsayed, Abeer M.

    2011-09-15

    Celecoxib, an inhibitor of cyclooxygenase-2, is being investigated for enhancement of chemotherapy efficacy in cancer clinical trials. This study investigates the ability of cyclooxygenase-2 inhibitors to sensitize cells from different origins to several chemotherapeutic agents. The effect of the drug's mechanism of action and sequence of administration are also investigated. The sensitivity, cell cycle, apoptosis and DNA damage of five different cancer cell lines (HeLa, HCT116, HepG2, MCF7 and U251) to 5-FU, cisplatin, doxorubicin and etoposide {+-} celecoxib following different incubation schedules were analyzed. We found antagonism between celecoxib and the four drugs in the breast cancer cells MCF7 following all incubation schedules and between celecoxib and doxorubicin in all cell lines except for two combinations in HCT116 cells. Celecoxib with the other three drugs in the remaining four cell lines resulted in variable interactions. Mechanistic investigations revealed that celecoxib exerts different molecular effects in different cells. In some lines, it abrogates the drug-induced G2/M arrest enhancing pre-mature entry into mitosis with damaged DNA thus increasing apoptosis and resulting in synergism. In other cells, it enhances drug-induced G2/M arrest allowing time to repair drug-induced DNA damage before entry into mitosis and decreasing cell death resulting in antagonism. In some synergistic combinations, celecoxib-induced abrogation of G2/M arrest was not associated with apoptosis but permanent arrest in G1 phase. These results, if confirmed in-vivo, indicate that celecoxib is not a suitable chemosensitizer for breast cancer or with doxorubicin for other cancers. Moreover, combination of celecoxib with other drugs should be tailored to the tumor type, drug and administration schedule. - Graphical abstract: Display Omitted Highlights: > Celecoxib may enhance effects of anticancer drugs. > Its combination with four drugs was tested in five cancer cell lines. > It antagonized the effects of the four drugs in the breast cancer cell line MCF7. > Doxorubicin's cytotoxic effects were antagonized by celecoxib in four cell lines. > Cell cycle, apoptosis and DNA damage explain the different interactive effects.

  13. Mutation analysis of BRCA1 and BRCA2 in a male breast cancer population

    SciTech Connect (OSTI)

    Friedman, L.S.; Gayther, S.A.; Ponder, B.A.J.

    1997-02-01

    A population-based series of 54 male breast cancer cases from Southern California were analyzed for germ-line mutations in the inherited breast/ovarian cancer genes, BRCA1 and BRCA2. Nine (17%) of the patients had a family history of breast and/or ovarian cancer in at least one first-degree relative. A further seven (13%) of the patients reported breast/ovarian cancer in at least one second-degree relative and in no first-degree relatives. No germ-line BRCA1 mutations were found. Two male breast cancer patients (4% of the total) were found to carry novel truncating mutations in the BRCA2 gene. Only one of the two male breast cancer patients carrying a BRCA2 mutation had a family history of cancer, with one case of ovarian cancer in a first-degree relative. The remaining eight cases (89%) of male breast cancer with a family history of breast/ovarian cancer in first-degree relatives remain unaccounted for by mutations in either the BRCA1 gene or the BRCA2 gene. 23 refs., 1 fig., 5 tabs.

  14. A possible usage of a CDK4 inhibitor for breast cancer stem cell-targeted therapy

    SciTech Connect (OSTI)

    Han, Yu Kyeong; Lee, Jae Ho; Park, Ga-Young; Chun, Sung Hak; Han, Jeong Yun; Kim, Sung Dae; Lee, Janet; Center for Molecular Medicine, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, Gyeonggi 440-746 ; Lee, Chang-Woo; Center for Molecular Medicine, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, Gyeonggi 440-746; Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Suwon, Gyeonggi 440-746 ; Yang, Kwangmo; Department of Radiation Oncology, Dongnam Institute of Radiological and Medical Sciences, Busan 619-953; Department of Radiation Oncology, Korea Institute of Radiological and Medical Sciences, Seoul 139-709 ; Lee, Chang Geun

    2013-01-25

    Highlights: ? A CDK4 inhibitor may be used for breast cancer stem cell-targeted therapy. ? The CDK4 inhibitor differentiated the cancer stem cell population (CD24{sup ?}/CD44{sup +}) of MDA-MB-231. ? The differentiation of the cancer stem cells by the CDK4 inhibitor radiosensitized MDA-MB-231. -- Abstract: Cancer stem cells (CSCs) are one of the main reasons behind cancer recurrence due to their resistance to conventional anti-cancer therapies. Thus, many efforts are being devoted to developing CSC-targeted therapies to overcome the resistance of CSCs to conventional anti-cancer therapies and decrease cancer recurrence. Differentiation therapy is one potential approach to achieve CSC-targeted therapies. This method involves inducing immature cancer cells with stem cell characteristics into more mature or differentiated cancer cells. In this study, we found that a CDK4 inhibitor sensitized MDA-MB-231 cells but not MCF7 cells to irradiation. This difference appeared to be associated with the relative percentage of CSC-population between the two breast cancer cells. The CDK4 inhibitor induced differentiation and reduced the cancer stem cell activity of MDA-MB-231 cells, which are shown by multiple marker or phenotypes of CSCs. Thus, these results suggest that radiosensitization effects may be caused by reducing the CSC-population of MDA-MB-231 through the use of the CDK4 inhibitor. Thus, further investigations into the possible application of the CDK4 inhibitor for CSC-targeted therapy should be performed to enhance the efficacy of radiotherapy for breast cancer.

  15. Proteogenomic characterization of human colon and rectal cancer

    SciTech Connect (OSTI)

    Zhang, Bing; Wang, Jing; Wang, Xiaojing; Zhu, Jing; Liu, Qi; Shi, Zhiao; Chambers, Matthew C.; Zimmerman, Lisa J.; Shaddox, Kent F.; Kim, Sangtae; Davies, Sherri; Wang, Sean; Wang, Pei; Kinsinger, Christopher; Rivers, Robert; Rodriguez, Henry; Townsend, Reid; Ellis, Matthew; Carr, Steven A.; Tabb, David L.; Coffey, Robert J.; Slebos, Robbert; Liebler, Daniel

    2014-09-18

    We analyzed proteomes of colon and rectal tumors previously characterized by the Cancer Genome Atlas (TCGA) and performed integrated proteogenomic analyses. Protein sequence variants encoded by somatic genomic variations displayed reduced expression compared to protein variants encoded by germline variations. mRNA transcript abundance did not reliably predict protein expression differences between tumors. Proteomics identified five protein expression subtypes, two of which were associated with the TCGA "MSI/CIMP" transcriptional subtype, but had distinct mutation and methylation patterns and associated with different clinical outcomes. Although CNAs showed strong cis- and trans-effects on mRNA expression, relatively few of these extend to the protein level. Thus, proteomics data enabled prioritization of candidate driver genes. Our analyses identified HNF4A, a novel candidate driver gene in tumors with chromosome 20q amplifications. Integrated proteogenomic analysis provides functional context to interpret genomic abnormalities and affords novel insights into cancer biology.

  16. The significance of macrophage phenotype in cancer and biomaterials

    SciTech Connect (OSTI)

    Bygd, Hannah C.; Forsmark, Kiva D.; Bratlie, Kaitlin M.

    2014-11-25

    Macrophages have long been known to exhibit heterogeneous and plastic phenotypes. They show functional diversity with roles in homeostasis, tissue repair, immunity and disease. There exists a spectrum of macrophage phenotypes with varied effector functions, molecular determinants, cytokine and chemokine profiles, as well as receptor expression. In tumor microenvironments, the subset of macrophages known as tumor-associated macrophages generates byproducts that enhance tumor growth and angiogenesis, making them attractive targets for anti-cancer therapeutics. With respect to wound healing and the foreign body response, there is a necessity for balance between pro-inflammatory, wound healing, and regulatory macrophages in order to achieve successful implantation of a scaffold for tissue engineering. In this review, we discuss the multitude of ways macrophages are known to be important in cancer therapies and implanted biomaterials.

  17. The significance of macrophage phenotype in cancer and biomaterials

    DOE Public Access Gateway for Energy & Science Beta (PAGES Beta)

    Bygd, Hannah C.; Forsmark, Kiva D.; Bratlie, Kaitlin M.

    2014-11-25

    Macrophages have long been known to exhibit heterogeneous and plastic phenotypes. They show functional diversity with roles in homeostasis, tissue repair, immunity and disease. There exists a spectrum of macrophage phenotypes with varied effector functions, molecular determinants, cytokine and chemokine profiles, as well as receptor expression. In tumor microenvironments, the subset of macrophages known as tumor-associated macrophages generates byproducts that enhance tumor growth and angiogenesis, making them attractive targets for anti-cancer therapeutics. With respect to wound healing and the foreign body response, there is a necessity for balance between pro-inflammatory, wound healing, and regulatory macrophages in order to achieve successfulmore » implantation of a scaffold for tissue engineering. In this review, we discuss the multitude of ways macrophages are known to be important in cancer therapies and implanted biomaterials.« less

  18. Topo II: An Enzyme Target for Antibacterial and Cancer Drugs

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    Topo II: An Enzyme Target for Antibacterial and Cancer Drugs Print The veil has finally been lifted on an enzyme that is critical to the process of DNA transcription and replication and is a prime target of antibacterial and anticancer drugs. Researchers at Berkeley Lab and the University of California, Berkeley, have produced the first three-dimensional structural images of a DNA-bound type II topoisomerase (topo II) that is responsible for untangling coiled strands of the chromosome during

  19. Insight into Alzheimer's, cancer, anemia gleaned from ribosome research

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    Insights from ribosome research Insight into Alzheimer's, cancer, anemia gleaned from ribosome research Groundbreaking study of the human ribosome reveals tiny molecular machine is more versatile than previously understood December 22, 2014 The newly discovered rolling movement shown in (A) three-dimensional cryo-electron microscopy image of ribosome, and (B) computer-generated atomic-resolution model of the human ribosome consistent with microscopy. Figure 3. The newly discovered rolling

  20. Topo II: An Enzyme Target for Antibacterial and Cancer Drugs

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    Topo II: An Enzyme Target for Antibacterial and Cancer Drugs Print The veil has finally been lifted on an enzyme that is critical to the process of DNA transcription and replication and is a prime target of antibacterial and anticancer drugs. Researchers at Berkeley Lab and the University of California, Berkeley, have produced the first three-dimensional structural images of a DNA-bound type II topoisomerase (topo II) that is responsible for untangling coiled strands of the chromosome during

  1. Topo II: An Enzyme Target for Antibacterial and Cancer Drugs

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    Topo II: An Enzyme Target for Antibacterial and Cancer Drugs Print The veil has finally been lifted on an enzyme that is critical to the process of DNA transcription and replication and is a prime target of antibacterial and anticancer drugs. Researchers at Berkeley Lab and the University of California, Berkeley, have produced the first three-dimensional structural images of a DNA-bound type II topoisomerase (topo II) that is responsible for untangling coiled strands of the chromosome during

  2. Topo II: An Enzyme Target for Antibacterial and Cancer Drugs

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    Topo II: An Enzyme Target for Antibacterial and Cancer Drugs Print The veil has finally been lifted on an enzyme that is critical to the process of DNA transcription and replication and is a prime target of antibacterial and anticancer drugs. Researchers at Berkeley Lab and the University of California, Berkeley, have produced the first three-dimensional structural images of a DNA-bound type II topoisomerase (topo II) that is responsible for untangling coiled strands of the chromosome during

  3. 6.21 Improving Neutron Beams for Cancer Treatment

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    1 6/1/2011 6.21 Improving Neutron Beams for Cancer Treatment Beams of neutrons long have been used in scientific experiments, but recently, for the first time, a novel type of neutron beam was generated for use in a medical reactor. The innovation by Otto K. Harling of Massachusetts Institute of Technology involved the adaptation of existing nuclear fission converter technology. The Office of Science supported the detailed scientific and engineering design needed to put the concept to practical

  4. External Beam Radiotherapy for Colon Cancer: Patterns of Care

    SciTech Connect (OSTI)

    Dunn, Emily F., E-mail: dunn@humonc.wisc.ed [Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI (United States); Kozak, Kevin R. [Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI (United States); Moody, John S. [Division of Radiation Oncology, Moses Cone Regional Cancer Center, Greensboro, NC (United States)

    2010-04-15

    Purpose: Despite its common and well characterized use in other gastrointestinal malignancies, little is known about radiotherapy (RT) use in nonmetastatic colon cancer in the United States. To address the paucity of data regarding RT use in colon cancer management, we examined the RT patterns of care in this patient population. Methods and Materials: Patients with nonmetastatic colon cancer, diagnosed between 1988 and 2005, were identified in the Surveillance, Epidemiology, and End Results (SEER) database. Univariate and multivariate methods were used to identify factors associated with RT use. Results: On univariate analysis, tumor location, age, sex, race, T stage, N stage, and geographic location were each associated with differences in RT use (all p < 0.01). In general, younger patients, male patients, and patients with more advanced disease were more likely to receive RT. On multivariate analysis, tumor location, age, gender, T and N stage, time of diagnosis and geographic location were significantly associated with RT use (all p < 0.001). Race, however, was not associated with RT use. On multivariate analysis, patients diagnosed in 1988 were 2.5 times more likely to receive RT than those diagnosed in 2005 (p = 0.001). Temporal changes in RT use reflect a responsiveness to evolving evidence related to the therapeutic benefits of adjuvant RT. Conclusions: External beam RT is infrequently used for colon cancer, and its use varies according to patient and tumor characteristics. RT use has declined markedly since the late 1980s; however, it continues to be used for nonmetastatic disease in a highly individualized manner.

  5. Approaches to cancer assessment in EPA's Integrated Risk Information System

    SciTech Connect (OSTI)

    Gehlhaus, Martin W.; Gift, Jeffrey S.; Hogan, Karen A.; Kopylev, Leonid; Schlosser, Paul M.; Kadry, Abdel-Razak

    2011-07-15

    The U.S. Environmental Protection Agency's (EPA) Integrated Risk Information System (IRIS) Program develops assessments of health effects that may result from chronic exposure to chemicals in the environment. The IRIS database contains more than 540 assessments. When supported by available data, IRIS assessments provide quantitative analyses of carcinogenic effects. Since publication of EPA's 2005 Guidelines for Carcinogen Risk Assessment, IRIS cancer assessments have implemented new approaches recommended in these guidelines and expanded the use of complex scientific methods to perform quantitative dose-response assessments. Two case studies of the application of the mode of action framework from the 2005 Cancer Guidelines are presented in this paper. The first is a case study of 1,2,3-trichloropropane, as an example of a chemical with a mutagenic mode of carcinogenic action thus warranting the application of age-dependent adjustment factors for early-life exposure; the second is a case study of ethylene glycol monobutyl ether, as an example of a chemical with a carcinogenic action consistent with a nonlinear extrapolation approach. The use of physiologically based pharmacokinetic (PBPK) modeling to quantify interindividual variability and account for human parameter uncertainty as part of a quantitative cancer assessment is illustrated using a case study involving probabilistic PBPK modeling for dichloromethane. We also discuss statistical issues in assessing trends and model fit for tumor dose-response data, analysis of the combined risk from multiple types of tumors, and application of life-table methods for using human data to derive cancer risk estimates. These issues reflect the complexity and challenges faced in assessing the carcinogenic risks from exposure to environmental chemicals, and provide a view of the current trends in IRIS carcinogenicity risk assessment.

  6. Software speeds detection of diseases and cancer-treatment targets

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    Software speeds detection of diseases Software speeds detection of diseases and cancer-treatment targets The Lab has released an updated version of software that is now capable of identifying DNA from viruses and all parts of the Tree of Life. December 1, 2014 With Sequedex, a laptop computer can analyze DNA sequences faster than any current DNA sequencer can create them. With Sequedex, a laptop computer can analyze DNA sequences faster than any current DNA sequencer can create them. Contact

  7. Mechanism-based inhibition of cancer metastasis with (?)-epigallocatechin gallate

    SciTech Connect (OSTI)

    Takahashi, Atsushi; Graduate School of Science and Engineering, Saitama University, Saitama 338-8570; Green Tea Laboratory, Saitama Prefectural Agriculture and Forestry Research Center, Saitama 358-0042 ; Watanabe, Tatsuro; Mondal, Anupom; Suzuki, Kaori; Kurusu-Kanno, Miki; Li, Zhenghao; Yamazaki, Takashi; Graduate School of Science and Engineering, Saitama University, Saitama 338-8570 ; Fujiki, Hirota; Suganuma, Masami

    2014-01-03

    Highlights: EGCG reduced cell motility of highly metastatic human lung cancer cells. EGCG increased cell stiffness of the cells, indicating the inhibition of phenotypes of EMT. EGCG inhibited expression of vimentin and Slug in the cells at the leading edge of scratch. Treatment of M?CD increased cell stiffness, and inhibited cell motility and vimentin expression. Inhibition of EMT phenotypes with EGCG is a mechanism-based inhibition of cancer metastasis. -- Abstract: Cell motility and cell stiffness are closely related to metastatic activity of cancer cells. (?)-Epigallocatechin gallate (EGCG) has been shown to inhibit spontaneous metastasis of melanoma cell line into the lungs of mice, so we studied the effects of EGCG on cell motility, cell stiffness, and expression of vimentin and Slug, which are molecular phenotypes of epithelialmesenchymal transition (EMT). Treatments of human non-small cell lung cancer cell lines H1299 and Lu99 with 50 and 100 ?M EGCG reduced cell motility to 67.5% and 43.7% in H1299, and 71.7% and 31.5% in Lu99, respectively in in vitro wound healing assay. Studies on cell stiffness using atomic force microscope (AFM) revealed that treatment with 50 ?M EGCG increased Youngs modulus of H1299 from 1.24 to 2.25 kPa and that of Lu99 from 1.29 to 2.28 kPa, showing a 2-fold increase in cell stiffness, i.e. rigid elasticity of cell membrane. Furthermore, treatment with 50 ?M EGCG inhibited high expression of vimentin and Slug in the cells at a leading edge of scratch. Methyl-?-cyclodextrin, a reagent to deplete cholesterol in plasma membrane, showed inhibition of EMT phenotypes similar that by EGCG, suggesting that EGCG induces inhibition of EMT phenotypes by alteration of membrane organization.

  8. Open questions: The disrupted circuitry of the cancer cell

    SciTech Connect (OSTI)

    Wiley, H. Steven

    2014-10-18

    Every new decade of biology brings with it a change in outlook driven by new technologies and fresh perspectives. Such is the case for cancer and how we consider the disease. The advent of molecular biology led to the identification of altered signaling molecules and 'oncogenes' that were proposed to drive uncontrolled cell proliferation. The rise of cell biology and new imaging and culturing technologies led to the idea that disruptions in the extracellular environment prime cells for transformation. In the current genomics era, cancer is most commonly seen as a genetic disorder where an unstable genome gives rise to a variety of different cell variants that are selected for proliferation and survival. All of these views are partially correct, of course, and are simply different ways of saying that genetic alterations in cancer cells result in a loss of growth homeostasis. They also take the view that molecular changes 'drive' a cell to grow uncontrollably, rather than tip the balance from one normal state (quiescence) to another (proliferation). Underlying this oversimplification is a profound ignorance of what controls homeostatic cell growth in the first place and how specific mutations impact it. Normal, proliferation-competent cells can accurately monitor their environment and respond appropriately to perturbation, whether it is a loss of neighbors or an inflammatory stimulus. Cancer cells either proliferate or refuse to die where and when they should not, which clearly indicates that they have problems in detecting or responding to their environment. Thus, an enormous amount of effort has gone into defining the signaling pathways that can trigger a proliferative response and the biochemical mechanisms underlying these pathways. Far less work has focused on understanding the higher-order logic of these pathways and the roles played by all of the components as part of an integrated system. In other words, we do not really understand how cells process information and make decisions and thus cannot predict how any given molecular change will alter what a cell does.

  9. A MULTISCALE, CELL-BASED FRAMEWORK FOR MODELING CANCER DEVELOPMENT

    SciTech Connect (OSTI)

    JIANG, YI

    2007-01-16

    Cancer remains to be one of the leading causes of death due to diseases. We use a systems approach that combines mathematical modeling, numerical simulation, in vivo and in vitro experiments, to develop a predictive model that medical researchers can use to study and treat cancerous tumors. The multiscale, cell-based model includes intracellular regulations, cellular level dynamics and intercellular interactions, and extracellular level chemical dynamics. The intracellular level protein regulations and signaling pathways are described by Boolean networks. The cellular level growth and division dynamics, cellular adhesion and interaction with the extracellular matrix is described by a lattice Monte Carlo model (the Cellular Potts Model). The extracellular dynamics of the signaling molecules and metabolites are described by a system of reaction-diffusion equations. All three levels of the model are integrated through a hybrid parallel scheme into a high-performance simulation tool. The simulation results reproduce experimental data in both avasular tumors and tumor angiogenesis. By combining the model with experimental data to construct biologically accurate simulations of tumors and their vascular systems, this model will enable medical researchers to gain a deeper understanding of the cellular and molecular interactions associated with cancer progression and treatment.

  10. Anandamide inhibits adhesion and migration of breast cancer cells

    SciTech Connect (OSTI)

    Grimaldi, Claudia; Pisanti, Simona; Laezza, Chiara; Malfitano, Anna Maria; Santoro, Antonietta; Vitale, Mario; Caruso, Maria Gabriella; Notarnicola, Maria; Iacuzzo, Irma; Portella, Giuseppe; Di Marzo, Vincenzo . E-mail: vdimarzo@icmib.na.cnr.it; Bifulco, Maurizio . E-mail: maubiful@unina.it

    2006-02-15

    The endocannabinoid system regulates cell proliferation in human breast cancer cells. We reasoned that stimulation of cannabinoid CB{sub 1} receptors could induce a non-invasive phenotype in breast mtastatic cells. In a model of metastatic spreading in vivo, the metabolically stable anandamide analogue, 2-methyl-2'-F-anandamide (Met-F-AEA), significantly reduced the number and dimension of metastatic nodes, this effect being antagonized by the selective CB{sub 1} antagonist SR141716A. In MDA-MB-231 cells, a highly invasive human breast cancer cell line, and in TSA-E1 cells, a murine breast cancer cell line, Met-F-AEA inhibited adhesion and migration on type IV collagen in vitro without modifying integrin expression: both these effects were antagonized by SR141716A. In order to understand the molecular mechanism involved in these processes, we analyzed the phosphorylation of FAK and Src, two tyrosine kinases involved in migration and adhesion. In Met-F-AEA-treated cells, we observed a decreased tyrosine phosphorylation of both FAK and Src, this effect being attenuated by SR141716A. We propose that CB{sub 1} receptor agonists inhibit tumor cell invasion and metastasis by modulating FAK phosphorylation, and that CB{sub 1} receptor activation might represent a novel therapeutic strategy to slow down the growth of breast carcinoma and to inhibit its metastatic diffusion in vivo.

  11. Feeding Arteries of Primary Tongue Cancers on Intra-arterial Infusion

    Office of Scientific and Technical Information (OSTI)

    Chemotherapy (Journal Article) | SciTech Connect Feeding Arteries of Primary Tongue Cancers on Intra-arterial Infusion Chemotherapy Citation Details In-Document Search Title: Feeding Arteries of Primary Tongue Cancers on Intra-arterial Infusion Chemotherapy PurposeTo evaluate the frequency and the predictive factor of each feeding artery on intra-arterial infusion chemotherapy (IAIC) in primary tongue cancer.Materials and MethodsWe retrospectively evaluated 20 patients who received IAIC for

  12. Boron-Nitride Nanotubes Show Potential in Cancer Treatment | Jefferson Lab

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    Boron-Nitride Nanotubes Show Potential in Cancer Treatment Boron-Nitride Nanotubes Show Potential in Cancer Treatment NEWPORT NEWS, VA, April 26 - A new study has shown that adding boron-nitride nanotubes to the surface of cancer cells can double the effectiveness of Irreversible Electroporation, a minimally invasive treatment for soft tissue tumors in the liver, lung, prostate, head and neck, kidney and pancreas. Although this research is in the very early stages, it could one day lead to

  13. Los Alamos turns its nuclear weapons power to war on cancer

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    Los Alamos turns its nuclear weapons power to war on cancer Los Alamos turns its nuclear weapons power to war on cancer Los Alamos Physicist Eva Birnbaum shows how the laboratory is manufacturing a radioactive treatment that targets tumors, without killing the surrounding healthy tissue. December 20, 2015 LANL physicist Eva Birnbaum LANL physicist Eva Birnbaum Los Alamos turns its nuclear weapons power to war on cancer NBC News got exclusive access to Los Alamos National Laboratory where

  14. Risk Factors Associated With Secondary Sarcomas in Childhood Cancer Survivors: A Report From the Childhood Cancer Survivor Study

    SciTech Connect (OSTI)

    Henderson, Tara O.; Rajaraman, Preetha; Stovall, Marilyn; Constine, Louis S.; Olive, Aliza; Smith, Susan A.; Mertens, Ann; Meadows, Anna; Neglia, Joseph P.; Hammond, Sue; Whitton, John; Inskip, Peter D.; Robison, Leslie L.; Diller, Lisa

    2012-09-01

    Purpose: Childhood cancer survivors have an increased risk of secondary sarcomas. To better identify those at risk, the relationship between therapeutic dose of chemotherapy and radiation and secondary sarcoma should be quantified. Methods and Materials: We conducted a nested case-control study of secondary sarcomas (105 cases, 422 matched controls) in a cohort of 14,372 childhood cancer survivors. Radiation dose at the second malignant neoplasm (SMN) site and use of chemotherapy were estimated from detailed review of medical records. Odds ratios (ORs) and 95% confidence intervals were estimated by conditional logistic regression. Excess odds ratio (EOR) was modeled as a function of radiation dose, chemotherapy, and host factors. Results: Sarcomas occurred a median of 11.8 years (range, 5.3-31.3 years) from original diagnosis. Any exposure to radiation was associated with increased risk of secondary sarcoma (OR = 4.1, 95% CI = 1.8-9.5). A dose-response relation was observed, with elevated risks at doses between 10 and 29.9 Gy (OR = 15.6, 95% CI = 4.5-53.9), 30-49.9 Gy (OR = 16.0, 95% CI 3.8-67.8) and >50 Gy (OR = 114.1, 95% CI 13.5-964.8). Anthracycline exposure was associated with sarcoma risk (OR = 3.5, 95% CI = 1.6-7.7) adjusting for radiation dose, other chemotherapy, and primary cancer. Adjusting for treatment, survivors with a first diagnosis of Hodgkin lymphoma (OR = 10.7, 95% CI = 3.1-37.4) or primary sarcoma (OR = 8.4, 95% CI = 3.2-22.3) were more likely to develop a sarcoma. Conclusions: Of the risk factors evaluated, radiation exposure was the most important for secondary sarcoma development in childhood cancer survivors; anthracycline chemotherapy exposure was also associated with increased risk.

  15. Environmental assessment for the transfer of the DP Road tract to the County of Los Alamos. Final document

    SciTech Connect (OSTI)

    1997-01-23

    The purpose of an Environmental Assessment (EA) is to provide the DOE with sufficient evidence and analysis to determine whether to prepare an Environmental Impact Statement (EIS) or a Finding of No Significant Impact (FONSI). Additional considerations (such as costs, timing, or non-environmental legal issues) that influence DOE decisions are not analyzed in this EA. As part of its initiative to fulfill its responsibilities to provide support for the County of Los Alamos (the County), in northern New Mexico, the US Department of Energy (DOE) proposes to transfer ownership of the undeveloped, so called, DP Road property to the County. Transfer of this tract would permanently reduce the size of Los Alamos National Laboratory (LANL) by approximately 0.1%. Approximately 12 hectares (28 acres) would be changed from an undeveloped to a developed status. This would result in an equivalent loss of wildlife habitat. A hypothetical accident was analyzed that evaluated potential radiological dose to the public at the DP Road tract from LANL operations. The dose to the hypothetical worker population of 450 new employees could result in an increase of approximately three latent cancer fatalities in the population. The DOE finds that there would be no significant impact from proceeding with the transfer of the 28-acre tract for development and use as a business park or for light industrial purposes.

  16. Id-1 and Id-2 genes and products as markers of epithelial cancer

    DOE Patents [OSTI]

    Desprez, Pierre-Yves; Campisi, Judith

    2008-09-30

    A method for detection and prognosis of breast cancer and other types of cancer. The method comprises detecting expression, if any, for both an Id-1 and an Id-2 genes, or the ratio thereof, of gene products in samples of breast tissue obtained from a patient. When expressed, Id-1 gene is a prognostic indicator that breast cancer cells are invasive and metastatic, whereas Id-2 gene is a prognostic indicator that breast cancer cells are localized and noninvasive in the breast tissue.

  17. Proteolytic Processing of ErbB4 in Breast Cancer (Journal Article...

    Office of Scientific and Technical Information (OSTI)

    Journal Article: Proteolytic Processing of ErbB4 in Breast Cancer Citation Details ... Publication Date: 2015-08-28 OSTI Identifier: 1188818 Resource Type: Journal Article ...

  18. Id-1 and Id-2 genes and products as markers of epithelial cancer

    DOE Patents [OSTI]

    Desprez, Pierre-Yves; Campisi, Judith

    2011-10-04

    A method for detection and prognosis of breast cancer and other types of cancer. The method comprises detecting expression, if any, for both an Id-1 and an Id-2 genes, or the ratio thereof, of gene products in samples of breast tissue obtained from a patient. When expressed, Id-1 gene is a prognostic indicator that breast cancer cells are invasive and metastatic, whereas Id-2 gene is a prognostic indicator that breast cancer cells are localized and noninvasive in the breast tissue.

  19. Bonus-- Cameras Designed To Strengthen Nuclear Security Can Also Detect Cancer

    Broader source: Energy.gov [DOE]

    Thanks to researchers from Brookhaven National Laboratory, a high-resolution gamma camera exists that can be used to detect prostate cancer.

  20. KPNA7, a nuclear transport receptor, promotes malignant properties of pancreatic cancer cells in vitro

    SciTech Connect (OSTI)

    Laurila, Eeva; Vuorinen, Elisa; Savinainen, Kimmo; Rauhala, Hanna; Kallioniemi, Anne

    2014-03-10

    Pancreatic cancer is an aggressive malignancy and one of the leading causes of cancer deaths. The high mortality rate is mostly due to the lack of appropriate tools for early detection of the disease and a shortage of effective therapies. We have previously shown that karyopherin alpha 7 (KPNA7), the newest member of the alpha karyopherin family of nuclear import receptors, is frequently amplified and overexpressed in pancreatic cancer. Here, we report that KPNA7 expression is absent in practically all normal human adult tissues but elevated in several pancreatic cancer cell lines. Inhibition of KPNA7 expression in AsPC-1 and Hs700T pancreatic cancer cells led to a reduction in cell growth and decreased anchorage independent growth, as well as increased autophagy. The cell growth effects were accompanied by an induction of the cell cycle regulator p21 and a G1 arrest of the cell cycle. Interestingly, the p21 induction was caused by increased mRNA synthesis and not defective nuclear transport. These data strongly demonstrate that KPNA7 silencing inhibits the malignant properties of pancreatic cancer cells in vitro and thereby provide the first evidence on the functional role for KPNA7 in human cancer. - Highlights: KPNA7 expression is elevated in several pancreatic cancer cell lines. KPNA7 silencing in high expressing cancer cells leads to growth inhibition. The cell growth reduction is associated with p21 induction and G1 arrest. KPNA7 silencing is also accompanied with increased autophagy.

  1. From the Cold War to the War on Cancer | National Nuclear Security...

    National Nuclear Security Administration (NNSA)

    From the Cold War to the War on Cancer | National Nuclear Security Administration Facebook Twitter Youtube Flickr RSS People Mission Managing the Stockpile Preventing Proliferation...

  2. Linkage analysis of chromosome 17q markers and breast-ovarian cancer in Icelandic families, and possible relationship to prostatic cancer

    SciTech Connect (OSTI)

    Arason, A.; Barkardottir, R.B.; Egilsson, V. )

    1993-04-01

    Seven families, selected for breast cancer segregation, have been analyzed for chromosome 17q12-q23 linkage to breast and ovarian cancer. In two of them, linkage is seen with most markers tested, increasing toward the most proximal region, but without informative recombinations above NM23. In the remaining families, no linkage is observed. Families with 17q linkage are not easily distinguished by clinical characteristics such as early onset (mean age at diagnosis [le]45 years) or organs involved. In fact, the family with the highest lod scores ([ge]2.3) belongs to the [open quotes]later onset[close quotes] (>45 years) category of families. Interestingly, prostatic cancer is the most frequent malignancy, after breast cancer, in the families that were studied (13 cases total, all metastasizing) and is especially prevalent in males presumed to carry the trait. Of 16 paternal carriers, 7 (44%) had developed prostatic cancer. Haplotype analysis in families with 17q linkage reveals two further prostatic cases as potential carriers. The authors propose that breast cancer genes may predispose to prostatic cancer in male carriers. 12 refs., 2 figs., 2 tabs.

  3. SU-D-9A-07: Imaging Dose and Cancer Risk in Image-Guided Radiotherapy of Cancers

    SciTech Connect (OSTI)

    Zhou, L; Bai, S; Zhang, Y; Ming, X; Zhang, Y; Deng, J

    2014-06-01

    Purpose: To systematically evaluate the imaging doses and cancer risks associated with various imaging procedures involving ionizing radiation during image-guided radiotherapy of an increasingly large number of cancer patients. Methods: 141 patients (52 brain cases, 47 thoracic cases, 42 abdominal cases, aged 3 to 91 years old) treated between October 2009 and March 2010 were included in this IRB-approved retrospective study. During the whole radiotherapy course, each patient underwent at least one type of imaging procedures, i.e., kV portal, MV portal and kVCBCT, besides CT simulations. Based on Monte Carlo modeling and particle transport in human anatomy of various dimensions, the correlations between the radiation doses to the various organs-at-risk (OARs) at the head, the thoracic and the abdominal regions and one's weight, circumference, scan mAs and kVp have been obtained and used to estimate the radiation dose from a specific imaging procedure. The radiation-induced excess relative risk (ERR) was then estimated with BEIR VII formulism based on one's gender, age and radiation dose. 1+ ERR was reported in this study as relative cancer risk. Results: For the whole cohort of 141 patients, the mean imaging doses from various imaging procedures were 8.3 cGy to the brain, 10.5 cGy to the lungs and 19.2 cGy to the red bone marrow, respectively. Accordingly, the cancer risks were 1.140, 1.369 and 2.671, respectively. In comparison, MV portal deposited largest doses to the lungs while kVCBCT delivered the highest doses to the red bone marrow. Conclusion: The compiled imaging doses to a patient during his/her treatment course were patient-specific and site-dependent, varying from 1.2 to 263.5 cGy on average, which were clinically significant and should be included in the treatment planning and overall decision-making. Our results indicated the necessity of personalized imaging to maximize its clinical benefits while reducing the associated cancer risks. Sichuan University Scholarship.

  4. Second cancer incidence risk estimates using BEIR VII models for standard and complex external beam radiotherapy for early breast cancer

    SciTech Connect (OSTI)

    Donovan, E. M.; James, H.; Bonora, M.; Yarnold, J. R.; Evans, P. M.

    2012-10-15

    Purpose: To compare organ specific cancer incidence risks for standard and complex external beam radiotherapy (including cone beam CT verification) following breast conservation surgery for early breast cancer.Method: Doses from breast radiotherapy and kilovoltage cone beam CT (CBCT) exposures were obtained from thermoluminescent dosimeter measurements in an anthropomorphic phantom in which the positions of radiosensitive organs were delineated. Five treatment deliveries were investigated: (i) conventional tangential field whole breast radiotherapy (WBRT), (ii) noncoplanar conformal delivery applicable to accelerated partial beast irradiation (APBI), (iii) two-volume simultaneous integrated boost (SIB) treatment, (iv) forward planned three-volume SIB, and (v) inverse-planned three volume SIB. Conformal and intensity modulated radiotherapy methods were used to plan the complex treatments. Techniques spanned the range from simple methods appropriate for patient cohorts with a low cancer recurrence risk to complex plans relevant to cohorts with high recurrence risk. Delineated organs at risk included brain, salivary glands, thyroid, contralateral breast, left and right lung, esophagus, stomach, liver, colon, and bladder. Biological Effects of Ionizing Radiation (BEIR) VII cancer incidence models were applied to the measured mean organ doses to determine lifetime attributable risk (LAR) for ages at exposure from 35 to 80 yr according to radiotherapy techniques, and included dose from the CBCT imaging. Results: All LAR decreased with age at exposure and were lowest for brain, thyroid, liver, and bladder (<0.1%). There was little dependence of LAR on radiotherapy technique for these organs and for colon and stomach. LAR values for the lungs for the three SIB techniques were two to three times those from WBRT and APBI. Uncertainties in the LAR models outweigh any differences in lung LAR between the SIB methods. Constraints in the planning of the SIB methods ensured that contralateral breast doses and LAR were comparable to WBRT, despite their added complexity. The smaller irradiated volume of the ABPI plan contributed to a halving of LAR for contralateral breast compared with the other plan types. Daily image guided radiotherapy (IGRT) for a left breast protocol using kilovoltage CBCT contributed <10% to LAR for the majority of organs, and did not exceed 22% of total organ dose. Conclusions: Phantom measurements and calculations of LAR from the BEIR VII models predict that complex breast radiotherapy techniques do not increase the theoretical risk of second cancer incidence for organs distant from the treated breast, or the contralateral breast where appropriate plan constraints are applied. Complex SIB treatments are predicted to increase the risk of second cancer incidence in the lungs compared to standard whole breast radiotherapy; this is outweighed by the threefold reduction in 5 yr local recurrence risk for patients of high risk of recurrence, and young age, from the use of radiotherapy. APBI may have a favorable impact on risk of second cancer in the contralateral breast and lung for older patients at low risk of recurrence. Intensive use of IGRTincreased the estimated values of LAR but these are dominated by the effect of the dose from the radiotherapy, and any increase in LAR from IGRT is much lower than the models' uncertainties.

  5. Hedgehog pathway regulators influence cervical cancer cell proliferation, survival and migration

    SciTech Connect (OSTI)

    Samarzija, Ivana; Beard, Peter

    2012-08-17

    Highlights: Black-Right-Pointing-Pointer Unknown cellular mutations complement papillomavirus-induced carcinogenesis. Black-Right-Pointing-Pointer Hedgehog pathway components are expressed by cervical cancer cells. Black-Right-Pointing-Pointer Hedgehog pathway activators and inhibitors regulate cervical cancer cell biology. Black-Right-Pointing-Pointer Cell immortalization by papillomavirus and activation of Hedgehog are independent. -- Abstract: Human papillomavirus (HPV) infection is considered to be a primary hit that causes cervical cancer. However, infection with this agent, although needed, is not sufficient for a cancer to develop. Additional cellular changes are required to complement the action of HPV, but the precise nature of these changes is not clear. Here, we studied the function of the Hedgehog (Hh) signaling pathway in cervical cancer. The Hh pathway can have a role in a number of cancers, including those of liver, lung and digestive tract. We found that components of the Hh pathway are expressed in several cervical cancer cell lines, indicating that there could exists an autocrine Hh signaling loop in these cells. Inhibition of Hh signaling reduces proliferation and survival of the cervical cancer cells and induces their apoptosis as seen by the up-regulation of the pro-apoptotic protein cleaved caspase 3. Our results indicate that Hh signaling is not induced directly by HPV-encoded proteins but rather that Hh-activating mutations are selected in cells initially immortalized by HPV. Sonic Hedgehog (Shh) ligand induces proliferation and promotes migration of the cervical cancer cells studied. Together, these results indicate pro-survival and protective roles of an activated Hh signaling pathway in cervical cancer-derived cells, and suggest that inhibition of this pathway may be a therapeutic option in fighting cervical cancer.

  6. Plasma Biomarker Profiles Differ Depending on Breast Cancer Subtype but RANTES is Consistently Increased

    SciTech Connect (OSTI)

    Gonzales, Rachel M.; Daly, Don S.; Tan, Ruimin; Marks, Jeffrey R.; Zangar, Richard C.

    2011-07-01

    Background: Current biomarkers for breast cancer have little potential for detection. We determined if breast cancer subtypes influence circulating protein biomarkers. Methods: A sandwich-ELISA microarray platform was used to evaluate 23 candidate biomarkers in plasma samples that were obtained from subjects with either benign breast disease or invasive breast cancer. All plasma samples were collected at the time of biopsy, after a referral due to a suspicious screen (e.g., mammography). Cancer samples were evaluated based on breast cancer subtypes, as defined by the HER2 and estrogen receptor statuses. Results: Ten proteins were statistically altered in at least one breast cancer subtype, including four epidermal growth factor receptor ligands, two matrix metalloproteases, two cytokines, and two angiogenic factors. Only one cytokine, RANTES, was significantly increased (P<0.01 for each analysis) in all four subtypes, with areas under receiver operating characteristic curves (AUC) that ranged from 0.76 to 0.82, depending on cancer subtype. The best AUC values were observed for analyses that combined data from multiple biomarkers, with values ranging from 0.70 to 0.99, depending on the cancer subtype. Although the results for RANTES are consistent with previous publications, the multi-assay results need to be validated in independent sample sets. Conclusions: Different breast cancer subtypes produce distinct biomarker profiles, and circulating protein biomarkers have potential to differentiate between true and false positive screens for breast cancer. Impact: Subtype-specific biomarker panels may be useful for detecting breast cancer or as an adjunct assay to improve the accuracy of current screening methods.

  7. Inhibitory effect of Disulfiram/copper complex on non-small cell lung cancer cells

    SciTech Connect (OSTI)

    Duan, Lincan; Shen, Hongmei; Zhao, Guangqiang; Yang, Runxiang; Cai, Xinyi; Zhang, Lijuan; Jin, Congguo; Huang, Yunchao

    2014-04-18

    Highlights: Disulfiram and copper synergistically inhibit lung cancer cell proliferation. Lung cancer cell colony formation ability is inhibited by Disulfiram/copper. Disulfiram/copper increases the sensitivity of cisplatin to lung cancer cells. Lung cancer stem cells are specifically targeted by Disulfiram/copper complex. - Abstract: Non-small cell lung cancer (NSCLC) is the most common cause of cancer-related death in both men and women worldwide. Recently, Disulfiram has been reported to be able to inhibit glioblastoma, prostate, or breast cancer cell proliferation. In this study, the synergistic effect of Disulfiram and copper on NSCLC cell growth was investigated. Inhibition of cancer cell proliferation was detected by 1-(4,5-Dimethylthiazol-2-yl)-3,5-diphenylformazan (MTT) assay and cell cycle analysis. Liquid colony formation and tumor spheroid formation assays were used to evaluate their effect on cancer cell clonogenicity. Real-time PCR was performed to test the mRNA level of cancer stem cell related genes. We found that Disulfiram or copper alone did not potently inhibit NSCLC cell proliferation in vitro. However, the presence of copper significantly enhanced inhibitory effect of Disulfiram on NSCLC cell growth, indicating a synergistic effect between Disulfiram and copper. Cell cycle analysis showed that Disulfiram/copper complex caused NSCLC cell cycle arrest in G2/M phase. Furthermore, Disulfiram/copper significantly increased the sensitivity of cisplatin in NSCLC cells tested by MTT assay. Liquid colony formation assay revealed that copper dramatically increased the inhibitory effect of Disulfiram on NSCLC cell colony forming ability. Disulfiram combined with copper significantly attenuated NSCLC cell spheroid formation and recuded the mRNA expression of lung cancer stem cell related genes. Our data suggest that Disulfiram/copper complex alone or combined with other chemotherapy is a potential therapeutic strategy for NSCLC patients.

  8. SU-E-I-39: Molecular Image Guided Cancer Stem Cells Therapy

    SciTech Connect (OSTI)

    Abdollahi, H

    2014-06-01

    Purpose: Cancer stem cells resistance to radiation is a problematic issue that has caused a big fail in cancer treatment. Methods: As a primary work, molecular imaging can indicate the main mechanisms of radiation resistance of cancer stem cells. By developing and commissioning new probes and nanomolecules and biomarkers, radiation scientist will able to identify the essential pathways of radiation resistance of cancer stem cells. As the second solution, molecular imaging is a best way to find biological target volume and delineate cancer stem cell tissues. In the other hand, by molecular imaging techniques one can image the treatment response in tumor and also in normal tissue. In this issue, the response of cancer stem cells to radiation during therapy course can be imaged, also the main mechanisms of radiation resistance and finding the best radiation modifiers (sensitizers) can be achieved by molecular imaging modalities. In adaptive radiotherapy the molecular imaging plays a vital role to have higher tumor control probability by delivering high radiation doses to cancer stem cells in any time of treatment. The outcome of a feasible treatment is dependent to high cancer stem cells response to radiation and removing all of which, so a good imaging modality can show this issue and preventing of tumor recurrence and metastasis. Results: Our results are dependent to use of molecular imaging as a new modality in the clinic. We propose molecular imaging as a new radiobiological technique to solve radiation therapy problems due to cancer stem cells. Conclusion: Molecular imaging guided cancer stem cell diagnosis and therapy is a new approach in the field of cancer treatment. This new radiobiological imaging technique should be developed in all clinics as a feasible tool that is more biological than physical imaging.

  9. Historical Trends in the Use of Radiation Therapy for Pediatric Cancers: 1973-2008

    SciTech Connect (OSTI)

    Jairam, Vikram; Roberts, Kenneth B.; Yale Cancer Center, New Haven, Connecticut; Cancer Outcomes, Public Policy, and Effectiveness Research Center at Yale, New Haven, Connecticut ; Yu, James B.

    2013-03-01

    Purpose: This study was undertaken to assess historical trends in the use of radiation therapy (RT) for pediatric cancers over the past 4 decades. Methods: The National Cancer Institute's Surveillance, Epidemiology, and End Results database of the 9 original tumor registries (SEER-9) was queried to identify patients aged 0 to 19 years with acute lymphoblastic leukemia, acute myeloid leukemia, bone and joint cancer, cancer of the brain and nervous system, Hodgkin lymphoma, neuroblastoma, non-Hodgkin lymphoma, soft tissue cancer, Wilms tumor, or retinoblastoma from 1973 to 2008. Patients were grouped into 4-year time epochs. The number and percentage of patients who received RT as part of their initial treatment were calculated per epoch by each diagnosis group from 1973 to 2008. Results: RT use for acute lymphoblastic leukemia, non-Hodgkin lymphoma, and retinoblastoma declined sharply from 57%, 57%, and 30% in 1973 to 1976 to 11%, 15%, and 2%, respectively, in 2005 to 2008. Similarly, smaller declines in RT use were also seen in brain cancer (70%-39%), bone cancer (41%-21%), Wilms tumor (75%-53%), and neuroblastoma (60%-25%). RT use curves for Wilms tumor and neuroblastoma were nonlinear with nadirs in 1993 to 1996 at 39% and 19%, respectively. There were minimal changes in RT use for Hodgkin lymphoma, soft tissue cancer, or acute myeloid leukemia, roughly stable at 72%, 40%, and 11%, respectively. Almost all patients treated with RT were given external beam RT exclusively. However, from 1985 to 2008, treatments involving brachytherapy, radioisotopes, or combination therapy increased in frequency, comprising 1.8%, 4.6%, and 11.9% of RT treatments in brain cancer, soft tissue cancer, and retinoblastoma, respectively. Conclusions: The use of RT is declining over time in 7 of 10 pediatric cancer categories. A limitation of this study is a potential under-ascertainment of RT use in the SEER-9 database including the delayed use of RT.

  10. Delineation of Supraclavicular Target Volumes in Breast Cancer Radiation Therapy

    SciTech Connect (OSTI)

    Brown, Lindsay C.; Diehn, Felix E.; Boughey, Judy C.; Childs, Stephanie K.; Park, Sean S.; Yan, Elizabeth S.; Petersen, Ivy A.; Mutter, Robert W.

    2015-07-01

    Purpose: To map the location of gross supraclavicular metastases in patients with breast cancer, in order to determine areas at highest risk of harboring subclinical disease. Methods and Materials: Patients with axial imaging of gross supraclavicular disease were identified from an institutional breast cancer registry. Locations of the metastatic lymph nodes were transferred onto representative axial computed tomography images of the supraclavicular region and compared with the Radiation Therapy Oncology Group (RTOG) breast cancer atlas for radiation therapy planning. Results: Sixty-two patients with 161 supraclavicular nodal metastases were eligible for study inclusion. At the time of diagnosis, 117 nodal metastases were present in 44 patients. Forty-four nodal metastases in 18 patients were detected at disease recurrence, 4 of whom had received prior radiation to the supraclavicular fossa. Of the 161 nodal metastases, 95 (59%) were within the RTOG consensus volume, 4 nodal metastases (2%) in 3 patients were marginally within the volume, and 62 nodal metastases (39%) in 30 patients were outside the volume. Supraclavicular disease outside the RTOG consensus volume was located in 3 regions: at the level of the cricoid and thyroid cartilage (superior to the RTOG volume), in the posterolateral supraclavicular fossa (posterolateral to the RTOG volume), and in the lateral low supraclavicular fossa (lateral to the RTOG volume). Only women with multiple supraclavicular metastases had nodal disease that extended superiorly to the level of the thyroid cartilage. Conclusions: For women with risk of harboring subclinical supraclavicular disease warranting the addition of supraclavicular radiation, coverage of the posterior triangle and the lateral low supraclavicular region should be considered. For women with known supraclavicular disease, extension of neck coverage superior to the cricoid cartilage may be warranted.

  11. Dosimetrically Triggered Adaptive Intensity Modulated Radiation Therapy for Cervical Cancer

    SciTech Connect (OSTI)

    Lim, Karen; Stewart, James; Kelly, Valerie; Xie, Jason; Brock, Kristy K.; Moseley, Joanne; Cho, Young-Bin; Fyles, Anthony; Lundin, Anna; Rehbinder, Henrik; Lf, Johan; Jaffray, David A.; Milosevic, Michael

    2014-09-01

    Purpose: The widespread use of intensity modulated radiation therapy (IMRT) for cervical cancer has been limited by internal target and normal tissue motion. Such motion increases the risk of underdosing the target, especially as planning margins are reduced in an effort to reduce toxicity. This study explored 2 adaptive strategies to mitigate this risk and proposes a new, automated method that minimizes replanning workload. Methods and Materials: Thirty patients with cervical cancer participated in a prospective clinical study and underwent pretreatment and weekly magnetic resonance (MR) scans over a 5-week course of daily external beam radiation therapy. Target volumes and organs at risk (OARs) were contoured on each of the scans. Deformable image registration was used to model the accumulated dose (the real dose delivered to the target and OARs) for 2 adaptive replanning scenarios that assumed a very small PTV margin of only 3mm to account for setup and internal interfractional motion: (1)a preprogrammed, anatomy-driven midtreatment replan (A-IMRT); and (2) a dosimetry-triggered replan driven by target dose accumulation over time (D-IMRT). Results: Across all 30 patients, clinically relevant target dose thresholds failed for 8 patients (27%) if 3-mm margins were used without replanning. A-IMRT failed in only 3 patients and also yielded an additional small reduction in OAR doses at the cost of 30 replans. D-IMRT assured adequate target coverage in all patients, with only 23 replans in 16 patients. Conclusions: A novel, dosimetry-triggered adaptive IMRT strategy for patients with cervical cancer can minimize the risk of target underdosing in the setting of very small margins and substantial interfractional motion while minimizing programmatic workload and cost.

  12. Draft Supplemental Environmental Impact Statement for the Production...

    Broader source: Energy.gov (indexed) [DOE]

    that there are 3 chances in 1 million that the associated result (for example, a fatal cancer) will occur in the period covered by the analysis. METRIC PREFIXES Prefix Symbol...

  13. Modeling the Performance of Engineered Systems for Closure and...

    Office of Environmental Management (EM)

    yr - IAEA mandatory intervention 100,000 mrem - Dose leading to 5% chance of Fatal Cancer (UNSCEAR) Graphics from NCRP Report No. 93 Typical Annual Sources of Public Exposure...

  14. Chest wall invasion by lung cancer: limitations of CT evaluation

    SciTech Connect (OSTI)

    Pennes, D.R.; Glazer, G.M.; Wimbish, K.J.; Gross, B.H.; Long, R.W.; Orringer, M.B.

    1985-03-01

    Thirty-three patients with peripheral pulmonary malignancies contiguous with a pleural surface were evaluated for chest wall invasion by computed tomography (CT). CT criteria included pleural thickening adjacent to the tumor, encroachment on or increased density of the extrapleural fat, asymmetry of the extrapleural soft tissues adjacent to the tumor, apparent mass invading the chest wall, and rib destruction. The CT scans were classified as positive, negative, or equivocal for invasion, and a decision matrix was constructed comparing CT results with pathologic data. CT scanning has low accuracy in assessing chest wall invasion in patients with peripheral lung cancers.

  15. Scanxiety: Waiting anxiously for childhood cancer test results | GE Global

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    Research Scanxiety - waiting anxiously for the results that could change your life Click to email this to a friend (Opens in new window) Share on Facebook (Opens in new window) Click to share (Opens in new window) Click to share on LinkedIn (Opens in new window) Click to share on Tumblr (Opens in new window) Scanxiety - waiting anxiously for the results that could change your life Mark Frontera 2015.09.18 September is Childhood Cancer Awareness Month and we are publishing a series of blog

  16. Fulvestrant radiosensitizes human estrogen receptor-positive breast cancer cells

    SciTech Connect (OSTI)

    Wang, Jing; Department of Oncology, Affiliated Hospital of Qingdao University Medical College, Shandong Province ; Yang, Qifeng; Haffty, Bruce G.; Li, Xiaoyan; Moran, Meena S.

    2013-02-08

    Highlights: ? Fulvestrant radiosensitizes MCF-7 cells. ? Fulvestrant increases G1 arrest and decreases S phase in MCF-7 cells. ? Fulvestrant down-regulates DNA-PKcs and RAD51 in MCF-7 cells. -- Abstract: The optimal sequencing for hormonal therapy and radiation are yet to be determined. We utilized fulvestrant, which is showing promise as an alternative to other agents in the clinical setting of hormonal therapy, to assess the cellular effects of concomitant anti-estrogen therapy (fulvestrant) with radiation (F + RT). This study was conducted to assess the effects of fulvestrant alone vs. F + RT on hormone-receptor positive breast cancer to determine if any positive or negative combined effects exist. The effects of F + RT on human breast cancer cells were assessed using MCF-7 clonogenic and tetrazolium salt colorimetric (MTT) assays. The assays were irradiated with a dose of 0, 2, 4, 6 Gy fulvestrant. The effects of F + RT vs. single adjuvant treatment alone on cell-cycle distribution were assessed using flow cytometry; relative expression of repair proteins (Ku70, Ku80, DNA-PKcs, Rad51) was assessed using Western Blot analysis. Cell growth for radiation alone vs. F + RT was 0.885 0.013 vs. 0.622 0.029 @2 Gy, 0.599 0.045 vs. 0.475 0.054 @4 Gy, and 0.472 0.021 vs. 0.380 0.018 @6 Gy RT (p = 0.003). While irradiation alone induced G2/M cell cycle arrest, the combination of F + RT induced cell redistribution in the G1 phase and produced a significant decrease in the proportion of cells in G2 phase arrest and in the S phase in breast cancer cells (p < 0.01). Furthermore, levels of repair proteins DNA-PKcs and Rad51 were significantly decreased in the cells treated with F + RT compared with irradiation alone. F + RT leads to a decrease in the surviving fraction, increased cell cycle arrest, down regulating of nonhomologous repair protein DNA-PKcs and homologous recombination repair protein RAD51. Thus, our findings suggest that F + RT increases breast cancer cell radiosensitivity compared with radiation alone. These findings have salient implications for designing clinical trials using fulvestrant and radiation therapy.

  17. Open questions: The disrupted circuitry of the cancer cell

    DOE Public Access Gateway for Energy & Science Beta (PAGES Beta)

    Wiley, H. Steven

    2014-10-18

    Every new decade of biology brings with it a change in outlook driven by new technologies and fresh perspectives. Such is the case for cancer and how we consider the disease. The advent of molecular biology led to the identification of altered signaling molecules and 'oncogenes' that were proposed to drive uncontrolled cell proliferation. The rise of cell biology and new imaging and culturing technologies led to the idea that disruptions in the extracellular environment prime cells for transformation. In the current genomics era, cancer is most commonly seen as a genetic disorder where an unstable genome gives rise tomore » a variety of different cell variants that are selected for proliferation and survival. All of these views are partially correct, of course, and are simply different ways of saying that genetic alterations in cancer cells result in a loss of growth homeostasis. They also take the view that molecular changes 'drive' a cell to grow uncontrollably, rather than tip the balance from one normal state (quiescence) to another (proliferation). Underlying this oversimplification is a profound ignorance of what controls homeostatic cell growth in the first place and how specific mutations impact it. Normal, proliferation-competent cells can accurately monitor their environment and respond appropriately to perturbation, whether it is a loss of neighbors or an inflammatory stimulus. Cancer cells either proliferate or refuse to die where and when they should not, which clearly indicates that they have problems in detecting or responding to their environment. Thus, an enormous amount of effort has gone into defining the signaling pathways that can trigger a proliferative response and the biochemical mechanisms underlying these pathways. Far less work has focused on understanding the higher-order logic of these pathways and the roles played by all of the components as part of an integrated system. In other words, we do not really understand how cells process information and make decisions and thus cannot predict how any given molecular change will alter what a cell does.« less

  18. Designer Proteins Target Epstein-Barr-Virus-Associated Cancer

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    Designer Proteins Target Epstein-Barr-Virus-Associated Cancer Print Immortality is not a good thing for cells, and in fact, cells will destroy themselves in a process called apoptosis when they are a danger to other cells. For instance, when a cell is infected by a virus it becomes an unwilling factory for the virus, which uses the cell machinery to produce ever more copies of itself. Eventually, if the cell doesn't die, it will spew all those new viruses into the bloodstream. The process of

  19. Designer Proteins Target Epstein-Barr-Virus-Associated Cancer

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    Designer Proteins Target Epstein-Barr-Virus-Associated Cancer Print Immortality is not a good thing for cells, and in fact, cells will destroy themselves in a process called apoptosis when they are a danger to other cells. For instance, when a cell is infected by a virus it becomes an unwilling factory for the virus, which uses the cell machinery to produce ever more copies of itself. Eventually, if the cell doesn't die, it will spew all those new viruses into the bloodstream. The process of

  20. Designer Proteins Target Epstein-Barr-Virus-Associated Cancer

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    Designer Proteins Target Epstein-Barr-Virus-Associated Cancer Print Immortality is not a good thing for cells, and in fact, cells will destroy themselves in a process called apoptosis when they are a danger to other cells. For instance, when a cell is infected by a virus it becomes an unwilling factory for the virus, which uses the cell machinery to produce ever more copies of itself. Eventually, if the cell doesn't die, it will spew all those new viruses into the bloodstream. The process of

  1. Designer Proteins Target Epstein-Barr-Virus-Associated Cancer

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    Designer Proteins Target Epstein-Barr-Virus-Associated Cancer Print Immortality is not a good thing for cells, and in fact, cells will destroy themselves in a process called apoptosis when they are a danger to other cells. For instance, when a cell is infected by a virus it becomes an unwilling factory for the virus, which uses the cell machinery to produce ever more copies of itself. Eventually, if the cell doesn't die, it will spew all those new viruses into the bloodstream. The process of

  2. Radioimmunotoxin Therapy of Experimental Colon and Ovarian Cancer

    SciTech Connect (OSTI)

    Buchsbaum, Donald J.; Vallera, Daniel A.

    2006-02-09

    To pursue the development of radiolabeled immunotoxins (RIT) for colon cancer, it was first necessary to identify an immunotoxin (IT) that could selectively kill colon cancer cell lines. Recently, our collaborators in the Vallera laboratory have observed that potent recombinant IT can be synthesized using recombinant single chain antibodies (sFv) spliced to truncated diphtheria toxin (DT) consisting of the first 390 amino acids of native DT. DT was chosen as a toxin because it is a catalytic bacterial toxin that is easily manipulated in genetic engineering studies. Also, the Vallera lab has developed new procedures for preparing the sFv fusion toxins from bacterial inclusion bodies such as DT and another good genetic engineering toxin pseudomonas exotoxin (PE) based on detergent refolding. This allows for enhanced yields and higher purity that is essential for generating the protein that will be needed for preparation of larger amounts of RIT for therapy. Many potential sFvs were considered for targeting colon cancer. The best results have been obtained with an sFv recognizing EpCam. EpCam, also known as ESA or EGP40, is a 40 kDa epithelial transmembrane glycoprotein found on the basolateral surface of simple, pseudostratified, and transitional epithelia. It has been found overexpressed on 81% of adenocarcinomas of the colon (Went et al. Human pathology 35:122, 2004). EpCam sliced to DT (DTEpCam) was highly potent in studies in which we measured its ability to inhibit the proliferation of the HT-29 and COLO 205 colon cancer cell lines since we measured its IC50 at 1-2 x 10-2 nM. Potency is important, but is also critical that DTEpCam is selective in its cytotoxicity against EpCam-expressing target colon cancer cells. The activity of DTEpCam was highly selective since irrelevant control IT that did not recognize any markers on cancer cells, did not show any activity against the same colon cancer cell lines. Also, blocking studies were performed in which DTEpCam was mixed with the EpCam sFv that was synthesized without any toxin attached. The proliferation studies showed that EpCam sFv was able to block the killing of the EpCam expressing cells by DTEpCam. An irrelevant control protein, 1D10Fc was unable to block. Together, these studies indicated that EpCam was exquisitely selective. In order to produce an IT of even greater potency, we used a toxin containing the Golgi retention sequence KDEL. The same EpCam sFv was spliced to truncated PE containing the terminal KDEL sequence. The addition of KDEL enhanced the potency of the EpCam sFv IT at least 6 logs or 1000-fold with an IC50 of 2 to 7 x 10-8 nM. This conjugate was also shown to be highly selective. Taken together, all of these studies indicate that in vitro experiments have shown that we have a highly potent IT that selectively kills colon cancer cells. The next step was to show that the EpCam IT had the ability to inhibit the growth of flank tumors in vivo in nude mice. The same human colon tumor cells, HT29 used in the in vitro studies were injected into the flank of nude mice. Tumor cells were injected into groups of mice and when tumors reached the size of 0.5 cm3, we injected our best-performing EpCam IT called EpCamKDEL intratumorally. There was a significant drop in tumor size indicating that this agent was very effective against human colon cancer. Since the EpCamKDEL was injected intratumorally, it did not have to travel through the systemic circulation to find its target. Our next step will be to inject EpCamKDEL intravenously into mice with flank tumors to determine if EpCamKDEL has the ability to migrate to the tumor systemically. The next step was to radiolabel EpCamKDEL to see whether it could serve as an RIT. We radiolabeled EpCam with 111In as a surrogate for 90Y and then incubated it with HT29. The labeling efficiency was over 90% indicating that a high percentage of the protein molecules could be readily radiolabeled. However, the immunoreactivity was only 20% indicating that only 20% of those molecules were able to specifically bind antigen once t

  3. Prediction of epigenetically regulated genes in breast cancer cell lines

    SciTech Connect (OSTI)

    Loss, Leandro A; Sadanandam, Anguraj; Durinck, Steffen; Nautiyal, Shivani; Flaucher, Diane; Carlton, Victoria EH; Moorhead, Martin; Lu, Yontao; Gray, Joe W; Faham, Malek; Spellman, Paul; Parvin, Bahram

    2010-05-04

    Methylation of CpG islands within the DNA promoter regions is one mechanism that leads to aberrant gene expression in cancer. In particular, the abnormal methylation of CpG islands may silence associated genes. Therefore, using high-throughput microarrays to measure CpG island methylation will lead to better understanding of tumor pathobiology and progression, while revealing potentially new biomarkers. We have examined a recently developed high-throughput technology for measuring genome-wide methylation patterns called mTACL. Here, we propose a computational pipeline for integrating gene expression and CpG island methylation profles to identify epigenetically regulated genes for a panel of 45 breast cancer cell lines, which is widely used in the Integrative Cancer Biology Program (ICBP). The pipeline (i) reduces the dimensionality of the methylation data, (ii) associates the reduced methylation data with gene expression data, and (iii) ranks methylation-expression associations according to their epigenetic regulation. Dimensionality reduction is performed in two steps: (i) methylation sites are grouped across the genome to identify regions of interest, and (ii) methylation profles are clustered within each region. Associations between the clustered methylation and the gene expression data sets generate candidate matches within a fxed neighborhood around each gene. Finally, the methylation-expression associations are ranked through a logistic regression, and their significance is quantified through permutation analysis. Our two-step dimensionality reduction compressed 90% of the original data, reducing 137,688 methylation sites to 14,505 clusters. Methylation-expression associations produced 18,312 correspondences, which were used to further analyze epigenetic regulation. Logistic regression was used to identify 58 genes from these correspondences that showed a statistically signifcant negative correlation between methylation profles and gene expression in the panel of breast cancer cell lines. Subnetwork enrichment of these genes has identifed 35 common regulators with 6 or more predicted markers. In addition to identifying epigenetically regulated genes, we show evidence of differentially expressed methylation patterns between the basal and luminal subtypes. Our results indicate that the proposed computational protocol is a viable platform for identifying epigenetically regulated genes. Our protocol has generated a list of predictors including COL1A2, TOP2A, TFF1, and VAV3, genes whose key roles in epigenetic regulation is documented in the literature. Subnetwork enrichment of these predicted markers further suggests that epigenetic regulation of individual genes occurs in a coordinated fashion and through common regulators.

  4. Id-1 gene and gene products as therapeutic targets for treatment of breast cancer and other types of carcinoma

    DOE Patents [OSTI]

    Desprez, Pierre-Yves; Campisi, Judith

    2014-08-19

    A method for treatment of breast cancer and other types of cancer. The method comprises targeting and modulating Id-1 gene expression, if any, for the Id-1 gene, or gene products in breast or other epithelial cancers in a patient by delivering products that modulate Id-1 gene expression. When expressed, Id-1 gene is a prognostic indicator that cancer cells are invasive and metastatic.

  5. Genetic heterogeneity and localization of a familial breast-ovarian cancer gene on chromosome 17q12-q21

    SciTech Connect (OSTI)

    Smith, S.A.; Ponder, M.; Pye, C.; Ponder, B.A.J. ); Easton, D.F.; Ford, D.; Peto, J.; Anderson, K.; Averill, D.; Stratton, M. )

    1993-04-01

    In a study of 31 breast cancer families and 12 breast-ovarian cancer families, we have obtained clear evidence of linkage to markers on chromosome 17q in the families with ovarian cancer (maximum lod score 3.34 at [theta] = .04) but only weak evidence in those without ovarian cancer. Recombinant events indicate that the gene lies between D17S588 and D17S250. 9 refs., 2 figs., 4 tabs.

  6. Atractylenolide I-mediated Notch pathway inhibition attenuates gastric cancer stem cell traits

    SciTech Connect (OSTI)

    Ma, Li; Mao, Rurong; Shen, Ke; Zheng, Yuanhong; Li, Yueqi; Liu, Jianwen; Ni, Lei

    2014-07-18

    Highlights: This paper supports the anti-tumor effects of AT-I on gastric cancer in vitro. AT-I attenuates gastric cancer stem cell traits. It is the systematic study regarding AT-I suppression of Notch pathway in GC and GCSLCs. - Abstract: Atractylenolide I (AT-I), one of the main naturally occurring compounds of Rhizoma Atractylodis Macrocephalae, has remarkable anti-cancer effects on various cancers. However, its effects on the treatment of gastric cancer remain unclear. Via multiple cellular and molecular approaches, we demonstrated that AT-I could potently inhibit cancer cell proliferation and induce apoptosis through inactivating Notch pathway. AT-I treatment led to the reduction of expressions of Notch1, Jagged1, and its downstream Hes1/ Hey1. Our results showed that AT-I inhibited the self-renewal capacity of gastric stem-like cells (GCSLCs) by suppression of their sphere formation capacity and cell viability. AT-I attenuated gastric cancer stem cell (GCSC) traits partly through inactivating Notch1, leading to reducing the expressions of its downstream target Hes1, Hey1 and CD44 in vitro. Collectively, our results suggest that AT-I might develop as a potential therapeutic drug for the treatment of gastric cancer.

  7. Zodiac: A Comprehensive Depiction of Genetic Interactions in Cancer by Integrating TCGA Data

    SciTech Connect (OSTI)

    Zhu, Yitan; Xu, Yanxun; Helseth, Donald L.; Gulukota, Kamalakar; Yang, Shengjie; Pesce, Lorenzo L.; Mitra, Riten; Muller, Peter; Sengupta, Subhajit; Guo, Wentian; Foster, Ian; Bullock, JaQuel A.

    2015-08-01

    Background: Genetic interactions play a critical role in cancer development. Existing knowledge about cancer genetic interactions is incomplete, especially lacking evidences derived from large-scale cancer genomics data. The Cancer Genome Atlas (TCGA) produces multimodal measurements across genomics and features of thousands of tumors, which provide an unprecedented opportunity to investigate the interplays of genes in cancer. Methods: We introduce Zodiac, a computational tool and resource to integrate existing knowledge about cancer genetic interactions with new information contained in TCGA data. It is an evolution of existing knowledge by treating it as a prior graph, integrating it with a likelihood model derived by Bayesian graphical model based on TCGA data, and producing a posterior graph as updated and data-enhanced knowledge. In short, Zodiac realizes “Prior interaction map + TCGA data → Posterior interaction map.” Results: Zodiac provides molecular interactions for about 200 million pairs of genes. All the results are generated from a big-data analysis and organized into a comprehensive database allowing customized search. In addition, Zodiac provides data processing and analysis tools that allow users to customize the prior networks and update the genetic pathways of their interest. Zodiac is publicly available at www.compgenome.org/ZODIAC. Conclusions: Zodiac recapitulates and extends existing knowledge of molecular interactions in cancer. It can be used to explore novel gene-gene interactions, transcriptional regulation, and other types of molecular interplays in cancer.

  8. Anti-cancer agents based on 6-trifluoromethoxybenzimidazole derivatives and method of making

    DOE Patents [OSTI]

    Gakh, Andrei A; Vovk, Mykhaylo V; Mel'nychenko, Nina V; Sukach, Volodymyr A

    2012-10-23

    The present disclosure relates to novel compounds having the structural Formulas (1a,1b), stereoisomers, tautomers, racemics, prodrugs, metabolites thereof, or pharmaceutically acceptable salt and/or solvate thereof as chemotherapy agents for treating of cancer, particularly androgen-independent prostate cancer. The disclosure also relates to methods for preparing said compounds, and to pharmaceutical compositions comprising said compounds.

  9. An association between the risk of ovarian cancer and rare HRAS1 alleles

    SciTech Connect (OSTI)

    Weitzel, J.N.; Patel, J.; Smith, D.M.

    1994-09-01

    The highly polymorphic HRAS1 minisatellite locus just downstream from the proto-oncogene H-ras-1 on chromosome 11p consists of four common progenitor alleles and several dozen rare alleles, which apparently derive from mutations of the progenitors. Mutant alleles of this locus represent a major risk factor for common types of cancer. Rare-sized HRAS1 alleles have been found more frequently in patients with carcinoma of the breast, colorectum, and urinary bladder and acute leukemia, compared to cancer-free controls. This highly significant association (p<1.001) results in a modest relative risk for patients with one rare allele, but the prevalence of this class of mutant alleles implies an important attributable risk: 1 in 11 cancers of the breast, colorectum, and bladder. Therefore, we performed a case-control study using conventional (Southern blot) and PCR-based methods to score HRAS1 alleles in the leukocyte DNA from 59 patients with ovarian cancer, and 51 cancer-free controls. Our preliminary data suggest an increased incidence of rare and intermediate HRAS1 alleles in caucasian ovarian cancer patients (13%) compared to cancer-free controls (4%). These results parallel the allele distribution seen in the large published series, and lend support for a significant association between rare HRAS1 alleles and ovarian cancer predisposition.

  10. Receptor tyrosine kinase EphA5 is a functional molecular target in human lung cancer

    DOE Public Access Gateway for Energy & Science Beta (PAGES Beta)

    Staquicini, Fernanda I.; Qian, Ming D.; Salameh, Ahmad; Dobroff, Andrey S.; Edwards, Julianna K.; Cimino, Daniel F.; Moeller, Benjamin J.; Kelly, Patrick; Nunez, Maria I.; Tang, Ximing; et al

    2015-03-20

    Lung cancer is often refractory to radiotherapy, but molecular mechanisms of tumor resistance remain poorly defined. Here we show that the receptor tyrosine kinase EphA5 is specifically overexpressed in lung cancer and is involved in regulating cellular responses to genotoxic insult. In the absence of EphA5, lung cancer cells displayed a defective G1/S cell cycle checkpoint, were unable to resolve DNA damage, and became radiosensitive. Upon irradiation, EphA5 was transported into the nucleus where it interacted with activated ATM (ataxia-telangiectasia mutated) at sites of DNA repair. In conclusion, we demonstrate that a new monoclonal antibody against human EphA5 sensitized lungmore » cancer cells and human lung cancer xenografts to radiotherapy and significantly prolonged survival, thus suggesting the likelihood of translational applications.« less

  11. Receptor tyrosine kinase EphA5 is a functional molecular target in human lung cancer

    SciTech Connect (OSTI)

    Staquicini, Fernanda I.; Qian, Ming D.; Salameh, Ahmad; Dobroff, Andrey S.; Edwards, Julianna K.; Cimino, Daniel F.; Moeller, Benjamin J.; Kelly, Patrick; Nunez, Maria I.; Tang, Ximing; Liu, Diane D.; Lee, J. Jack; Hong, Waun Ki; Ferrara, Fortunato; Bradbury, Andrew R. M.; Lobb, Roy R.; Edelman, Martin J.; Sidman, Richard L.; Wistuba, Ignacio I.; Arap, Wadih; Pasqualini, Renata

    2015-03-20

    Lung cancer is often refractory to radiotherapy, but molecular mechanisms of tumor resistance remain poorly defined. Here we show that the receptor tyrosine kinase EphA5 is specifically overexpressed in lung cancer and is involved in regulating cellular responses to genotoxic insult. In the absence of EphA5, lung cancer cells displayed a defective G1/S cell cycle checkpoint, were unable to resolve DNA damage, and became radiosensitive. Upon irradiation, EphA5 was transported into the nucleus where it interacted with activated ATM (ataxia-telangiectasia mutated) at sites of DNA repair. In conclusion, we demonstrate that a new monoclonal antibody against human EphA5 sensitized lung cancer cells and human lung cancer xenografts to radiotherapy and significantly prolonged survival, thus suggesting the likelihood of translational applications.

  12. miR-30a suppresses breast cancer cell proliferation and migration by targeting Eya2

    SciTech Connect (OSTI)

    Fu, Jing; Xu, Xiaojie; Kang, Lei; Zhou, Liying; Wang, Shibin; Lu, Juming; Cheng, Long; Fan, Zhongyi; Yuan, Bin; Tian, Peirong; Zheng, Xiaofei; Yu, Chengze; Ye, Qinong; Lv, Zhaohui

    2014-03-07

    Highlights: miR-30a represses Eya2 expression by binding to the 3?-untranslated region of Eya2. The miR-30a/EYA2 axis regulates breast cancer cell proliferation and migration. The miR-30a/EYA2 axis modulates G1/S cell cycle progression. The miR-30a/EYA2 axis is dysregulated in breast cancer patients. - Abstract: Eye absent (Eya) proteins are involved in cell fate determination in a broad spectrum of cells and tissues. Aberrant expression of Eya2 has been documented in a variety of cancers and correlates with clinical outcome. However, whether microRNAs (miRNAs) can regulate Eya2 expression remains unknown. Here, we show that miR-30a represses Eya2 expression by binding to the 3?-untranslated region of Eya2. Overexpression of Eya2 in miR-30a-transfected breast cancer cells effectively rescued the inhibition of cell proliferation and migration caused by miR-30a. Knockdown of Eya2 by small-interfering RNA (siRNA) in breast cancer cells mimicked the effect induced by miR-30a and abolished the ability of miR-30a to regulate breast cancer cell proliferation and migration. The miR-30a/Eya2 axis could regulate G1/S cell cycle progression, accompanied by the modulation of expression of cell cycle-related proteins, including cyclin A, cyclin D1, cyclin E, and c-Myc. Moreover, miR-30a expression was downregulated in breast cancer patients, and negatively correlated with Eya2, which was upregulated in breast cancer patients. These data suggest that the miR-30a/Eya2 axis may play an important role in breast cancer development and progression and that miR-30a activation or Eya2 inhibition may be a useful strategy for cancer treatment.

  13. miRNA-205 affects infiltration and metastasis of breast cancer

    SciTech Connect (OSTI)

    Wang, Zhouquan; Department of Tumor, SenGong Hospital of Shaanxi, Xian 710300 ; Liao, Hehe; Deng, Zhiping; Yang, Po; Du, Ning; Zhanng, Yunfeng; Ren, Hong

    2013-11-08

    Highlights: We detected expression of miR-205 in breast cancer cell lines and tissue samples. We suggest miR-205 is downregulated in human breast cancer tissues and MCF7 cells. We suggest the lower expression of miR-205 play a role in breast cancer onset. These data suggest that miR-205 directly targets HER3 in human breast cancer. -- Abstract: Background: An increasing number of studies have shown that miRNAs are commonly deregulated in human malignancies, but little is known about the function of miRNA-205 (miR-205) in human breast cancer. The present study investigated the influence of miR-205 on breast cancer malignancy. Methods: The expression level of miR-205 in the MCF7 breast cancer cell line was determined by quantitative (q)RT-PCR. We then analyzed the expression of miR-205 in breast cancer and paired non-tumor tissues. Finally, the roles of miR-205 in regulating tumor proliferation, apoptosis, migration, and target gene expression were studied by MTT assay, flow cytometry, qRT-PCR, Western blotting and luciferase assay. Results: miR-205 was downregulated in breast cancer cells or tissues compared with normal breast cell lines or non-tumor tissues. Overexpression of miR-205 reduced the growth and colony-formation capacity of MCF7 cells by inducing apoptosis. Overexpression of miR-205 inhibited MCF7 cell migration and invasiveness. By bioinformation analysis, miR-205 was predicted to bind to the 3? untranslated regions of human epidermal growth factor receptor (HER)3 mRNA, and upregulation of miR-205 reduced HER3 protein expression. Conclusion: miR-205 is a tumor suppressor in human breast cancer by post-transcriptional inhibition of HER3 expression.

  14. Organic cation secretion by Cancer borealis urinary bladder

    SciTech Connect (OSTI)

    Miller, D.S.; Holliday, C.W.

    1987-01-01

    In the crab, Cancer borealis, initial clearance studies showed a potent renal excretory system for the model organic cation, tetraethylammonium (TEA). (/sup 14/C)-TEA clearance averaged 145 +/- 32 ml/day, which was 18 times the paired polyethylene glycol clearance. TEA uptake by slices of urinary bladder was concentrative, saturable, inhibitable by N/sup 1/-methylnicotinamide chloride, and dependent on glycolytic, but not oxidative, metabolism. When mounted in flux chambers, bladders exhibited a large net secretory flux. For 0.1 mM TEA, the ratio of secretory to reabsorptive fluxes was 65. Urinary bladders from another crab, Cancer irroratus, and a lobster, Homarus americanus, also exhibited net TEA secretion. In C. borealis bladder, secretory transport was concentrative, saturable, and nearly abolished by addition of 1 mM quinine to the serosol bath. Reabsorptive transport was not concentrative and was not reduced by luminal quinine. The data are consistent with a secretory pathway that is transcellular and mediated by carriers at both the serosal and luminal membranes.

  15. Bispecific Antibody Pretargeting for Improving Cancer Imaging and Therapy

    SciTech Connect (OSTI)

    Sharkey, Robert M.

    2005-02-04

    The main objective of this project was to evaluate pretargeting systems that use a bispecific antibody (bsMAb) to improve the detection and treatment of cancer. A bsMAb has specificity to a tumor antigen, which is used to bind the tumor, while the other specificity is to a peptide that can be radiolabeled. Pretargeting is the process by which the unlabeled bsMAb is given first, and after a sufficient time (1-2 days) is given for it to localize in the tumor and clear from the blood, a small molecular weight radiolabeled peptide is given. According to a dynamic imaging study using a 99mTc-labeled peptide, the radiolabeled peptide localizes in the tumor in less than 1 hour, with > 80% of it clearing from the blood and body within this same time. Tumor/nontumor targeting ratios that are nearly 50 times better than that with a directly radiolabeled Fab fragment have been observed (Sharkey et al., ''Signal amplification in molecular imaging by a multivalent bispecific nanobody'' submitted). The bsMAbs used in this project have been composed of 3 antibodies that will target antigens found in colorectal and pancreatic cancers (CEA, CSAp, and MUC1). For the ''peptide binding moiety'' of the bsMAb, we initially examined an antibody directed to DOTA, but subsequently focused on another antibody directed against a novel compound, HSG (histamine-succinyl-glycine).

  16. PIK3CA is implicated as an oncogene in ovarian cancer

    SciTech Connect (OSTI)

    Shayesteh, Laleh; Lu, Yiling; Kuo, Wen-Lin; Baldocchi, Russell; Godfrey, Tony; Collins, Colin; Pinkel, Daniel; Powell, Bethan; Mills,Gordon B.; Gray, Joe W.

    1998-03-25

    Ovarian cancer is the leading cause of death from gynecological malignancy and the fourth leading cause of cancer death among American women, yet little is known about its molecular aetiology. Studies using comparative genomic hybridization (CGH) have revealed several regions of recurrent, abnormal, DNA sequence copy number that may encode genes involved in the genesis or progression of the disease. One region at 3q26 found to be increased in copy number in approximately 40 percent of ovarian and other cancers contains PIK3CA, which encodes the p110 a catalytic subunit of phosphatidylinositol 3-kinase(PI3-kinase). The association between PIK3CA copy number and PI3-kinase activity makes PIK3CA a candidate oncogene because a broad range of cancer-related functions have been associated with PI3-kinase mediated signaling. These include proliferation, glucose transport and catabolism, cell adhesion, apoptosis, RAS signaling and oncogenic transformation. In addition, downstream effectors of PI3-kinase,AKT1 and AKT2, have been found to be amplified or activated in human tumors, including ovarian cancer. We show here that PIK3CA is frequently increased in copy number in ovarian cancers, that the increased copy number is associated with increased PIK3CA transcription, p110 a protein expression and PI3-kinase activity and that treatment with the PI3-kinase inhibitor LY294002 decreases proliferation and increases apoptosis. Our observations suggest PIK3CA is an oncogene that has an important role in ovarian cancer.

  17. Anti-cancer effect of bee venom toxin and melittin in ovarian cancer cells through induction of death receptors and inhibition of JAK2/STAT3 pathway

    SciTech Connect (OSTI)

    Jo, Miran; Park, Mi Hee; Kollipara, Pushpa Saranya; An, Byeong Jun; Song, Ho Sueb; Han, Sang Bae; Kim, Jang Heub; Song, Min Jong; Hong, Jin Tae

    2012-01-01

    We investigated whether bee venom and melittin, a major component of bee venom, inhibit cell growth through enhancement of death receptor expressions in the human ovarian cancer cells, SKOV3 and PA-1. Bee venom (15 ?g/ml) and melittin (0.52 ?g/ml) inhibited the growth of SKOV3 and PA-1 ovarian cancer cells by the induction of apoptotic cell death in a dose dependent manner. Consistent with apoptotic cell death, expression of death receptor (DR) 3 and DR6 was increased in both cancer cells, but expression of DR4 was increased only in PA-1 cells. Expression of DR downstream pro-apoptotic proteins including caspase-3, 8, and Bax was concomitantly increased, but the phosphorylation of JAK2 and STAT3 and the expression of Bcl-2 were inhibited by treatment with bee venom and melittin in SKOV3 and PA-1 cells. Expression of cleaved caspase-3 was increased in SKOV3, but cleaved caspase-8 was increased in PA-1 cells. Moreover, deletion of DR3, DR4, and DR6 by small interfering RNA significantly reversed bee venom and melittin-induced cell growth inhibitory effect as well as down regulation of STAT3 by bee venom and melittin in SKOV3 and PA-1 ovarian cancer cell. These results suggest that bee venom and melittin induce apoptotic cell death in ovarian cancer cells through enhancement of DR3, DR4, and DR6 expression and inhibition of STAT3 pathway. -- Highlights: ? Some studies have showed that bee venom and/or melittin have anti-cancer effects. ? We found that bee venom and melittin inhibited cell growth in ovarian cancer cells. ? Bee venom and melittin induce apoptosis in SKOV3 and PA-1.

  18. Treatment of HER2-Expressing Breast Cancer and Ovarian Cancer Cells With Alpha Particle-Emitting {sup 227}Th-Trastuzumab

    SciTech Connect (OSTI)

    Heyerdahl, Helen; Krogh, Cecilie; Borrebaek, Jorgen; Larsen, Asmund; Dahle, Jostein

    2011-02-01

    Purpose: To evaluate the cytotoxic effects of low-dose-rate alpha particle-emitting radioimmunoconjugate {sup 227}Th-p-isothiocyanato-benzyl-DOTA-trastuzumab ({sup 227}Th-trastuzumab [where DOTA is 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid]) internalized by breast and ovarian cancer cell lines in order to assess the potential of {sup 227}Th-trastuzumab as a therapeutic agent against metastatic cancers that overexpress the HER2 oncogene. Methods and Materials: Clonogenic survival and cell growth rates of breast cancer cells treated with {sup 227}Th-trastuzumab were compared with rates of cells treated with nonbinding {sup 227}Th-rituximab, cold trastuzumab, and X-radiation. Cell growth experiments were also performed with ovarian cancer cells. Cell-associated radioactivity was measured at several time points, and the mean radiation dose to cells was calculated. Results: SKBR-3 cells got 50% of the mean absorbed radiation dose from internalized activity and 50% from cell surface-bound activity, while BT-474 and SKOV-3 cells got 75% radiation dose from internalized activity and 25% from cell surface-bound activity. Incubation of breast cancer cells with 2.5 kBq/ml {sup 227}Th-trastuzumab for 1 h at 4{sup o}C, followed by washing, resulted in mean absorbed radiation doses of 2 to 2.5 Gy. A dose-dependent inhibition of cell growth and an increase in apoptosis were induced in all cell lines. Conclusions: Clinically relevant activity concentrations of {sup 227}Th-trastuzumab induced a specific cytotoxic effect in three HER2-expressing cell lines. The cytotoxic effect of {sup 227}Th-trastuzumab was higher than that of single-dose X-radiation (relative biological effectiveness = 1.2). These results warrant further studies of treatment of breast cancer and ovarian cancer with {sup 227}Th-trastuzumab.

  19. Familial site-specific Ovarian cancer is linked to BRCA1 on 17q12-21

    SciTech Connect (OSTI)

    Steichen-Gersdorf, E.; Gallion, H.H.; Ponder, M.A.; Pye, C.; Mazoyer, S.; Smith, S.A.; Ponder, B.A.J.; Ford, D.; Easton, D.F.; Girodet, C.

    1994-11-01

    In a study of nine families with {open_quotes}site-specific{close_quotes} ovarian cancer (criterion: three or more cases of epithelial ovarian cancer and no cases of breast cancer diagnosed at age <50 years) we have obtained evidence of linkage to the breast-ovarian cancer susceptibility gene, BRCA1 on 17q12-21. If the risk of cancer in these families is assumed to be restricted to the ovary, the best estimate of the proportion of families linked to BRCA1 is .78 (95% confidence interval .32-1.0). If predisposition to both breast and ovarian cancer is assumed, the proportion linked is 1.0 (95% confidence interval .46-1.0). The linkage of familial site-specific ovarian cancer to BRCA1 indicates the possibility of predictive testing in such families; however, this is only appropriate in families where the evidence for linkage to BRCA1 is conclusive. 17 refs., 3 figs., 1 tab.

  20. Differential expression of nanog1 and nanogp8 in colon cancer cells

    SciTech Connect (OSTI)

    Ishiguro, Tatsuya; Sato, Ai; Ohata, Hirokazu; Sakai, Hiroaki; Nakagama, Hitoshi; Okamoto, Koji

    2012-02-10

    Highlights: Black-Right-Pointing-Pointer Nanog is expressed in a majority of colon cancer cell lines examined. Black-Right-Pointing-Pointer Both nanog1 and nanogp8 are expressed in colon cancer cells with varying ratios. Black-Right-Pointing-Pointer Nanog mediates cell proliferation of colon cancer cells. Black-Right-Pointing-Pointer Nanog predominantly localizes in cytoplasm of colon cancer cells. -- Abstract: Nanog, a homeodomain transcription factor, is an essential regulator for promotion of self-renewal of embryonic stem cells and inhibition of their differentiation. It has been demonstrated that nanog1 as well as nanogp8, a retrogene of nanog1, is preferentially expressed in advanced stages of several types of cancer, suggesting their involvement during cancer progression. Here, we investigated the expression of Nanog in well-characterized colon cancer cell lines. Expression of Nanog was detectable in 5 (HCT116, HT29, RKO, SW48, SW620) out of seven cell lines examined. RNA expression analyses of nanog1 and nanogp8 indicated that, while nanog1 was a major form in SW620 as well as in teratoma cells Tera-2, nanogp8 was preferentially expressed in HT29 and HCT116. In accordance with this, shRNA-mediated knockdown of nanog1 caused the reduction of Nanog in SW620 but not in HT29. Inhibition of Nanog in SW620 cells negatively affected cell proliferation and tumor formation in mouse xenograft. Biochemical subcellular fractionation and immunostaining analyses revealed predominant localization of Nanog in cytoplasm in SW620 and HT29, while it was mainly localized in nucleus in Tera-2. Our data indicate that nanog1 and nanogp8 are differentially expressed in colon cancer cells, and suggest that their expression contributes to proliferation of colon cancer cells.

  1. Matrigel Basement Membrane Matrix influences expression of microRNAs in cancer cell lines

    SciTech Connect (OSTI)

    Price, Karina J.; School of Medicine and Pharmacology, University of Western Australia, Nedlands, WA 6008 ; Tsykin, Anna; School of Molecular and Biomedical Science, University of Adelaide, Adelaide, SA 5005 ; Giles, Keith M.; Sladic, Rosemary T.; Epis, Michael R.; Ganss, Ruth; Goodall, Gregory J.; School of Molecular and Biomedical Science, University of Adelaide, Adelaide, SA 5005; Department of Medicine, University of Adelaide, Adelaide, SA 5005 ; Leedman, Peter J.

    2012-10-19

    Highlights: Black-Right-Pointing-Pointer Matrigel alters cancer cell line miRNA expression relative to culture on plastic. Black-Right-Pointing-Pointer Many identified Matrigel-regulated miRNAs are implicated in cancer. Black-Right-Pointing-Pointer miR-1290, -210, -32 and -29b represent a Matrigel-induced miRNA signature. Black-Right-Pointing-Pointer miR-32 down-regulates Integrin alpha 5 (ITGA5) mRNA. -- Abstract: Matrigel is a medium rich in extracellular matrix (ECM) components used for three-dimensional cell culture and is known to alter cellular phenotypes and gene expression. microRNAs (miRNAs) are small, non-coding RNAs that regulate gene expression and have roles in cancer. While miRNA profiles of numerous cell lines cultured on plastic have been reported, the influence of Matrigel-based culture on cancer cell miRNA expression is largely unknown. This study investigated the influence of Matrigel on the expression of miRNAs that might facilitate ECM-associated cancer cell growth. We performed miRNA profiling by microarray using two colon cancer cell lines (SW480 and SW620), identifying significant differential expression of miRNAs between cells cultured in Matrigel and on plastic. Many of these miRNAs have previously been implicated in cancer-related processes. A common Matrigel-induced miRNA signature comprised of up-regulated miR-1290 and miR-210 and down-regulated miR-29b and miR-32 was identified using RT-qPCR across five epithelial cancer cell lines (SW480, SW620, HT-29, A549 and MDA-MB-231). Experimental modulation of these miRNAs altered expression of their known target mRNAs involved in cell adhesion, proliferation and invasion, in colon cancer cell lines. Furthermore, ITGA5 was identified as a novel putative target of miR-32 that may facilitate cancer cell interactions with the ECM. We propose that culture of cancer cell lines in Matrigel more accurately recapitulates miRNA expression and function in cancer than culture on plastic and thus is a valuable approach to the in vitro study of miRNAs.

  2. Connecting Genomic Alterations to Cancer Biology with Proteomics: The NCI Clinical Proteomic Tumor Analysis Consortium

    SciTech Connect (OSTI)

    Ellis, Matthew; Gillette, Michael; Carr, Steven A.; Paulovich, Amanda G.; Smith, Richard D.; Rodland, Karin D.; Townsend, Reid; Kinsinger, Christopher; Mesri, Mehdi; Rodriguez, Henry; Liebler, Daniel

    2013-10-03

    The National Cancer Institute (NCI) Clinical Proteomic Tumor Analysis Consortium is applying the latest generation of proteomic technologies to genomically annotated tumors from The Cancer Genome Atlas (TCGA) program, a joint initiative of the NCI and the National Human Genome Research Institute. By providing a fully integrated accounting of DNA, RNA, and protein abnormalities in individual tumors, these datasets will illuminate the complex relationship between genomic abnormalities and cancer phenotypes, thus producing biologic insights as well as a wave of novel candidate biomarkers and therapeutic targets amenable to verifi cation using targeted mass spectrometry methods.

  3. Chemoradiotherapeutic wrinkled mesoporous silica nanoparticles for use in cancer therapy

    SciTech Connect (OSTI)

    Munaweera, Imalka; Balkus, Kenneth J. Jr. E-mail: Anthony.DiPasqua@unthsc.edu; Koneru, Bhuvaneswari; Shi, Yi; Di Pasqua, Anthony J. E-mail: Anthony.DiPasqua@unthsc.edu

    2014-11-01

    Over the last decade, the development and application of nanotechnology in cancer detection, diagnosis, and therapy have been widely reported. Engineering of vehicles for the simultaneous delivery of chemo- and radiotherapeutics increases the effectiveness of the therapy and reduces the dosage of each individual drug required to produce an observable therapeutic response. We here developed a novel chemoradiotherapeutic 1,2-dioleoyl-sn-glycero-3-phosphocholine lipid coated/uncoated platinum drug loaded, holmium-containing, wrinkled mesoporous silica nanoparticle. The materials were characterized with TEM, FTIR, {sup 1}H NMR, energy dispersive x-ray, inductively coupled plasma-mass spectrometry, and zeta potential measurements. In vitro platinum drug release from both lipid coated and uncoated chemoradiotherapeutic wrinkled mesoporous silica are reported. Various kinetic models were used to analyze the release kinetics. The radioactivity of the chemoradiotherapeutic nanocarriers was measured after neutron-activation.

  4. Laser-induced differential normalized fluorescence method for cancer diagnosis

    DOE Patents [OSTI]

    Vo-Dinh, T.; Panjehpour, M.; Overholt, B.F.

    1996-12-03

    An apparatus and method for cancer diagnosis are disclosed. The diagnostic method includes the steps of irradiating a tissue sample with monochromatic excitation light, producing a laser-induced fluorescence spectrum from emission radiation generated by interaction of the excitation light with the tissue sample, and dividing the intensity at each wavelength of the laser-induced fluorescence spectrum by the integrated area under the laser-induced fluorescence spectrum to produce a normalized spectrum. A mathematical difference between the normalized spectrum and an average value of a reference set of normalized spectra which correspond to normal tissues is calculated, which provides for amplifying small changes in weak signals from malignant tissues for improved analysis. The calculated differential normalized spectrum is correlated to a specific condition of a tissue sample. 5 figs.

  5. Laser-induced differential normalized fluorescence method for cancer diagnosis

    DOE Patents [OSTI]

    Vo-Dinh, Tuan; Panjehpour, Masoud; Overholt, Bergein F.

    1996-01-01

    An apparatus and method for cancer diagnosis are disclosed. The diagnostic method includes the steps of irradiating a tissue sample with monochromatic excitation light, producing a laser-induced fluorescence spectrum from emission radiation generated by interaction of the excitation light with the tissue sample, and dividing the intensity at each wavelength of the laser-induced fluorescence spectrum by the integrated area under the laser-induced fluorescence spectrum to produce a normalized spectrum. A mathematical difference between the normalized spectrum and an average value of a reference set of normalized spectra which correspond to normal tissues is calculated, which provides for amplifying small changes in weak signals from malignant tissues for improved analysis. The calculated differential normalized spectrum is correlated to a specific condition of a tissue sample.

  6. In situ quantification of genomic instability in breast cancer progression

    SciTech Connect (OSTI)

    Ortiz de Solorzano, Carlos; Chin, Koei; Gray, Joe W.; Lockett, Stephen J.

    2003-05-15

    Genomic instability is a hallmark of breast and other solid cancers. Presumably caused by critical telomere reduction, GI is responsible for providing the genetic diversity required in the multi-step progression of the disease. We have used multicolor fluorescence in situ hybridization and 3D image analysis to quantify genomic instability cell-by-cell in thick, intact tissue sections of normal breast epithelium, preneoplastic lesions (usual ductal hyperplasia), ductal carcinona is situ or invasive carcinoma of the breast. Our in situ-cell by cell-analysis of genomic instability shows an important increase of genomic instability in the transition from hyperplasia to in situ carcinoma, followed by a reduction of instability in invasive carcinoma. This pattern suggests that the transition from hyperplasia to in situ carcinoma corresponds to telomere crisis and invasive carcinoma is a consequence of telomerase reactivation afertelomere crisis.

  7. Once-Daily Radiation Therapy for Inflammatory Breast Cancer

    SciTech Connect (OSTI)

    Brown, Lindsay; Harmsen, William; Blanchard, Miran; Goetz, Matthew; Jakub, James; Mutter, Robert; Petersen, Ivy; Rooney, Jessica; Stauder, Michael; Yan, Elizabeth; Laack, Nadia

    2014-08-01

    Purpose: Inflammatory breast cancer (IBC) is a rare and aggressive breast cancer variant treated with multimodality therapy. A variety of approaches intended to escalate the intensity and efficacy of radiation therapy have been reported, including twice-daily radiation therapy, dose escalation, and aggressive use of bolus. Herein, we examine our outcomes for patients treated with once-daily radiation therapy with aggressive bolus utilization, focusing on treatment technique. Methods and Materials: A retrospective review of patients with nonmetastatic IBC treated from January 1, 2000, through December 31, 2010, was performed. Locoregional control (LRC), disease-free survival (DFS), overall survival (OS) and predictors thereof were assessed. Results: Fifty-two women with IBC were identified, 49 (94%) of whom were treated with neoadjuvant chemotherapy. All underwent mastectomy followed by adjuvant radiation therapy. Radiation was delivered in once-daily fractions of 1.8 to 2.25 Gy (median, 2 Gy). Patients were typically treated with daily 1-cm bolus throughout treatment, and 33 (63%) received a subsequent boost to the mastectomy scar. Five-year Kaplan Meier survival estimates for LRC, DFS, and OS were 81%, 56%, and 64%, respectively. Locoregional recurrence was associated with poorer OS (P<.001; hazard ratio [HR], 4.1). Extracapsular extension was associated with worse LRC (P=.02), DFS (P=.007), and OS (P=.002). Age greater than 50 years was associated with better DFS (P=.03). Pathologic complete response was associated with a trend toward improved LRC (P=.06). Conclusions: Once-daily radiation therapy with aggressive use of bolus for IBC results in outcomes consistent with previous reports using various intensified radiation therapy regimens. LRC remains a challenge despite modern systemic therapy. Extracapsular extension, age ≤50 years, and lack of complete response to chemotherapy appear to be associated with worse outcomes. Novel strategies are needed in IBC, particularly among these subsets of patients.

  8. Expression of hPNAS-4 Radiosensitizes Lewis Lung Cancer

    SciTech Connect (OSTI)

    Zeng Hui; Yuan Zhu; Zhu Hong; Li Lei; Shi Huashan; Wang Zi; Fan Yu; Deng Qian; Zeng Jianshuang; He Yinbo; Xiao Jianghong; Li Zhiping

    2012-11-15

    Purpose: This study aimed to transfer the hPNAS-4 gene, a novel apoptosis-related human gene, into Lewis lung cancer (LL2) and observe its radiosensitive effect on radiation therapy in vitro and in vivo. Methods and Materials: The hPNAS-4 gene was transfected into LL2 cells, and its expression was detected via western blot. Colony formation assay and flow cytometry were used to detect the growth and apoptosis of cells treated with irradiation/PNAS-4 in vitro. The hPNAS-4 gene was transferred into LL2-bearing mice through tail vein injection of the liposome/gene complex. The tumor volumes were recorded after radiation therapy. Proliferating cell nuclear antigen (PCNA) immunohistochemistry staining and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay were performed to detect the tumor cell growth and apoptosis in vivo. Results: The hPNAS-4 gene was successfully transferred into LL2 cells and tumor tissue, and its overexpressions were confirmed via western blot analysis. Compared with the control, empty plasmid, hPNAS-4, radiation, and empty plasmid plus radiation groups, the hPNAS-4 plus radiation group more significantly inhibited growth and enhanced apoptosis of LL2 cells in vitro and in vivo (P<.05). Conclusions: The hPNAS-4 gene was successfully transferred into LL2 cells and tumor tissue and was expressed in both LL2 cell and tumor tissue. The hPNAS-4 gene therapy significantly enhanced growth inhibition and apoptosis of LL2 tumor cells by radiation therapy in vitro and in vivo. Therefore, it may be a potential radiosensitive treatment of radiation therapy for lung cancer.

  9. PET: An Emerging Tool in the Fight Against Cancer |GE Global...

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    Today, doctors are armed with more weapons than ever before, ... Cancer is complex If there is one universal lesson we can ... allowing doctors to monitor for any change over time. ...

  10. Innovative biomagnetic imaging sensors for breast cancer: A model-based study

    SciTech Connect (OSTI)

    Deng, Y.; Golkowski, M.

    2012-04-01

    Breast cancer is a serious potential health problem for all women and is the second leading cause of cancer deaths in the United States. The current screening procedures and imaging techniques, including x-ray mammography, clinical biopsy, ultrasound imaging, and magnetic resonance imaging, provide only 73% accuracy in detecting breast cancer. This gives the impetus to explore alternate techniques for imaging the breast and detecting early stage tumors. Among the complementary methods, the noninvasive biomagnetic breast imaging is attractive and promising, because both ionizing radiation and breast compressions that the prevalent x-ray mammography suffers from are avoided. It furthermore offers very high contrast because of the significant electromagnetic properties' differences between the cancerous, benign, and normal breast tissues. In this paper, a hybrid and accurate modeling tool for biomagnetic breast imaging is developed, which couples the electromagnetic and ultrasonic energies, and initial validations between the model predication and experimental findings are conducted.

  11. Low-Dose Spiral CT Scans for Early Lung Cancer Detection

    Broader source: Energy.gov [DOE]

    Low-dose spiral computed tomography (CT) scanning is a noninvasive medical imaging test that has been used for the early detection of lung cancer for over 16 years (Sone et al. 1998; Henschke et.al. 1999).

  12. Method for palliation of pain in human bone cancer using therapeutic tin-117m compositions

    DOE Patents [OSTI]

    Srivastava, S.C.; Meinken, G.E.; Mausner, L.F.; Atkins, H.L.

    1998-12-29

    The invention provides a method for the palliation of bone pain due to cancer by the administration of a unique dosage of a tin-117m (Sn-117m) stannic chelate complex in a pharmaceutically acceptable composition. In addition, the invention provides a method for simultaneous palliation of bone pain and radiotherapy in cancer patients using compositions containing Sn-117m chelates. The invention also provides a method for palliating bone pain in cancer patients using Sn-117m-containing compositions and monitoring patient status by imaging the distribution of the Sn-117m in the patients. Also provided are pharmaceutically acceptable compositions containing Sn-117m chelate complexes for the palliation of bone pain in cancer patients. 5 figs.

  13. Method for detecting cancer in a single cell using mitochondrial correlation microscopy

    DOE Patents [OSTI]

    Gourley, Paul L.

    2012-03-06

    A method for distinguishing a normal cell from an abnormal cell, such as, for example a cancer cell or diseased cell, of the same tissue type using mitochondrial correlation microscopy.

  14. Method of detecting cancer in a single cell using mitochondrial correlation microscopy

    DOE Patents [OSTI]

    Gourley, Paul L

    2013-06-25

    A method for distinguishing a normal cell from an abnormal cell, such as, for example a cancer cell or diseased cell, of the same tissue type using mitochondrial correlation microscopy.

  15. Method for palliation of pain in human bone cancer using therapeutic tin-117m compositions

    DOE Patents [OSTI]

    Srivastava, Suresh C.; Meinken, George E.; Mausner, Leonard F.; Atkins, Harold L.

    1998-12-29

    The invention provides a method for the palliation of bone pain due to cancer by the administration of a unique dosage of a tin-117m (Sn-117m) stannic chelate complex in a pharmaceutically acceptable composition. In addition, the invention provides a method for simultaneous palliation of bone pain and radiotherapy in cancer patients using compositions containing Sn-117m chelates. The invention also provides a method for palliating bone pain in cancer patients using Sn-117m-containing compositions and monitoring patient status by imaging the distribution of the Sn-117m in the patients. Also provided are pharmaceutically acceptable compositions containing Sn-117m chelate complexes for the palliation of bone pain in cancer patients.

  16. Resolving Cancer Heterogeneity by Single Cell Sequencing (7th Annual SFAF Meeting, 2012)

    ScienceCinema (OSTI)

    Xu, Xun [BGI

    2013-02-11

    Xun Xu on "Resolving Cancer Heterogeneity by Single Cell Sequencing" at the 2012 Sequencing, Finishing, Analysis in the Future Meeting held June 5-7, 2012 in Santa Fe, New Mexico.

  17. EA-0965: Cancer Research Center Indiana University School of Medicine, Argonne, Illinois

    Broader source: Energy.gov [DOE]

    This EA evaluates the environmental impacts of the proposal to construct and equip the proposed Cancer Research Center (CRC), which would be located on the Indianapolis campus of the Indiana...

  18. A breast-ovarian cancer susceptibility gene maps to chromosome 17q21

    SciTech Connect (OSTI)

    Feunteun, J. ); Narod, S.A.; Parboosingh, J. ); Lynch, H.T.; Watson, P.; Conway, T.; Lynch, J. ); O'Connell, P.; White, R. ); Lenoir, G.M. )

    1993-04-01

    Nineteen North American Caucasian families that contain a minimum of four confirmed cases of breast or ovarian cancer have been studied. Four polymorphisms (cLB17.1, D17S579, D17S588, and D17S74), which span a region of approximately 15 cM on chromosome 17q12, were typed. The data confirm the location of a dominant gene conferring susceptibility to breast and ovarian cancer (maximum lod = 9.78) and suggest that the breast-ovarian cancer syndrome is genetically heterogeneous. Two recombinants in one large family suggest that the breast-ovarian cancer locus lies between D17S588 and D17S579. 14 refs., 3 figs., 3 tabs.

  19. Genes and the Microenvironment: Two Faces of Breast Cancer (LBNL Science at the Theater)

    ScienceCinema (OSTI)

    Gray, Joe; Love, Susan M.; Bissell, Min; Barcellos-Hoff, Mary Helen

    2011-10-04

    In this April 21, 2008 Berkeley Lab event, a dynamic panel of Berkeley Lab scientists highlight breast cancer research advances related to susceptibility, early detection, prevention, and therapy - a biological systems approach to tackling the disease from the molecular and cellular levels, to tissues and organs, and ultimately the whole individual. Joe Gray, Berkeley Lab Life Sciences Division Director, explores how chromosomal abnormalities contribute to cancer and respond to gene-targeted therapies. Mina Bissell, former Life Sciences Division Director, approaches the challenge of breast cancer from the breast's three dimensional tissue microenvironment and how the intracellular ''conversation'' triggers malignancies. Mary Helen Barcellos-Hoff, Deputy Director, Life Sciences Division, identifies what exposure to ionizing radiation can tell us about how normal tissues suppress carcinogenesis. The panel is moderated by Susan M. Love, breast cancer research pioneer, author, President and Medical Director of the Dr. Susan Love Research Foundation.

  20. Stromal COX-2 signaling activated by deoxycholic acid mediates proliferation and invasiveness of colorectal epithelial cancer cells

    SciTech Connect (OSTI)

    Zhu, Yingting; Tissue Tech Inc., Miami, FL 33173 ; Zhu, Min; Lance, Peter

    2012-08-31

    Highlights: Black-Right-Pointing-Pointer Human colonic cancer associated fibroblasts are major sources of COX-2 and PGE{sub 2}. Black-Right-Pointing-Pointer The fibroblasts interact with human colonic epithelial cancer cells. Black-Right-Pointing-Pointer Activation of COX-2 signaling in the fibroblasts affects behavior of the epithelia. Black-Right-Pointing-Pointer Protein Kinase C controls the activation of COX-2 signaling. -- Abstract: COX-2 is a major regulator implicated in colonic cancer. However, how COX-2 signaling affects colonic carcinogenesis at cellular level is not clear. In this article, we investigated whether activation of COX-2 signaling by deoxycholic acid (DCA) in primary human normal and cancer associated fibroblasts play a significant role in regulation of proliferation and invasiveness of colonic epithelial cancer cells. Our results demonstrated while COX-2 signaling can be activated by DCA in both normal and cancer associated fibroblasts, the level of activation of COX-2 signaling is significantly greater in cancer associated fibroblasts than that in normal fibroblasts. In addition, we discovered that the proliferative and invasive potential of colonic epithelial cancer cells were much greater when the cells were co-cultured with cancer associated fibroblasts pre-treated with DCA than with normal fibroblasts pre-treated with DCA. Moreover, COX-2 siRNA attenuated the proliferative and invasive effect of both normal and cancer associate fibroblasts pre-treated with DCA on the colonic cancer cells. Further studies indicated that the activation of COX-2 signaling by DCA is through protein kinase C signaling. We speculate that activation of COX-2 signaling especially in cancer associated fibroblasts promotes progression of colonic cancer.

  1. Structures of Lung Cancer-Derived EGFR Mutants and Inhibitor Complexes:

    Office of Scientific and Technical Information (OSTI)

    Mechanism of Activation and Insights into Differential Inhibitor Sensitivity (Journal Article) | SciTech Connect Structures of Lung Cancer-Derived EGFR Mutants and Inhibitor Complexes: Mechanism of Activation and Insights into Differential Inhibitor Sensitivity Citation Details In-Document Search Title: Structures of Lung Cancer-Derived EGFR Mutants and Inhibitor Complexes: Mechanism of Activation and Insights into Differential Inhibitor Sensitivity Authors: Yun, C.H. ; Boggon, T.J. ; Li, Y.

  2. Combined therapeutic potential of nuclear receptors with receptor tyrosine kinase inhibitors in lung cancer

    SciTech Connect (OSTI)

    Wairagu, Peninah M.; Park, Kwang Hwa; Kim, Jihye; Choi, Jong-Whan; Kim, Hyun-Won; Yeh, Byung-Il; Jung, Soon-Hee; Yong, Suk-Joong; Jeong, Yangsik

    2014-05-09

    Highlights: The 48 NR genes and 48 biological anti-cancer targets are profiled in paired-cells. Growth inhibition by NR ligands or TKIs is target receptor level-dependent. T0901317 with gefitinib/PHA665752 shows additive growth inhibition in lung cells. - Abstract: Cancer heterogeneity is a big hurdle in achieving complete cancer treatment, which has led to the emergence of combinational therapy. In this study, we investigated the potential use of nuclear receptor (NR) ligands for combinational therapy with other anti-cancer drugs. We first profiled all 48 NRs and 48 biological anti-cancer targets in four pairs of lung cell lines, where each pair was obtained from the same patient. Two sets of cell lines were normal and the corresponding tumor cell lines while the other two sets consisted of primary versus metastatic tumor cell lines. Analysis of the expression profile revealed 11 NRs and 15 cancer targets from the two pairs of normal versus tumor cell lines, and 9 NRs and 9 cancer targets from the primary versus metastatic tumor cell lines had distinct expression patterns in each category. Finally, the evaluation of nuclear receptor ligand T0901317 for liver X receptor (LXR) demonstrated its combined therapeutic potential with tyrosine kinase inhibitors. The combined treatment of cMET inhibitor PHA665752 or EGFR inhibitor gefitinib with T0901317 showed additive growth inhibition in both H2073 and H1993 cells. Mechanistically, the combined treatment suppressed cell cycle progression by inhibiting cyclinD1 and cyclinB expression. Taken together, this study provides insight into the potential use of NR ligands in combined therapeutics with other biological anti-cancer drugs.

  3. Assessment of uncertainties in radiation-induced cancer risk predictions at clinically relevant doses

    SciTech Connect (OSTI)

    Nguyen, J.; Moteabbed, M.; Paganetti, H.

    2015-01-15

    Purpose: Theoretical dose–response models offer the possibility to assess second cancer induction risks after external beam therapy. The parameters used in these models are determined with limited data from epidemiological studies. Risk estimations are thus associated with considerable uncertainties. This study aims at illustrating uncertainties when predicting the risk for organ-specific second cancers in the primary radiation field illustrated by choosing selected treatment plans for brain cancer patients. Methods: A widely used risk model was considered in this study. The uncertainties of the model parameters were estimated with reported data of second cancer incidences for various organs. Standard error propagation was then subsequently applied to assess the uncertainty in the risk model. Next, second cancer risks of five pediatric patients treated for cancer in the head and neck regions were calculated. For each case, treatment plans for proton and photon therapy were designed to estimate the uncertainties (a) in the lifetime attributable risk (LAR) for a given treatment modality and (b) when comparing risks of two different treatment modalities. Results: Uncertainties in excess of 100% of the risk were found for almost all organs considered. When applied to treatment plans, the calculated LAR values have uncertainties of the same magnitude. A comparison between cancer risks of different treatment modalities, however, does allow statistically significant conclusions. In the studied cases, the patient averaged LAR ratio of proton and photon treatments was 0.35, 0.56, and 0.59 for brain carcinoma, brain sarcoma, and bone sarcoma, respectively. Their corresponding uncertainties were estimated to be potentially below 5%, depending on uncertainties in dosimetry. Conclusions: The uncertainty in the dose–response curve in cancer risk models makes it currently impractical to predict the risk for an individual external beam treatment. On the other hand, the ratio of absolute risks between two modalities is less sensitive to the uncertainties in the risk model and can provide statistically significant estimates.

  4. SQUID-based ULF MRI and Superparamagnetic Relaxometry for Early Cancer

    Office of Scientific and Technical Information (OSTI)

    Diagnostics (Technical Report) | SciTech Connect SQUID-based ULF MRI and Superparamagnetic Relaxometry for Early Cancer Diagnostics Citation Details In-Document Search Title: SQUID-based ULF MRI and Superparamagnetic Relaxometry for Early Cancer Diagnostics Authors: Matlashov, Andrei N. [1] ; Magnelind, Per E. [1] ; Kim, Young Jin [1] ; Sandin, Jan Henrik [1] ; Espy, Michelle A. [1] ; Anderson, Aaron S. [1] ; Mukundan, Harshini [1] + Show Author Affiliations Los Alamos National Laboratory

  5. Integrated analysis of breast cancer cell lines reveals unique signaling pathways

    SciTech Connect (OSTI)

    Heiser, Laura M.; Wang, Nicholas J.; Talcott, Carolyn L.; Laderoute, Keith R.; Knapp, Merrill; Guan, Yinghui; Hu, Zhi; Ziyad, Safiyyah; Weber, Barbara L.; Laquerre, Sylvie; Jackson, Jeffrey R.; Wooster, Richard F.; Kuo, Wen-Lin; Gray, Joe W.; Spellman, Paul T.

    2009-03-31

    Cancer is a heterogeneous disease resulting from the accumulation of genetic defects that negatively impact control of cell division, motility, adhesion and apoptosis. Deregulation in signaling along the EGFR-MAPK pathway is common in breast cancer, though the manner in which deregulation occurs varies between both individuals and cancer subtypes. We were interested in identifying subnetworks within the EGFR-MAPK pathway that are similarly deregulated across subsets of breast cancers. To that end, we mapped genomic, transcriptional and proteomic profiles for 30 breast cancer cell lines onto a curated Pathway Logic symbolic systems model of EGFR-MEK signaling. This model was comprised of 539 molecular states and 396 rules governing signaling between active states. We analyzed these models and identified several subtype specific subnetworks, including one that suggested PAK1 is particularly important in regulating the MAPK cascade when it is over-expressed. We hypothesized that PAK1 overexpressing cell lines would have increased sensitivity to MEK inhibitors. We tested this experimentally by measuring quantitative responses of 20 breast cancer cell lines to three MEK inhibitors. We found that PAK1 over-expressing luminal breast cancer cell lines are significantly more sensitive to MEK inhibition as compared to those that express PAK1 at low levels. This indicates that PAK1 over-expression may be a useful clinical marker to identify patient populations that may be sensitive to MEK inhibitors. All together, our results support the utility of symbolic system biology models for identification of therapeutic approaches that will be effective against breast cancer subsets.

  6. Founding BRCA1 mutations in hereditary breast and ovarian cancer in southern Sweden

    SciTech Connect (OSTI)

    Johannsson, O.; Hakansson, S.; Johannson, U.

    1996-03-01

    Nine different germ-line mutations in the BRCA1 breast and ovarian cancer susceptibility gene were identified in 15 of 47 kindreds from southern Sweden, by use of SSCP and heteroduplex analysis of all exons and flanking intron region and by a protein-truncation test for exon 11, followed by direct sequencing. All but one of the mutations are predicted to give rise to premature translation termination and include seven frameshift insertions or deletions, a nonsense mutation, and a splice acceptor site mutation. The remaining mutation is a missense mutation (Cys61Gly) in the zinc-binding motif. Four novel Swedish founding mutations were identified: the nucleotide 2595 deletion A was found in five families, the C 1806 T nonsense mutation in three families, the 3166 insertion TGAGA in three families, and the nucleotide 1201 deletion 11 in two families. Analysis of the intragenic polymorphism D17S855 supports common origins of the mutations. Eleven of the 15 kindreds manifesting BRCA1 mutations were breast-ovarian cancer families, several of them with a predominant ovarian cancer phenotype. The set of 32 families in which no BRCA1 alterations were detected included 1 breast-ovarian cancer kindred manifesting clear linkage to the BRCA1 region and loss of the wild-type chromosome in associated tumors. Other tumor types found in BRCA1 mutation/haplotype carriers included prostatic, pancreas, skin, and lung cancer, a malignant melanoma, an oligodendroglioma, and a carcinosarcoma. In all, 12 of 16 kindreds manifesting BRCA1 mutation or linkage contained ovarian cancer, as compared with only 6 of the remaining 31 families (P < .001). The present study confirms the involvement of BRCA1 in disease predisposition for a subset of hereditary breast cancer families often characterized by ovarian cancers. 28 refs., 3 figs., 4 tabs.

  7. Radiotherapy in Small-Cell Lung Cancer: Lessons Learned and Future Directions

    SciTech Connect (OSTI)

    Slotman, Ben J.; Senan, Suresh

    2011-03-15

    Although chemotherapy is an essential component in the treatment of small-cell lung cancer, improvements in survival in the past two decades have been mainly achieved by the appropriate application of radiotherapy. The aim of the present study was to review the key developments in thoracic radiotherapy and prophylactic cranial radiotherapy and to discuss the rationale behind key ongoing studies in small-cell lung cancer.

  8. SU-E-J-03: A Comprehensive Comparison Between Alpha and Beta Emitters for Cancer Radioimmunotherapy

    SciTech Connect (OSTI)

    Huang, C.Y.; Guatelli, S; Oborn, B; Allen, B

    2014-06-01

    Purpose: The purpose of this study is to perform a comprehensive comparison of the therapeutic efficacy and cytotoxicity of alpha and beta emitters for Radioimmunotherapy (RIT). For each stage of cancer development, specific models were built for the separate objectives of RIT to be addressed:a) kill isolated cancer cells in transit in the lymphatic and vascular circulation,b) regress avascular cell clusters,c) regress tumor vasculature and tumors. Methods: Because of the nature of short range, high LET alpha and long energy beta radiation and heterogeneous antigen expression among cancer cells, the microdosimetric approach is essential for the RIT assessment. Geant4 based microdosimetric models are developed for the three different stages of cancer progression: cancer cells, cell clusters and tumors. The energy deposition, specific energy resulted from different source distribution in the three models was calculated separately for 4 alpha emitting radioisotopes ({sup 211}At, {sup 213}Bi, {sup 223}Ra and {sup 225}Ac) and 6 beta emitters ({sup 32}P, {sup 33}P, {sup 67}Cu, {sup 90}Y, {sup 131}I and {sup 177}Lu). The cell survival, therapeutic efficacy and cytotoxicity are determined and compared between alpha and beta emitters. Results: We show that internal targeted alpha radiation has advantages over beta radiation for killing isolated cancer cells, regressing small cell clusters and also solid tumors. Alpha particles have much higher dose specificity and potency than beta particles. They can deposit 3 logs more dose than beta emitters to single cells and solid tumor. Tumor control probability relies on deep penetration of radioisotopes to cancer cell clusters and solid tumors. Conclusion: The results of this study provide a quantitative understanding of the efficacy and cytotoxicity of RIT for each stage of cancer development.

  9. Lung Cancer Survival Prediction using Ensemble Data Mining on Seer Data

    DOE Public Access Gateway for Energy & Science Beta (PAGES Beta)

    Agrawal, Ankit; Misra, Sanchit; Narayanan, Ramanathan; Polepeddi, Lalith; Choudhary, Alok

    2012-01-01

    We analyze the lung cancer data available from the SEER program with the aim of developing accurate survival prediction models for lung cancer. Carefully designed preprocessing steps resulted in removal/modification/splitting of several attributes, and 2 of the 11 derived attributes were found to have significant predictive power. Several supervised classification methods were used on the preprocessed data along with various data mining optimizations and validations. In our experiments, ensemble voting of five decision tree based classifiers and meta-classifiers was found to result in the best prediction performance in terms of accuracy and area under the ROC curve. We have developedmore » an on-line lung cancer outcome calculator for estimating the risk of mortality after 6 months, 9 months, 1 year, 2 year and 5 years of diagnosis, for which a smaller non-redundant subset of 13 attributes was carefully selected using attribute selection techniques, while trying to retain the predictive power of the original set of attributes. Further, ensemble voting models were also created for predicting conditional survival outcome for lung cancer (estimating risk of mortality after 5 years of diagnosis, given that the patient has already survived for a period of time), and included in the calculator. The on-line lung cancer outcome calculator developed as a result of this study is available at http://info.eecs.northwestern.edu:8080/LungCancerOutcomeCalculator/.« less

  10. Activity of the kinesin spindle protein inhibitor ispinesib (SB-715992) in models of breast cancer

    SciTech Connect (OSTI)

    Purcell, James W; Davis, Jefferson; Reddy, Mamatha; Martin, Shamra; Samayoa, Kimberly; Vo, Hung; Thomsen, Karen; Bean, Peter; Kuo, Wen Lin; Ziyad, Safiyyah; Billig, Jessica; Feiler, Heidi S; Gray, Joe W; Wood, Kenneth W; Cases, Sylvaine

    2009-06-10

    Ispinesib (SB-715992) is a potent inhibitor of kinesin spindle protein (KSP), a kinesin motor protein essential for the formation of a bipolar mitotic spindle and cell cycle progression through mitosis. Clinical studies of ispinesib have demonstrated a 9% response rate in patients with locally advanced or metastatic breast cancer, and a favorable safety profile without significant neurotoxicities, gastrointestinal toxicities or hair loss. To better understand the potential of ispinesib in the treatment of breast cancer we explored the activity of ispinesib alone and in combination several therapies approved for the treatment of breast cancer. We measured the ispinesib sensitivity and pharmacodynamic response of breast cancer cell lines representative of various subtypes in vitro and as xenografts in vivo, and tested the ability of ispinesib to enhance the anti-tumor activity of approved therapies. In vitro, ispinesib displayed broad anti-proliferative activity against a panel of 53 breast cell-lines. In vivo, ispinesib produced regressions in each of five breast cancer models, and tumor free survivors in three of these models. The effects of ispinesib treatment on pharmacodynamic markers of mitosis and apoptosis were examined in vitro and in vivo, revealing a greater increase in both mitotic and apoptotic markers in the MDA-MB-468 model than in the less sensitive BT-474 model. In vivo, ispinesib enhanced the anti-tumor activity of trastuzumab, lapatinib, doxorubicin, and capecitabine, and exhibited activity comparable to paclitaxel and ixabepilone. These findings support further clinical exploration of KSP inhibitors for the treatment of breast cancer.

  11. Automated assessment of bilateral breast volume asymmetry as a breast cancer biomarker during mammographic screening

    SciTech Connect (OSTI)

    Williams, Alex C; Hitt, Austin N; Voisin, Sophie; Tourassi, Georgia

    2013-01-01

    The biological concept of bilateral symmetry as a marker of developmental stability and good health is well established. Although most individuals deviate slightly from perfect symmetry, humans are essentially considered bilaterally symmetrical. Consequently, increased fluctuating asymmetry of paired structures could be an indicator of disease. There are several published studies linking bilateral breast size asymmetry with increased breast cancer risk. These studies were based on radiologists manual measurements of breast size from mammographic images. We aim to develop a computerized technique to assess fluctuating breast volume asymmetry in screening mammograms and investigate whether it correlates with the presence of breast cancer. Using a large database of screening mammograms with known ground truth we applied automated breast region segmentation and automated breast size measurements in CC and MLO views using three well established methods. All three methods confirmed that indeed patients with breast cancer have statistically significantly higher fluctuating asymmetry of their breast volumes. However, statistically significant difference between patients with cancer and benign lesions was observed only for the MLO views. The study suggests that automated assessment of global bilateral asymmetry could serve as a breast cancer risk biomarker for women undergoing mammographic screening. Such biomarker could be used to alert radiologists or computer-assisted detection (CAD) systems to exercise increased vigilance if higher than normal cancer risk is suspected.

  12. Arsenic methylation and lung and bladder cancer in a case-control study in northern Chile

    SciTech Connect (OSTI)

    Melak, Dawit; Ferreccio, Catterina; Kalman, David; Parra, Roxana; Acevedo, Johanna; Pérez, Liliana; Cortés, Sandra; Smith, Allan H.; Yuan, Yan; Liaw, Jane; Steinmaus, Craig

    2014-01-15

    In humans, ingested inorganic arsenic is metabolized to monomethylarsenic (MMA) then to dimethylarsenic (DMA), although this process is not complete in most people. The trivalent form of MMA is highly toxic in vitro and previous studies have identified associations between the proportion of urinary arsenic as MMA (%MMA) and several arsenic-related diseases. To date, however, relatively little is known about its role in lung cancer, the most common cause of arsenic-related death, or about its impacts on people drinking water with lower arsenic concentrations (e.g., < 200 μg/L). In this study, urinary arsenic metabolites were measured in 94 lung and 117 bladder cancer cases and 347 population-based controls from areas in northern Chile with a wide range of drinking water arsenic concentrations. Lung cancer odds ratios adjusted for age, sex, and smoking by increasing tertiles of %MMA were 1.00, 1.91 (95% confidence interval (CI), 0.99–3.67), and 3.26 (1.76–6.04) (p-trend < 0.001). Corresponding odds ratios for bladder cancer were 1.00, 1.81 (1.06–3.11), and 2.02 (1.15–3.54) (p-trend < 0.001). In analyses confined to subjects only with arsenic water concentrations < 200 μg/L (median = 60 μg/L), lung and bladder cancer odds ratios for subjects in the upper tertile of %MMA compared to subjects in the lower two tertiles were 2.48 (1.08–5.68) and 2.37 (1.01–5.57), respectively. Overall, these findings provide evidence that inter-individual differences in arsenic metabolism may be an important risk factor for arsenic-related lung cancer, and may play a role in cancer risks among people exposed to relatively low arsenic water concentrations. - Highlights: • Urine arsenic metabolites were measured in cancer cases and controls from Chile. • Higher urine %MMA values were associated with increased lung and bladder cancer. • %MMA-cancer associations were seen at drinking water arsenic levels < 200 μg/L.

  13. Hematologic Toxicity in RTOG 0418: A Phase 2 Study of Postoperative IMRT for Gynecologic Cancer

    SciTech Connect (OSTI)

    Klopp, Ann H.; Moughan, Jennifer; Portelance, Lorraine; Miller, Brigitte E.; Salehpour, Mohammad R.; Hildebrandt, Evangeline; Nuanjing, Jenny; D'Souza, David; Souhami, Luis; Small, William; Gaur, Rakesh; Jhingran, Anuja

    2013-05-01

    Purpose: Intensity modulated radiation therapy (IMRT), compared with conventional 4-field treatment, can reduce the volume of bone marrow irradiated. Pelvic bone marrow sparing has produced a clinically significant reduction in hematologic toxicity (HT). This analysis investigated HT in Radiation Therapy Oncology Group (RTOG) 0418, a prospective study to test the feasibility of delivering postoperative IMRT for cervical and endometrial cancer in a multiinstitutional setting. Methods and Materials: Patients in the RTOG 0418 study were treated with postoperative IMRT to 50.4 Gy to the pelvic lymphatics and vagina. Endometrial cancer patients received IMRT alone, whereas patients with cervical cancer received IMRT and weekly cisplatin (40 mg/m{sup 2}). Pelvic bone marrow was defined within the treatment field by using a computed tomography density-based autocontouring algorithm. The volume of bone marrow receiving 10, 20, 30, and 40 Gy and the median dose to bone marrow were correlated with HT, graded by Common Terminology Criteria for Adverse Events, version 3.0, criteria. Results: Eighty-three patients were eligible for analysis (43 with endometrial cancer and 40 with cervical cancer). Patients with cervical cancer treated with weekly cisplatin and pelvic IMRT had grades 1-5 HT (23%, 33%, 25%, 0%, and 0% of patients, respectively). Among patients with cervical cancer, 83% received 5 or more cycles of cisplatin, and 90% received at least 4 cycles of cisplatin. The median percentage volume of bone marrow receiving 10, 20, 30, and 40 Gy in all 83 patients, respectively, was 96%, 84%, 61%, and 37%. Among cervical cancer patients with a V40 >37%, 75% had grade 2 or higher HT compared with 40% of patients with a V40 less than or equal to 37% (P =.025). Cervical cancer patients with a median bone marrow dose of >34.2 Gy also had higher rates of grade ?2 HT than did those with a dose of ?34.2 Gy (74% vs 43%, P=.049). Conclusions: Pelvic IMRT with weekly cisplatin is associated with low rates of HT and high rates of weekly cisplatin use. The volume of bone marrow receiving 40 Gy and the median dose to bone marrow correlated with higher rates of grade ?2 toxicity among patients receiving weekly cisplatin (cervical cancer patients). Evaluation and limitation of the volume of bone marrow treated with pelvic IMRT is warranted in patients receiving concurrent chemotherapy.

  14. A 45-year followup study of breast and other cancers in kindred 107 and linkage analysis of candidate loci

    SciTech Connect (OSTI)

    Goldgar, D.E.; Neuhausen, S.L.; Ward, J.H.

    1994-09-01

    One of the earliest large kindreds with inherited susceptibility to breast cancer was reported by Gardner and Stephens in 1950. This family, denoted K107, was ascertained in 1947 by a genetics student with two great aunts who died of breast cancer in their 40`s. Subsequent clinical and genealogical follow-up identified 7 additional cases of early-onset breast cancer. The family was updated several times, most notably in 1980. For the present study K107 was recently reinvestigated and over 75 blood samples gathered for genotyping. The kindred now contains 38 cases of female breast cancer, 3 cases of male breast cancer, and 6 cases of ovarian cancer, 18 of which have been identified since the 1980 report. Examination of the obligate carriers demonstrates that that gene responsible for the breast and ovarian cancer in K107 is highly penetrant. Other cancers appear to be associated with expression of this gene, most notably prostate cancer, melanoma, and uterine cancer. Linkage to the BRCA1 region in K107 was excluded based upon the analysis of genotypings at four loci covering the BRCA1 gene on chromosome 17q has been excluded in this family, using four highly polymorphic markers in the BRCA1 region (multipoint LOD score -3.27). Eight other candidate breast cancer susceptibility genes and candidate regions, including p53 and ESR have also been tested for linkage and excluded. Studies to formally re-estimate penetrance and test for excesses of all cancer sites and a genomic search in this family are in progress.

  15. PR_NA-03-13_FromColdWartoWaronCancer-PETRussia_10-03_.doc

    National Nuclear Security Administration (NNSA)

    U.S. Department of Energy For Immediate Release Bryan Wilkes October 28, 2003 202-586-7371 From the Cold War to the War on Cancer NNSA-sponsored program to employ Russian scientists in cancer treatment facility WASHINGTON, D.C. - Former nuclear weapons scientists, engineers and technicians will soon begin working in a Russian life-saving cancer treatment facility under an important nonproliferation program run by the National Nuclear Security Administration (NNSA). The Positron Emission

  16. CRADA Final Report: ErbB2 Targeted Cancer Therapeutics

    SciTech Connect (OSTI)

    Lupu, Ruth

    2002-08-27

    The aim of the study was to design novel therapeutic strategies for the treatment of carcinomas which overexpress the erbB-2 oncogene product and/or the activator (HRG). erbB-2 is a tyrosine kinase growth factor receptor, that overexpression of which in invasive breast, prostate, ovarian and lung carcinomas correlates with poor prognosis and poor overall survival. In breast carcinomas, erbB-2 is overexpressed in 25%-30% of the invasive phenotype and in 70% of ductal carcinomas in situ. On the other hand, the erbB-2 activator, heregulin (HRG) is expressed in about 30% of invasive breast carcinomas and it is highly expressed in other carcinoIl1as including, ovarian, lung, and prostate. Interestingly, only 6% of invasive breast carcinomas co-express both HRG and erbB-2. It is known today that tumors that overexpress erbB-2 are a leading cause of death, making erbB-2 and its activator HRG critical targets for therapy. Targeting both the receptors and the activator would be beneficial for a significant number of cancer patients. At the final stages of the project we had obtained significant improvements over the peptide quality but not significant improvements were made towards the generation of humanized monoclonal antibodies.

  17. XCR1 promotes cell growth and migration and is correlated with bone metastasis in non-small cell lung cancer

    SciTech Connect (OSTI)

    Wang, Ting; Han, Shuai; Wu, Zhipeng; Han, Zhitao; Yan, Wangjun; Liu, Tielong; Wei, Haifeng; Song, Dianwen; Zhou, Wang Yang, Xinghai Xiao, Jianru

    2015-08-21

    Bone metastasis occurs in approximately 30–40% patients with advanced non-small cell lung cancer (NSCLC), but the mechanism underlying this bone metastasis remains poorly understood. The chemokine super family is believed to play an important role in tumor metastasis in lung cancer. The chemokine receptor XCR1 has been identified to promote cell proliferation and migration in oral cancer and ovarian carcinoma, but the role of XCR1 in lung cancer has not been reported. In this study, we demonstrated for the first time that XCR1 was overexpressed in lung cancer bone metastasis as compared with that in patients with primary lung cancer. In addition, the XCR1 ligand XCL1 promoted the proliferation and migration of lung cancer cells markedly, and knockdown of XCR1 by siRNA abolished the effect of XCL1 in cell proliferation and migration. Furthermore, we identified JAK2/STAT3 as a novel downstream pathway of XCR1, while XCL1/XCR1 increased the mRNA level of the downstream of JAK2/STAT3 including PIM1, JunB, TTP, MMP2 and MMP9. These results indicate that XCR1 is a new potential therapeutic target for the treatment of lung cancer bone metastasis. - Highlights: • XCR1 is overexpressed in bone metastasis compared with primary NSCLC. • XCR1 activation by XCL1 promotes lung cancer cell proliferation and migration. • JAK2/STAT3 is a novel potential downstream pathway of XCR1.

  18. Estimates of the gene frequency of BRCA1 and its contribution to breast and ovarian cancer incidence

    SciTech Connect (OSTI)

    Ford, D.; Easton, D.F.; Peto, J.

    1995-12-01

    The majority of multiple-case families that segregate both breast and ovarian cancer in a dominant fashion are due to mutations in the BRCA1 gene on chromosome 17q. In this paper, we have combined penetrance estimates for BRCA1 with the results of two population-based genetic epidemiological studies to estimate the gene frequency of BRCA1. On the assumption that the excess risk of ovarian cancer in first degree relatives of breast cancer patients and the breast cancer excess in relatives of ovarian cancer patients are both entirely accounted for by BRCA1, we estimate that the BRCA1 gene frequency is 0.0006 (95% confidence interval [0.0002-0.001]) and that the proportion of breast cancer cases in the general population due to BRCA1 is 5.3% below age 40 years, 2.2% between ages 40 and 49 years, and 1.1% between ages 50 and 70 years. The corresponding estimates for ovarian cancer are 5.7%, 4.6%, and 2.1%, respectively. Our results suggest that the majority of breast cancer families with less than four cases and no ovarian cancer are not due to rare highly penetrant genes such as BRCA1 but are more likely to be due either to chance or to more common genes of lower penetrance. 22 refs., 3 tabs.

  19. MicroRNA-490-5p inhibits proliferation of bladder cancer by targeting c-Fos

    SciTech Connect (OSTI)

    Li, Shiqi; Xu, Xianglai; Xu, Xin; Hu, Zhenghui; Wu, Jian; Zhu, Yi; Chen, Hong; Mao, Yeqing; Lin, Yiwei; Luo, Jindan; Zheng, Xiangyi; Xie, Liping

    2013-11-29

    Highlights: We examined the level of miR-490-5p in bladder cancer tissues and three cancer cell lines. We are the first to show the function of miR-490-5p in bladder cancer. We demonstrate c-Fos may be a target of miR-490-5p. -- Abstract: MicroRNAs (miRNAs) are non-protein-coding sequences that play a crucial role in tumorigenesis by negatively regulating gene expression. Here, we found that miR-490-5p is down-regulated in human bladder cancer tissue and cell lines compared to normal adjacent tissue and a non-malignant cell line. To better characterize the function of miR-490-5p in bladder cancer, we over-expressed miR-490-5p in bladder cancer cell lines with chemically synthesized mimics. Enforced expression of miR-490-5p in bladder cancer cells significantly inhibited the cell proliferation via G1-phase arrest. Further studies found the decreased c-Fos expression at both mRNA and protein levels and Luciferase reporter assays demonstrated that c-Fos is a direct target of miR-490-5p in bladder cancer. These findings indicate miR-490-5p to be a novel tumor suppressor of bladder cancer cell proliferation through targeting c-Fos.

  20. Nanoscale mapping and organization analysis of target proteins on cancer cells from B-cell lymphoma patients

    SciTech Connect (OSTI)

    Li, Mi; Xiao, Xiubin; Liu, Lianqing; Xi, Ning; Wang, Yuechao; Dong, Zaili; Zhang, Weijing

    2013-11-01

    CD20, a membrane protein highly expressed on most B-cell lymphomas, is an effective target demonstrated in clinical practice for treating B-cell non-Hodgkin's lymphoma (NHL). Rituximab is a monoclonal antibody against CD20. In this work, we applied atomic force microscopy (AFM) to map the nanoscale distribution of CD20 molecules on the surface of cancer cells from clinical B-cell NHL patients under the assistance of ROR1 fluorescence recognition (ROR1 is a specific cell surface marker exclusively expressed on cancer cells). First, the ROR1 fluorescence labeling experiments showed that ROR1 was expressed on cancer cells from B-cell lymphoma patients, but not on normal cells from healthy volunteers. Next, under the guidance of ROR1 fluorescence, the rituximab-conjugated AFM tips were moved to cancer cells to image the cellular morphologies and detect the CD20-rituximab interactions on the cell surfaces. The distribution maps of CD20 on cancer cells were constructed by obtaining arrays of (1616) force curves in local areas (500500 nm{sup 2}) on the cell surfaces. The experimental results provide a new approach to directly investigate the nanoscale distribution of target protein on single clinical cancer cells. - Highlights: Cancer cells were recognized from healthy cells by ROR1 fluorescence labeling. The nanoscale distribution of CD20 on cancer cells was characterized. The distribution of CD20 was non-uniform on the surface of cancer cells.

  1. Mixed lineage kinase 3 is required for matrix metalloproteinase expression and invasion in ovarian cancer cells

    SciTech Connect (OSTI)

    Zhan, Yu; Abi Saab, Widian F.; Modi, Nidhi; Stewart, Amanda M.; Liu, Jinsong; Chadee, Deborah N.

    2012-08-15

    Mixed lineage kinase 3 (MLK3) is a mitogen-activated protein kinase kinase kinase (MAP3K) that activates MAPK signaling pathways and regulates cellular responses such as proliferation, migration and apoptosis. Here we report high levels of total and phospho-MLK3 in ovarian cancer cell lines in comparison to immortalized nontumorigenic ovarian epithelial cell lines. Using small interfering RNA (siRNA)-mediated gene silencing, we determined that MLK3 is required for the invasion of SKOV3 and HEY1B ovarian cancer cells. Furthermore, mlk3 silencing substantially reduced matrix metalloproteinase (MMP)-1, -2, -9 and -12 gene expression and MMP-2 and -9 activities in SKOV3 and HEY1B ovarian cancer cells. MMP-1, -2, -9 and-12 expression, and MLK3-induced activation of MMP-2 and MMP-9 requires both extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) activities. In addition, inhibition of activator protein-1 (AP-1) reduced MMP-1, MMP-9 and MMP-12 gene expression. Collectively, these findings establish MLK3 as an important regulator of MMP expression and invasion in ovarian cancer cells. -- Highlights: Black-Right-Pointing-Pointer Ovarian cancer cell lines have high levels of total and phosphorylated MLK3. Black-Right-Pointing-Pointer MLK3 is required for MMP expression and activity in ovarian cancer cells. Black-Right-Pointing-Pointer MLK3 is required for invasion of SKOV3 and HEY1B ovarian cancer cells. Black-Right-Pointing-Pointer MLK3-dependent regulation of MMP-2 and MMP-9 activities requires ERK and JNK.

  2. Phytoestrogens in menopausal supplements induce ER-dependent cell proliferation and overcome breast cancer treatment in an in vitro breast cancer model

    SciTech Connect (OSTI)

    Duursen, Majorie B.M. van; Smeets, Evelien E.J.W.; Rijk, Jeroen C.W.; Nijmeijer, Sandra M.; Berg, Martin van den

    2013-06-01

    Breast cancer treatment by the aromatase inhibitor Letrozole (LET) or Selective Estrogen Receptor Modulator Tamoxifen (TAM) can result in the onset of menopausal symptoms. Women often try to relieve these symptoms by taking menopausal supplements containing high levels of phytoestrogens. However, little is known about the potential interaction between these supplements and breast cancer treatment, especially aromatase inhibitors. In this study, interaction of phytoestrogens with the estrogen receptor alpha and TAM action was determined in an ER-reporter gene assay (BG1Luc4E2 cells) and human breast epithelial tumor cells (MCF-7). Potential interactions with aromatase activity and LET were determined in human adrenocorticocarcinoma H295R cells. We also used the previously described H295R/MCF-7 co-culture model to study interactions with steroidogenesis and tumor cell proliferation. In this model, genistein (GEN), 8-prenylnaringenin (8PN) and four commercially available menopausal supplements all induced ER-dependent tumor cell proliferation, which could not be prevented by physiologically relevant LET and 4OH-TAM concentrations. Differences in relative effect potencies between the H295R/MCF-7 co-culture model and ER-activation in BG1Luc4E2 cells, were due to the effects of the phytoestrogens on steroidogenesis. All tested supplements and GEN induced aromatase activity, while 8PN was a strong aromatase inhibitor. Steroidogenic profiles upon GEN and 8PN exposure indicated a strong inhibitory effect on steroidogenesis in H295R cells and H295R/MCF-7 co-cultures. Based on our in vitro data we suggest that menopausal supplement intake during breast cancer treatment should better be avoided, at least until more certainty regarding the safety of supplemental use in breast cancer patients can be provided. - Highlights: Supplements containing phytoestrogens are commonly used by women with breast cancer. Phytoestrogens alter steroidogenesis in a co-culture breast cancer model. Letrozole or tamoxifen treatment is used to inhibit ER-dependent breast tumor growth. Phytoestrogens induce in vitro tumor cell growth, even in combination with LET or TAM. Use of phytoestrogens during breast cancer treatment should better be avoided.

  3. Cancer incidence among residents of the Three Mile Island accident area: 1982-1995

    SciTech Connect (OSTI)

    Han, Yueh-Ying; Youk, Ada O.; Sasser, Howell; Talbott, Evelyn O.

    2011-11-15

    Background: The Pennsylvania Department of Health established a registry of the Three Mile Island (TMI) nuclear power plant accident in 1979. Over 93% of the population present on the day of the accident within a 5-mile radius was enrolled and interviewed. We used the registry to investigate the potential cancer risk from low-dose radiation exposure among the TMI population. Methods: Cancer incidence data among the TMI cohort were available from 1982 to 1995. Because more than 97% of the population were white and few cancer cases were reported for those younger than 18 years of age, we included whites of age 18 years and older (10,446 men and 11,048 women) for further analyses. Cox regression models were used to estimate the relative risk (RR) per 0.1 m Sv and 95% confident interval (CI) of cancer by radiation-related exposures. The cancers of interest were all malignant neoplasms, cancer of bronchus, trachea, and lung, cancer of lymphatic and hematopoietic tissues, leukemia, and female breast. Results: Among men and women, there was no evidence of an increased risk for all malignant neoplasms among the TMI cohort exposed to higher maximum and likely {gamma} radiation (RR=1.00, 95% CI=0.97, 1.01 and RR=0.99, 95% CI=0.94, 1.03, respectively) after adjusting for age, gender, education, smoking, and background radiation. Elevation in risk was noted for cancer of the bronchus, trachea, and lung in relation to higher background radiation exposure (RR=1.45, 95% CI=1.02-2.05 at 8.0-8.8 {mu}R/h compared to 5.2-7.2 {mu}R/h). An increased risk of leukemia was found among men exposed to higher maximum and likely {gamma} radiation related to TMI exposure during the ten days following the accident (RR=1.15, 95% CI=1.04, 1.29 and RR=1.36, 95% CI=1.08, 1.71, respectively). This relationship was not found in women. Conclusion: Increased cancer risks from low-level radiation exposure within the TMI cohort were small and mostly statistically non-significant. However, additional follow-up on this population is warranted, especially to explore the increased risk of leukemia found in men.

  4. Survival analysis of colorectal cancer patients with tumor recurrence using global score test methodology

    SciTech Connect (OSTI)

    Zain, Zakiyah Ahmad, Yuhaniz; Azwan, Zairul E-mail: farhanaraduan@gmail.com Raduan, Farhana E-mail: farhanaraduan@gmail.com Sagap, Ismail E-mail: farhanaraduan@gmail.com; Aziz, Nazrina

    2014-12-04

    Colorectal cancer is the third and the second most common cancer worldwide in men and women respectively, and the second in Malaysia for both genders. Surgery, chemotherapy and radiotherapy are among the options available for treatment of patients with colorectal cancer. In clinical trials, the main purpose is often to compare efficacy between experimental and control treatments. Treatment comparisons often involve several responses or endpoints, and this situation complicates the analysis. In the case of colorectal cancer, sets of responses concerned with survival times include: times from tumor removal until the first, the second and the third tumor recurrences, and time to death. For a patient, the time to recurrence is correlated to the overall survival. In this study, global score test methodology is used in combining the univariate score statistics for comparing treatments with respect to each survival endpoint into a single statistic. The data of tumor recurrence and overall survival of colorectal cancer patients are taken from a Malaysian hospital. The results are found to be similar to those computed using the established Wei, Lin and Weissfeld method. Key factors such as ethnic, gender, age and stage at diagnose are also reported.

  5. Receipt of Guideline-Concordant Treatment in Elderly Prostate Cancer Patients

    SciTech Connect (OSTI)

    Chen, Ronald C., E-mail: Ronald_chen@med.unc.edu [Department of Radiation Oncology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (United States); Sheps Center for Health Services Research, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (United States); Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (United States); Carpenter, William R. [Sheps Center for Health Services Research, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (United States); Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (United States); Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (United States); Hendrix, Laura H. [Department of Radiation Oncology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (United States); Bainbridge, John [Sheps Center for Health Services Research, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (United States); Wang, Andrew Z. [Department of Radiation Oncology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (United States); Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (United States); Nielsen, Matthew E. [Sheps Center for Health Services Research, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (United States); Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (United States); Department of Urology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (United States); and others

    2014-02-01

    Purpose: To examine the proportion of elderly prostate cancer patients receiving guideline-concordant treatment, using the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database. Methods and Materials: A total of 29,001 men diagnosed in 2004-2007 with localized prostate cancer, aged 66 to 79 years, were included. We characterized the proportion of men who received treatment concordant with the National Comprehensive Cancer Network guidelines, stratified by risk group and age. Logistic regression was used to examine covariates associated with receipt of guideline-concordant management. Results: Guideline concordance was 79%-89% for patients with low- or intermediate-risk disease. Among high-risk patients, 66.6% of those aged 66-69 years received guideline-concordant management, compared with 51.9% of those aged 75-79 years. Discordance was mainly due to conservative managementno treatment or hormone therapy alone. Among the subgroup of patients aged ?76 years with no measured comorbidity, findings were similar. On multivariable analysis, older age (75-79 vs 66-69 years, odds ratio 0.51, 95% confidence interval 0.50-0.57) was associated with a lower likelihood of guideline concordance for high-risk prostate cancer, but comorbidity was not. Conclusions: There is undertreatment of elderly but healthy patients with high-risk prostate cancer, the most aggressive form of this disease.

  6. Adherence to Vaginal Dilation Following High Dose Rate Brachytherapy for Endometrial Cancer

    SciTech Connect (OSTI)

    Friedman, Lois C., E-mail: Lois.Friedman@UHhospitals.org [Department of Psychiatry, CASE Comprehensive Cancer Center and University Hospitals of Cleveland, Cleveland, OH (United States); Abdallah, Rita [Ireland Cancer Center, CASE Comprehensive Cancer Center and University Hospitals of Cleveland, Cleveland, OH (Ireland); Schluchter, Mark; Panneerselvam, Ashok [Department of Epidemiology and Biostatistics, CASE Comprehensive Cancer Center and University Hospitals of Cleveland, Cleveland, OH (United States); Kunos, Charles A. [Department of Radiation Oncology, CASE Comprehensive Cancer Center and University Hospitals of Cleveland, Cleveland, OH (United States)

    2011-07-01

    Purpose: We report demographic, clinical, and psychosocial factors associated with adherence to vaginal dilation and describe the sexual and marital or nonmarital dyadic functioning of women following high dose rate (HDR) brachytherapy for endometrial cancer. Methods and Materials: We retrospectively evaluated women aged 18 years or older in whom early-stage endometrial (IAgr3-IIB) cancers were treated by HDR intravaginal brachytherapy within the past 3.5 years. Women with or without a sexual partner were eligible. Patients completed questionnaires by mail or by telephone assessing demographic and clinical variables, adherence to vaginal dilation, dyadic satisfaction, sexual functioning, and health beliefs. Results: Seventy-eight of 89 (88%) eligible women with early-stage endometrial cancer treated with HDR brachytherapy completed questionnaires. Only 33% of patients were adherers, based on reporting having used a dilator more than two times per week in the first month following radiation. Nonadherers who reported a perceived change in vaginal dimension following radiation reported that their vaginas were subjectively smaller after brachytherapy (p = 0.013). Adherers reported more worry about their sex lives or lack thereof than nonadherers (p = 0.047). Patients reported considerable sexual dysfunction following completion of HDR brachytherapy. Conclusions: Adherence to recommendations for vaginal dilator use following HDR brachytherapy for endometrial cancer is poor. Interventions designed to educate women about dilator use benefit may increase adherence. Although sexual functioning was compromised, it is likely that this existed before having cancer for many women in our study.

  7. Cancer Associated Fibroblasts express pro-inflammatory factors in human breast and ovarian tumors

    SciTech Connect (OSTI)

    Erez, Neta; Glanz, Sarah; Raz, Yael; Department of Obstetrics and Gynecology, LIS Maternity Hospital, Tel Aviv Sourasky Medical Center, affiliated with Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv ; Avivi, Camilla; Barshack, Iris; Department of Pathology, Sheba Medical Center, Tel Hashomer, affiliated with Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv

    2013-08-02

    Highlights: CAFs in human breast and ovarian tumors express pro-inflammatory factors. Expression of pro-inflammatory factors correlates with tumor invasiveness. Expression of pro-inflammatory factors is associated with NF-?b activation in CAFs. -- Abstract: Inflammation has been established in recent years as a hallmark of cancer. Cancer Associated Fibroblasts (CAFs) support tumorigenesis by stimulating angiogenesis, cancer cell proliferation and invasion. We previously demonstrated that CAFs also mediate tumor-enhancing inflammation in a mouse model of skin carcinoma. Breast and ovarian carcinomas are amongst the leading causes of cancer-related mortality in women and cancer-related inflammation is linked with both these tumor types. However, the role of CAFs in mediating inflammation in these malignancies remains obscure. Here we show that CAFs in human breast and ovarian tumors express high levels of the pro-inflammatory factors IL-6, COX-2 and CXCL1, previously identified to be part of a CAF pro-inflammatory gene signature. Moreover, we show that both pro-inflammatory signaling by CAFs and leukocyte infiltration of tumors are enhanced in invasive ductal carcinoma as compared with ductal carcinoma in situ. The pro-inflammatory genes expressed by CAFs are known NF-?B targets and we show that NF-?B is up-regulated in breast and ovarian CAFs. Our data imply that CAFs mediate tumor-promoting inflammation in human breast and ovarian tumors and thus may be an attractive target for stromal-directed therapeutics.

  8. Recursive Partitioning Analysis for New Classification of Patients With Esophageal Cancer Treated by Chemoradiotherapy

    SciTech Connect (OSTI)

    Nomura, Motoo; Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya; Department of Radiation Oncology, Aichi Cancer Center Hospital, Nagoya ; Shitara, Kohei; Kodaira, Takeshi; Kondoh, Chihiro; Takahari, Daisuke; Ura, Takashi; Kojima, Hiroyuki; Kamata, Minoru; Muro, Kei; Sawada, Satoshi

    2012-11-01

    Background: The 7th edition of the American Joint Committee on Cancer staging system does not include lymph node size in the guidelines for staging patients with esophageal cancer. The objectives of this study were to determine the prognostic impact of the maximum metastatic lymph node diameter (ND) on survival and to develop and validate a new staging system for patients with esophageal squamous cell cancer who were treated with definitive chemoradiotherapy (CRT). Methods: Information on 402 patients with esophageal cancer undergoing CRT at two institutions was reviewed. Univariate and multivariate analyses of data from one institution were used to assess the impact of clinical factors on survival, and recursive partitioning analysis was performed to develop the new staging classification. To assess its clinical utility, the new classification was validated using data from the second institution. Results: By multivariate analysis, gender, T, N, and ND stages were independently and significantly associated with survival (p < 0.05). The resulting new staging classification was based on the T and ND. The four new stages led to good separation of survival curves in both the developmental and validation datasets (p < 0.05). Conclusions: Our results showed that lymph node size is a strong independent prognostic factor and that the new staging system, which incorporated lymph node size, provided good prognostic power, and discriminated effectively for patients with esophageal cancer undergoing CRT.

  9. BRAF activated non-coding RNA (BANCR) promoting gastric cancer cells proliferation via regulation of NF-κB1

    SciTech Connect (OSTI)

    Zhang, Zhi-Xin; Liu, Zhi-Qiang; Jiang, Biao; Lu, Xin-Yang; Ning, Xiao-Fei; Yuan, Chuan-Tao; Wang, Ai-Liang

    2015-09-18

    Background and objective: Long non-coding RNA, BANCR, has been demonstrated to contribute to the proliferation and migration of tumors. However, its molecular mechanism underlying gastric cancer is still unknown. In present study, we investigated whether BANCR was involved in the development of gastric cancer cells via regulation of NF-κB1. Methods: Human gastric cancer tissues were isolated as well as human gastric cell lines MGC803 and BGC823 were cultured to investigate the role of BANCR in gastric cancer. Results: BANCR expression was significantly up-regulated in gastric tumor tissues and gastric cell lines. Down-regulation of BANCR inhibited gastric cancer cell growth and promoted cell apoptosis, and it also contributed to a significant decrease of NF-κB1 (P50/105) expression and 3′UTR of NF-κB1 activity. Overexpression of NF-κB1 reversed the effect of BANCR on cancer cell growth and apoptosis. MiroRNA-9 (miR-9) targeted NF-κB1, and miR-9 inhibitor also reversed the effects of BANCR on gastric cancer cell growth and apoptosis. Conclusion: BANCR was highly expressed both in gastric tumor tissues and in cancer cells. NF-κB1 and miR-9 were involved in the role of BANCR in gastric cancer cell growth and apoptosis. - Highlights: • BANCR up-regulated in gastric cancer (GC) tissues and cell lines MGC803 and BGC823. • Down-regulation of BANCR inhibited GC cell growth and promoted cell apoptosis. • Down-regulation of BANCR contributed to decreased 3′UTR of NF-κB1 and its expression. • Overexpressed NF-κB1 reversed the effect of BANCR on GC cell growth. • miR-9 inhibitor reversed the effect of BANCR on cancer GC cell growth.

  10. Predictors of Postoperative Complications After Trimodality Therapy for Esophageal Cancer

    SciTech Connect (OSTI)

    Wang, Jingya [Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Wei, Caimiao [Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Tucker, Susan L. [Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Myles, Bevan; Palmer, Matthew [Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Hofstetter, Wayne L.; Swisher, Stephen G. [Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Ajani, Jaffer A. [Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Cox, James D.; Komaki, Ritsuko; Liao, Zhongxing [Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Lin, Steven H., E-mail: SHLin@mdanderson.org [Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States)

    2013-08-01

    Purpose: While trimodality therapy for esophageal cancer has improved patient outcomes, surgical complication rates remain high. The goal of this study was to identify modifiable factors associated with postoperative complications after neoadjuvant chemoradiation. Methods and Materials: From 1998 to 2011, 444 patients were treated at our institution with surgical resection after chemoradiation. Postoperative (pulmonary, gastrointestinal [GI], cardiac, wound healing) complications were recorded up to 30 days postoperatively. Kruskal-Wallis tests and ?{sup 2} or Fisher exact tests were used to assess associations between continuous and categorical variables. Multivariate logistic regression tested the association between perioperative complications and patient or treatment factors that were significant on univariate analysis. Results: The most frequent postoperative complications after trimodality therapy were pulmonary (25%) and GI (23%). Lung capacity and the type of radiation modality used were independent predictors of pulmonary and GI complications. After adjusting for confounding factors, pulmonary and GI complications were increased in patients treated with 3-dimensional conformal radiation therapy (3D-CRT) versus intensity modulated radiation therapy (IMRT; odds ratio [OR], 2.018; 95% confidence interval [CI], 1.104-3.688; OR, 1.704; 95% CI, 1.03-2.82, respectively) and for patients treated with 3D-CRT versus proton beam therapy (PBT; OR, 3.154; 95% CI, 1.365-7.289; OR, 1.55; 95% CI, 0.78-3.08, respectively). Mean lung radiation dose (MLD) was strongly associated with pulmonary complications, and the differences in toxicities seen for the radiation modalities could be fully accounted for by the MLD delivered by each of the modalities. Conclusions: The radiation modality used can be a strong mitigating factor of postoperative complications after neoadjuvant chemoradiation.

  11. Cancer Research Center Indiana University School of Medicine

    SciTech Connect (OSTI)

    Not Available

    1994-08-01

    The Department of Energy (DOE) proposes to authorize the Indiana School of Medicine to proceed with the detailed design, construction and equipping of the proposed Cancer Research Center (CRC). A grant was executed with the University on April 21, 1992. A four-story building with basement would be constructed on the proposed site over a 24-month period. The proposed project would bring together, in one building, three existing hematology/oncology basic research programs, with improved cost-effectiveness through the sharing of common resources. The proposed site is currently covered with asphaltic pavement and is used as a campus parking lot. The surrounding area is developed campus, characterized by buildings, walkways, with minimal lawns and plantings. The proposed site has no history of prior structures and no evidence of potential sources of prior contamination of the soil. Environmental impacts of construction would be limited to minor increases in traffic, and the typical noises associated with standard building construction. The proposed CRC project operation would involve the use radionuclides and various hazardous materials in conducting clinical studies. Storage, removal and disposal of hazardous wastes would be managed under existing University programs that comply with federal and state requirements. Radiological safety programs would be governed by Nuclear Regulatory Commission (NRC) license and applicable Environmental Protection Agency (EPA) regulations. There are no other NEPA reviews currently active which are in relationship to this proposed site. The proposed project is part of a Medical Campus master plan and is consistent with applicable local zoning and land use requirements.

  12. CFTB 04/22/2010 Revisions to the 2008 Census of Fatal Occupational...

    National Nuclear Security Administration (NNSA)

    maintenance, and repair occupations 345 354 9 6.6 6.7 0.1 Transportation and material moving occupations 1,330 1,376 46 15.5 16.1 0.6 Military occupations 53 57 4 NA...

  13. Level 1 Accident Report of the March 1, 2010 Bobcat Fatality...

    Energy Savers [EERE]

    at BPA's White Bluffs Substation Level 1 Accident Report of the March 1, 2010 Bobcat ... (BPA) Chief Safety Officer, a Level I Accident Investigation was convened to ...

  14. A Fern Fatale - X-ray Absorption Spectroscopy Imaging an Arsenic...

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    accumulate large amounts of it. What is more, the plant converts it to the most toxic inorganic form known. How does it do this? First some background; while there is some...

  15. CFTB 04/22/2010 Revisions to the 2008 Census of Fatal Occupational...

    National Nuclear Security Administration (NNSA)

    and warehousing 762 796 34 14.2 14.9 0.7 Professional and business services 389 403 14 2.7 2.8 0.1 Leisure and hospitality 233 238 5 2.2 2.2 - Government 7 522 544 22 2.3...

  16. Is a Higgs vacuum instability fatal for high-scale inflation?

    DOE Public Access Gateway for Energy & Science Beta (PAGES Beta)

    Kearney, John; Yoo, Hojin; Zurek, Kathryn M.

    2015-06-25

    We study the inflationary evolution of a scalar field h with an unstable potential for the case where the Hubble parameter H during inflation is larger than the instability scale ΛI of the potential. Quantum fluctuations in the field of size δh ~ H/2π imply that the unstable part of the potential is sampled during inflation. We investigate the evolution of these fluctuations to the unstable regime and in particular whether they generate cosmological defects or even terminate inflation. We apply the results of a toy scalar model to the case of the Standard Model (SM) Higgs boson, the quarticmore » of which evolves to negative values at high scales, and extend previous analyses of Higgs dynamics during inflation utilizing statistical methods to a perturbative and fully gauge-invariant formulation. We show that the dynamics are controlled by the renormalization group-improved quartic coupling λ(μ) evaluated at a scale μ = H, such that Higgs fluctuations are enhanced by the instability if H > ΛI. Even if H > ΛI, the instability in the Standard Model Higgs potential does not end inflation; instead the universe slowly sloughs off crunching patches of space that never come to dominate the evolution. As inflation proceeds past 50 e-folds, a significant proportion of patches exits inflation in the unstable vacuum, and as much as 1% of the spacetime can rapidly evolve to a defect. Depending on the nature of these defects, however, the resulting universe could still be compatible with ours.« less

  17. Are You Saved? HIM, an Intranet-based Expert System Reduces Fatality Risk

    SciTech Connect (OSTI)

    Crofts, Von David; Simpson, Wayne Winger; Hopkins, Deborah Jean; Hawke, Scott Allen

    2000-06-01

    On July 28, 1998 a devastating accident occurred at the Test Reactor Area of the Idaho National Engineering and Environmental Laboratory (INEEL). The accident cost a man his life and caused injury to others. In addition to the significant human loss, Lockheed Martin (LMITCO) experienced economic losses that reached millions of dollars. LMITCO eventually lost the managing and operating contract of a premier Department of Energy Laboratory. Just as with the INEEL, companies throughout industry today must face an ever increasingly complex world of government alphabet soup of regulationsOSHA, CAA, TSCA, FIFRA, ADA, and more. For businesses, non-compliance can quickly evaporate profits. For humans, mistakes can seriously affect health, and some work areas are so complicated that a single event could cost human life. Finally, adherence to the regulations can protect the community and the environment. Compliance with regulations is essential and multifaceted. Regulations require interpretation into company policy. Policies must be implemented as standard work practices. The workforce must be trained to follow the procedures. Management must coordinate flow down of requirements and policy for standardized work planning processes and consistent compliance with regulations. Implementing controls to ensure absolute compliance can be a very costly and cumbersome effort, thus, a graded approach is necessary to ensure cost effectiveness and relevance to actual work. The INEEL has developed technology for hazard evaluation and work planning called the Hazards Identification and Mitigation System. The HIM System is a web-based expert system that is available to all INEEL employees through the company Intranet. This tool simplifies and streamlines work planning by using a graded approach to standardize practices. The tool assists in evaluating hazards and ascertaining the required rigor for planning work. The tool integrates the knowledge of INEEL and DOE experts and previously proven review checklists and processes.The manual process is lengthysometimes taking 12 to 18 hours to complete. As such, it is difficult, prone to errors, and very tempting to shortcut. Automation of this process through the HIM system reduced a monumental hazard identification task for each work order, into a streamlined, efficient, and accurate process that can be completed in less than one hour. The result is that the process gets done, the regulations are met, and risk to human life is reduced.

  18. Residential Mobility and Lung Cancer Risk: Data-Driven Exploration Using Internet Sources

    SciTech Connect (OSTI)

    Yoon, Hong-Jun; Tourassi, Georgia; Xu, Songhua

    2015-01-01

    Frequent relocation has been linked to health decline, particularly with respect to emotional and psychological wellbeing. In this paper we investigate whether there is an association between frequent relocation and lung cancer risk. For the initial investigation we leverage two online data sources to collect cancer and control subjects using web crawling and tailored text mining. The two data sources share different strengths and weaknesses in terms of the amount of detail, population representation, and sample size. One data source includes online obituaries. The second data source includes augmented LinkedIn profiles. For each data source, the subjects spatiotemporal history is reconstructed from the available information provided in the obituaries and from the education and work experience provided in the LinkedIn profiles. The study shows that lung cancer subjects have higher mobility frequency than the control group. This trend is consistent for both data sources.

  19. A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1

    SciTech Connect (OSTI)

    Miki, Y.; Swenson, J.; Yakumo, K.; Lewis, C.; Neuhausen, S.; Goldgar, D.; Shattuck-Eidens, D.; Harshman, K.; Tavtigian, S.; Liu, Q.

    1994-10-07

    A strong candidate for the 17q-linked BRCA1 gene, which influences susceptibility to breast and ovarian cancer, has been identified by positional cloning methods. Probable predisposing mutations have been detected in five of eight kindreds presumed to segregate BRCA1 susceptibility alleles. The mutations include an 11-base pair deletion, a 1-base pair insertion, a stop codon, a missense substitution, and an inferred regulatory mutation. The BRCA1 gene is expressed in numerous tissues, including breast and ovary, and encodes a predicted protein of 1863 amino acids. This protein contains a zinc finger domain in its amino-terminal region, but is otherwise unrelated to previously described proteins. Identification of BRCA1 should facilitate early diagnosis of breast and ovarian cancer susceptibility in some individuals as well as a better understanding of breast cancer biology.

  20. Neoadjuvant Chemoradiation for Distal Rectal Cancer: 5-Year Updated Results of a Randomized Phase 2 Study of Neoadjuvant Combined Modality Chemoradiation for Distal Rectal Cancer

    SciTech Connect (OSTI)

    Mohiuddin, Mohammed, E-mail: asemuddin@gmail.com [King Faisal Specialist Hospital and Research Centre, Riyadh (Saudi Arabia)] [King Faisal Specialist Hospital and Research Centre, Riyadh (Saudi Arabia); Paulus, Rebecca [RTOG Statistical Department, Philadelphia, Pennsylvania (United States)] [RTOG Statistical Department, Philadelphia, Pennsylvania (United States); Mitchell, Edith [Thomas Jefferson University, Philadelphia, Pennsylvania (United States)] [Thomas Jefferson University, Philadelphia, Pennsylvania (United States); Hanna, Nader [Department of Surgical Oncology, University of Maryland Medical Center, Baltimore, Maryland (United States)] [Department of Surgical Oncology, University of Maryland Medical Center, Baltimore, Maryland (United States); Yuen, Albert [Reading Hospital and Medical Center, Reading, Pennsylvania (United States)] [Reading Hospital and Medical Center, Reading, Pennsylvania (United States); Nichols, Romaine [University of Florida Proton Therapy Institute, Jacksonville, Florida (United States)] [University of Florida Proton Therapy Institute, Jacksonville, Florida (United States); Yalavarthi, Salochna [Ingalls Memorial Hospital, Harvey, Illinois (United States)] [Ingalls Memorial Hospital, Harvey, Illinois (United States); Hayostek, Cherie [Santa Fe Cancer Center, Santa Fe, New Mexico (United States)] [Santa Fe Cancer Center, Santa Fe, New Mexico (United States); Willett, Christopher [Duke University Medical Center, Durham, North Carolina (United States)] [Duke University Medical Center, Durham, North Carolina (United States)

    2013-07-01

    Purpose: To assess the efficacy of 2 different approaches to neoadjuvant chemoradiation for distal rectal cancers. Methods and Materials: One hundred six patients with T3/T4 distal rectal cancers were randomized in a phase 2 study. Patients received either continuous venous infusion (CVI) of 5-Fluorouracil (5-FU), 225 mg/m{sup 2} per day, 7 days per week plus pelvic hyperfractionated radiation (HRT), 45.6 Gy at 1.2 Gy twice daily plus a boost of 9.6 to 14.4 Gy for T3 or T4 cancers (Arm 1), or CVI of 5-FU, 225 mg/m{sup 2} per day, Monday to Friday, plus irinotecan, 50 mg/m{sup 2} once weekly 4, plus pelvic radiation therapy (RT), 45 Gy at 1.8 Gy per day and a boost of 5.4 Gy for T3 and 9 Gy for T4 cancers (Arm 2). Surgery was performed 4 to 10 weeks later. Results: All eligible patients (n=103) are included in this analysis; 2 ineligible patients were excluded, and 1 patient withdrew consent. Ninety-eight of 103 patients (95%) underwent resection. Four patients did not undergo surgery for either disease progression or patient refusal, and 1 patient died during induction chemotherapy. The median time of follow-up was 6.4 years in Arm 1 and 7.0 years in Arm 2. The pathological complete response (pCR) rates were 30% in Arm 1 and 26% in Arm 2. Locoregional recurrence rates were 16% in Arm 1 and 17% in Arm 2. Five-year survival rates were 61% and 75% and Disease-specific survival rates were 78% and 85% for Arm1 and Arm 2, respectively. Five second primaries occurred in patients on Arm 1, and 1 second primary occurred in Arm 2. Conclusions: High rates of disease-specific survival were seen in each arm. Overall survival appears affected by the development of unrelated second cancers. The high pCR rates with 5-FU and higher dose radiation in T4 cancers provide opportunity for increased R0 resections and improved survival.

  1. Cancer cell-associated cytoplasmic B7–H4 is induced by hypoxia through hypoxia-inducible factor-1α and promotes cancer cell proliferation

    SciTech Connect (OSTI)

    Jeon, You-Kyoung; Park, Sae-Gwang; Choi, Il-Whan; Lee, Soo-Woong; Lee, Sang Min

    2015-04-03

    Aberrant B7–H4 expression in cancer tissues serves as a novel prognostic biomarker for poor survival in patients with cancer. However, the factor(s) that induce cancer cell-associated B7–H4 remain to be fully elucidated. We herein demonstrate that hypoxia upregulates B7–H4 transcription in primary CD138{sup +} multiple myeloma cells and cancer cell lines. In support of this finding, analysis of the Multiple Myeloma Genomics Portal (MMGP) data set revealed a positive correlation between the mRNA expression levels of B7–H4 and the endogenous hypoxia marker carbonic anhydrogenase 9. Hypoxia-induced B7–H4 expression was detected in the cytoplasm, but not in cancer cell membranes. Chromatin immunoprecipitation analysis demonstrated binding of hypoxia-inducible factor-1α (HIF-1α) to proximal hypoxia-response element (HRE) sites within the B7–H4 promoter. Knockdown of HIF-1α and pharmacological inhibition of HIF-1α diminished B7–H4 expression. Furthermore, knockdown of cytoplasmic B7–H4 in MCF-7 decreased the S-phase cell population under hypoxia. Finally, MMGP analysis revealed a positive correlation between the transcript levels of B7–H4 and proliferation-related genes including MKI67, CCNA1, and Myc in several patients with multiple myeloma. Our results provide insight into the mechanisms underlying B7–H4 upregulation and its role in cancer cell proliferation in a hypoxic tumor microenvironment. - Highlights: • Hypoxia upregulates B7–H4 transcription and protein expression. • Hypoxia-induced B7–H4 is detected in the cytoplasm, but not on membrane. • ChIP assay reveals a binding of HIF-1α to B7–H4 promoter at HRE site. • Knockdown and pharmacological inhibition of HIF-1α reduce B7–H4 expression. • B7–H4 knockdown decrease the number of cells in S-phase of cell cycle.

  2. MR-Guided High-Intensity Focused Ultrasound Ablation of Breast Cancer with a Dedicated Breast Platform

    SciTech Connect (OSTI)

    Merckel, Laura G.; Bartels, Lambertus W.; Koehler, Max O.; Bongard, H. J. G. Desiree van den; Deckers, Roel; Mali, Willem P. Th. M.; Binkert, Christoph A.; Moonen, Chrit T.; Gilhuijs, Kenneth G. A. Bosch, Maurice A. A. J. van den

    2013-04-15

    Optimizing the treatment of breast cancer remains a major topic of interest. In current clinical practice, breast-conserving therapy is the standard of care for patients with localized breast cancer. Technological developments have fueled interest in less invasive breast cancer treatment. Magnetic resonance-guided high-intensity focused ultrasound (MR-HIFU) is a completely noninvasive ablation technique. Focused beams of ultrasound are used for ablation of the target lesion without disrupting the skin and subcutaneous tissues in the beam path. MRI is an excellent imaging method for tumor targeting, treatment monitoring, and evaluation of treatment results. The combination of HIFU and MR imaging offers an opportunity for image-guided ablation of breast cancer. Previous studies of MR-HIFU in breast cancer patients reported a limited efficacy, which hampered the clinical translation of this technique. These prior studies were performed without an MR-HIFU system specifically developed for breast cancer treatment. In this article, a novel and dedicated MR-HIFU breast platform is presented. This system has been designed for safe and effective MR-HIFU ablation of breast cancer. Furthermore, both clinical and technical challenges are discussed, which have to be solved before MR-HIFU ablation of breast cancer can be implemented in routine clinical practice.

  3. Mangiferin exerts antitumor activity in breast cancer cells by regulating matrix metalloproteinases, epithelial to mesenchymal transition, and ?-catenin signaling pathway

    SciTech Connect (OSTI)

    Li, Hongzhong; Huang, Jing; Yang, Bing; Xiang, Tingxiu; Yin, Xuedong; Peng, Weiyan; Cheng, Wei; Wan, Jingyuan; Luo, Fuling; Li, Hongyuan; Ren, Guosheng

    2013-10-01

    Although mangiferin which is a naturally occurring glucosylxanthone has exhibited promising anticancer activities, the detailed molecular mechanism of mangiferin on cancers still remains enigmatic. In this study, the anticancer activity of mangiferin was evaluated in breast cancer cell line-based in vitro and in vivo models. We showed that mangiferin treatment resulted in decreased cell viability and suppression of metastatic potential in breast cancer cells. Further mechanistic investigation revealed that mangiferin induced decreased matrix metalloproteinase (MMP)-7 and -9, and reversal of epithelialmesenchymal transition (EMT). Moreover, it was demonstrated that mangiferin significantly inhibited the activation of ?-catenin pathway. Subsequent experiments showed that inhibiting ?-catenin pathway might play a central role in mangiferin-induced anticancer activity through modulation of MMP-7 and -9, and EMT. Consistent with these findings in vitro, the antitumor potential was also verified in mangiferin-treated MDA-MB-231 xenograft mice where significantly decreased tumor volume, weight and proliferation, and increased apoptosis were obtained, with lower expression of MMP-7 and -9, vimentin and active ?-catenin, and higher expression of E-cadherin. Taken together, our study suggests that mangiferin might be used as an effective chemopreventive agent against breast cancer. - Highlights: Mangiferin inhibits growth and metastatic potential in breast cancer cells. Mangiferin down-regulates MMP-7 and -9 in breast cancer cells. Mangiferin induces the reversal of EMT in metastatic breast cancer cells. Mangiferin inhibits the activation of ?-catenin pathway in breast cancer cells. Inhibiting ?-catenin is responsible for the antitumor activity of mangiferin.

  4. SciFri PM: Topics 03: The Global Task Force on Radiotherapy for Cancer Control: Core Investments

    SciTech Connect (OSTI)

    Van Dyk, J.; Jaffray, D. A.; MacPherson, M. S.

    2014-08-15

    The Union for International Cancer Control (UICC) is a membership-based, non-governmental organization with a mandate to to unite the cancer community to reduce the global cancer burden, to promote greater equity, and to integrate cancer control into the world health and development agenda. COMP is an associate member of the UICC. It is well recognized by the UICC that there are major gaps between high, and low and middle income countries, in terms of access to cancer services including access to radiation therapy. In this context, the UICC has developed a Global Task Force on Radiotherapy for Cancer Control with a charge to answer a single question: What does it cost to close the gap between what exists today and reasonable access to radiotherapy globally? The Task Force consists of leaders internationally recognized for their radiation treatment related expertise (radiation oncologists, medical physicists, radiation therapists) as well as those with global health and economics specialization. The Task Force has developed three working groups: (1) to look at the global burden of cancer; (2) to look at the infrastructure requirements (facilities, equipment, personnel); and (3) to consider outcomes in terms of numbers of lives saved and palliated patients. A report is due at the World Cancer Congress in December 2014. This presentation reviews the infrastructure considerations under analysis by the second work group. The infrastructure parameters being addressed include capital costs of buildings and equipment and operating costs, which include human resources, equipment servicing and quality control, and general overhead.

  5. Computerized detection of breast cancer on automated breast ultrasound imaging of women with dense breasts

    SciTech Connect (OSTI)

    Drukker, Karen Sennett, Charlene A.; Giger, Maryellen L.

    2014-01-15

    Purpose: Develop a computer-aided detection method and investigate its feasibility for detection of breast cancer in automated 3D ultrasound images of women with dense breasts. Methods: The HIPAA compliant study involved a dataset of volumetric ultrasound image data, views, acquired with an automated U-Systems SomoV{sup } ABUS system for 185 asymptomatic women with dense breasts (BI-RADS Composition/Density 3 or 4). For each patient, three whole-breast views (3D image volumes) per breast were acquired. A total of 52 patients had breast cancer (61 cancers), diagnosed through any follow-up at most 365 days after the original screening mammogram. Thirty-one of these patients (32 cancers) had a screening-mammogram with a clinically assigned BI-RADS Assessment Category 1 or 2, i.e., were mammographically negative. All software used for analysis was developed in-house and involved 3 steps: (1) detection of initial tumor candidates, (2) characterization of candidates, and (3) elimination of false-positive candidates. Performance was assessed by calculating the cancer detection sensitivity as a function of the number of marks (detections) per view. Results: At a single mark per view, i.e., six marks per patient, the median detection sensitivity by cancer was 50.0% (16/32) 6% for patients with a screening mammogram-assigned BI-RADS category 1 or 2similar to radiologists performance sensitivity (49.9%) for this dataset from a prior reader studyand 45.9% (28/61) 4% for all patients. Conclusions: Promising detection sensitivity was obtained for the computer on a 3D ultrasound dataset of women with dense breasts at a rate of false-positive detections that may be acceptable for clinical implementation.

  6. Homeobox A7 stimulates breast cancer cell proliferation by up-regulating estrogen receptor-alpha

    SciTech Connect (OSTI)

    Zhang, Yu; Department of Obstetrics and Gynaecology, Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia V5Z 4H4 ; Cheng, Jung-Chien; Huang, He-Feng; Leung, Peter C.K.

    2013-11-01

    Highlights: HOXA7 regulates MCF7 cell proliferation. HOXA7 up-regulates ER? expression. HOXA7 mediates estrogen-induced MCF7 cell proliferation. -- Abstract: Breast cancer is the most common hormone-dependent malignancy in women. Homeobox (HOX) transcription factors regulate many cellular functions, including cell migration, proliferation and differentiation. The aberrant expression of HOX genes has been reported to be associated with human reproductive cancers. Estradiol (E2) and its nuclear receptors, estrogen receptor (ER)-alpha and ER-beta, are known to play critical roles in the regulation of breast cancer cell growth. However, an understanding of the potential relationship between HOXA7 and ER in breast cancer cells is limited. In this study, our results demonstrate that knockdown of HOXA7 in MCF7 cells significantly decreased cell proliferation and ER? expression. In addition, HOXA7 knockdown attenuated E2-induced cell proliferation as well as progesterone receptor (PR) expression. The stimulatory effects of E2 on cell proliferation and PR expression were abolished by co-treatment with ICI 182780, a selective ER? antagonist. In contrast, overexpression of HOXA7 significantly stimulated cell proliferation and ER? expression. Moreover, E2-induced cell proliferation, as well as PR expression, was enhanced by the overexpression of HOXA7. Neither knockdown nor overexpression of HOXA7 affected the ER-beta levels. Our results demonstrate a novel mechanistic role for HOXA7 in modulating breast cancer cell proliferation via regulation of ER? expression. This finding contributes to our understanding of the role HOXA7 plays in regulating the proliferation of ER-positive cancer cells.

  7. Effects of Voice Rehabilitation After Radiation Therapy for Laryngeal Cancer: A Randomized Controlled Study

    SciTech Connect (OSTI)

    Tuomi, Lisa; Andrll, Paulin

    2014-08-01

    Background: Patients treated with radiation therapy for laryngeal cancer often experience voice problems. The aim of this randomized controlled trial was to assess the efficacy of voice rehabilitation for laryngeal cancer patients after having undergone radiation therapy and to investigate whether differences between different tumor localizations with regard to rehabilitation outcomes exist. Methods and Materials: Sixty-nine male patients irradiated for laryngeal cancer participated. Voice recordings and self-assessments of communicative dysfunction were performed 1 and 6 months after radiation therapy. Thirty-three patients were randomized to structured voice rehabilitation with a speech-language pathologist and 36 to a control group. Furthermore, comparisons with 23 healthy control individuals were made. Acoustic analyses were performed for all patients, including the healthy control individuals. The Swedish version of the Self Evaluation of Communication Experiences after Laryngeal Cancer and self-ratings of voice function were used to assess vocal and communicative function. Results: The patients who received vocal rehabilitation experienced improved self-rated vocal function after rehabilitation. Patients with supraglottic tumors who received voice rehabilitation had statistically significant improvements in voice quality and self-rated vocal function, whereas the control group did not. Conclusion: Voice rehabilitation for male patients with laryngeal cancer is efficacious regarding patient-reported outcome measurements. The patients experienced better voice function after rehabilitation. Patients with supraglottic tumors also showed an improvement in terms of acoustic voice outcomes. Rehabilitation with a speech-language pathologist is recommended for laryngeal cancer patients after radiation therapy, particularly for patients with supraglottic tumors.

  8. Noscapine induces mitochondria-mediated apoptosis in human colon cancer cells in vivo and in vitro

    SciTech Connect (OSTI)

    Yang, Zi-Rong; Liu, Meng; Peng, Xiu-Lan; Lei, Xiao-Fei; Zhang, Ji-Xiang; Dong, Wei-Guo

    2012-05-11

    Highlights: Black-Right-Pointing-Pointer Noscapine inhibited cell viability of colon cancer in a time- and dose- dependent manner. Black-Right-Pointing-Pointer G{sub 2}/M phase arrest and chromatin condensation and nuclear fragmentation were induced. Black-Right-Pointing-Pointer Noscapine promoted apoptosis via mitochondrial pathways. Black-Right-Pointing-Pointer Tumorigenicity was inhibited by noscapine. -- Abstract: Noscapine, a phthalide isoquinoline alkaloid derived from opium, has been widely used as a cough suppressant for decades. Noscapine has recently been shown to potentiate the anti-cancer effects of several therapies by inducing apoptosis in various malignant cells without any detectable toxicity in cells or tissues. However, the mechanism by which noscapine induces apoptosis in colon cancer cells remains unclear. The signaling pathways by which noscapine induces apoptosis were investigated in colon cancer cell lines treated with various noscapine concentrations for 72 h, and a dose-dependent inhibition of cell viability was observed. Noscapine effectively inhibited the proliferation of LoVo cells in vitro (IC{sub 50} = 75 {mu}M). This cytotoxicity was reflected by cell cycle arrest at G{sub 2}/M and subsequent apoptosis, as indicated by increased chromatin condensation and fragmentation, the upregulation of Bax and cytochrome c (Cyt-c), the downregulation of survivin and Bcl-2, and the activation of caspase-3 and caspase-9. Moreover, in a xenograft tumor model in mice, noscapine injection clearly inhibited tumor growth via the induction of apoptosis, which was demonstrated using a TUNEL assay. These results suggest that noscapine induces apoptosis in colon cancer cells via mitochondrial pathways. Noscapine may be a safe and effective chemotherapeutic agent for the treatment of human colon cancer.

  9. Expert Consensus Contouring Guidelines for Intensity Modulated Radiation Therapy in Esophageal and Gastroesophageal Junction Cancer

    SciTech Connect (OSTI)

    Wu, Abraham J.; Bosch, Walter R.; Chang, Daniel T.; Hong, Theodore S.; Jabbour, Salma K.; Kleinberg, Lawrence R.; Mamon, Harvey J.; Thomas, Charles R.; Goodman, Karyn A.

    2015-07-15

    Purpose/Objective(s): Current guidelines for esophageal cancer contouring are derived from traditional 2-dimensional fields based on bony landmarks, and they do not provide sufficient anatomic detail to ensure consistent contouring for more conformal radiation therapy techniques such as intensity modulated radiation therapy (IMRT). Therefore, we convened an expert panel with the specific aim to derive contouring guidelines and generate an atlas for the clinical target volume (CTV) in esophageal or gastroesophageal junction (GEJ) cancer. Methods and Materials: Eight expert academically based gastrointestinal radiation oncologists participated. Three sample cases were chosen: a GEJ cancer, a distal esophageal cancer, and a mid-upper esophageal cancer. Uniform computed tomographic (CT) simulation datasets and accompanying diagnostic positron emission tomographic/CT images were distributed to each expert, and the expert was instructed to generate gross tumor volume (GTV) and CTV contours for each case. All contours were aggregated and subjected to quantitative analysis to assess the degree of concordance between experts and to generate draft consensus contours. The panel then refined these contours to generate the contouring atlas. Results: The κ statistics indicated substantial agreement between panelists for each of the 3 test cases. A consensus CTV atlas was generated for the 3 test cases, each representing common anatomic presentations of esophageal cancer. The panel agreed on guidelines and principles to facilitate the generalizability of the atlas to individual cases. Conclusions: This expert panel successfully reached agreement on contouring guidelines for esophageal and GEJ IMRT and generated a reference CTV atlas. This atlas will serve as a reference for IMRT contours for clinical practice and prospective trial design. Subsequent patterns of failure analyses of clinical datasets using these guidelines may require modification in the future.

  10. Carcinoembryonic antigen promotes colorectal cancer progression by targeting adherens junction complexes

    SciTech Connect (OSTI)

    Bajenova, Olga; Chaika, Nina; Tolkunova, Elena; Davydov-Sinitsyn, Alexander; Gapon, Svetlana; Thomas, Peter; OBrien, Stephen

    2014-06-10

    Oncomarkers play important roles in the detection and management of human malignancies. Carcinoembryonic antigen (CEA, CEACAM5) and epithelial cadherin (E-cadherin) are considered as independent tumor markers in monitoring metastatic colorectal cancer. They are both expressed by cancer cells and can be detected in the blood serum. We investigated the effect of CEA production by MIP101 colorectal carcinoma cell lines on E-cadherin adherens junction (AJ) protein complexes. No direct interaction between E-cadherin and CEA was detected; however, the functional relationships between E-cadherin and its AJ partners: ?-, ?- and p120 catenins were impaired. We discovered a novel interaction between CEA and beta-catenin protein in the CEA producing cells. It is shown in the current study that CEA overexpression alters the splicing of p120 catenin and triggers the release of soluble E-cadherin. The influence of CEA production by colorectal cancer cells on the function of E-cadherin junction complexes may explain the link between the elevated levels of CEA and the increase in soluble E-cadherin during the progression of colorectal cancer. - Highlights: Elevated level of CEA increases the release of soluble E-cadherin during the progression of colorectal cancer. CEA over-expression alters the binding preferences between E-cadherin and its partners: ?-, ?- and p120 catenins in adherens junction complexes. CEA produced by colorectal cancer cells interacts with beta-catenin protein. CEA over-expression triggers the increase in nuclear beta-catenin. CEA over-expression alters the splicing of p120 catenin protein.

  11. Radiation Field Design and Patterns of Locoregional Recurrence Following Definitive Radiotherapy for Breast Cancer

    SciTech Connect (OSTI)

    Chen, Susie A.; Schuster, David M.; Mister, Donna; Liu Tian; Godette, Karen; Torres, Mylin A.

    2013-02-01

    Purpose: Locoregional control is associated with breast cancer-specific and overall survival in select women with breast cancer. Although several patient, tumor, and treatment characteristics have been shown to contribute to locoregional recurrence (LRR), studies evaluating factors related to radiotherapy (XRT) technique have been limited. We investigated the relationship between LRR location and XRT fields and dose delivered to the primary breast cancer in women experiencing subsequent locoregional relapse. Methods and Materials: We identified 21 women who were previously treated definitively with surgery and XRT for breast cancer. All patients developed biopsy-result proven LRR and presented to Emory University Hospital between 2004 and 2010 for treatment. Computed tomography (CT) simulation scans with XRT dose files for the initial breast cancer were fused with {sup 18}F-labeled fluorodeoxyglucose positron emission tomography (FDG PET)/CT images in DICOM (Digital Imaging and Communications in Medicine) format identifying the LRR. Each LRR was categorized as in-field, defined as {>=}95% of the LRR volume receiving {>=}95% of the prescribed whole-breast dose; marginal, defined as LRR at the field edge and/or not receiving {>=}95% of the prescribed dose to {>=}95% of the volume; or out-of-field, that is, LRR intentionally not treated with the original XRT plan. Results: Of the 24 identified LRRs (3 patients experienced two LRRs), 3 were in-field, 9 were marginal, and 12 were out-of-field. Two of the 3 in-field LRRs were marginal misses of the additional boost XRT dose. Out-of-field LRRs consisted of six supraclavicular and six internal mammary nodal recurrences. Conclusions: Most LRRs in our study occurred in areas not fully covered by the prescribed XRT dose or were purposely excluded from the original XRT fields. Our data suggest that XRT technique, field design, and dose play a critical role in preventing LRR in women with breast cancer.

  12. Downregulation of microRNA-498 in colorectal cancers and its cellular effects

    SciTech Connect (OSTI)

    Gopalan, Vinod; Smith, Robert A.; Lam, Alfred K.-Y.

    2015-01-15

    miR-498 is a non-coding RNA located intergenically in 19q13.41. Due to its predicted targeting of several genes involved in control of cellular growth, we examined the expression of miR-498 in colon cancer cell lines and a large cohort of patients with colorectal adenocarcinoma. Two colon cancer cancer cell lines (SW480 and SW48) and one normal colonic epithelial cell line (FHC) were recruited. The expression of miR-498 was tested in these cell lines by using quantitative real-time polymerase chain reaction (qRT-PCR). Tissues from 80 patients with surgical resection of colorectum (60 adenocarcinomas and 20 non-neoplastic tissues) were tested for miR-498 expression by qRT-PCR. In addition, an exogenous miR-498 (mimic) was used to detect the miRNA's effects on cell proliferation and cell cycle events in SW480 using MTT calorimetric assay and flow cytometry respectively. The colon cancer cell lines showed reduced expression of miR-498 compared to a normal colonic epithelial cell line. Mimic driven over expression of miR-498 in the SW480 cell line resulted in reduced cell proliferation and increased proportions of G2-M phase cells. In tissues, miR-498 expression was too low to be detected in all colorectal adenocarcinoma compared to non-neoplastic tissues. This suggests that the down regulation of miR-498 in colorectal cancer tissues and the direct suppressive cellular effect noted in cancer cell lines implies that miR-498 has some direct or indirect role in the pathogenesis of colorectal adenocarcinomas. - Highlights: • miR-498 is a non-coding RNA located in 19q13.41. • Colon cancer cell lines showed reduced expression of miR-498. • Mimic driven over expression of miR-498 in colon cancer cells resulted in lower cell proliferation. • miR-498 expression was down regulated in all colorectal adenocarcinoma tissues.

  13. Geek-Up[04.01.2011]: A Discovery to Fight Cancer and Other Diseases |

    Office of Energy Efficiency and Renewable Energy (EERE) Indexed Site

    Department of Energy 4.01.2011]: A Discovery to Fight Cancer and Other Diseases Geek-Up[04.01.2011]: A Discovery to Fight Cancer and Other Diseases April 1, 2011 - 5:52pm Addthis Two structures of the Mre11-Rad50 complex were solved independently and overlaid, further revealing a flexible hinge in Rad50 near the Mre11 binding site | Courtesy of Lawrence Berkeley National Laboratory Two structures of the Mre11-Rad50 complex were solved independently and overlaid, further revealing a flexible

  14. Anti-cancer agents based on 6-trifluoromethoxybenzimidazole derivatives and method of making

    DOE Patents [OSTI]

    Gakh, Andrei A.; Vovk, Mykhaylo V.; Mel'nychenko, Nina V.; Sukach, Volodymyr A.

    2012-08-14

    The present disclosure relates to novel compounds having the structural Formulas (1a,1b), stereoisomers, tautomers, racemics, prodrugs, metabolites thereof, or pharmaceutically acceptable salt and/or solvate thereof as chemotherapy agents for treating of cancer, particularly androgen-independent prostate cancer. The disclosure also relates to methods for preparing said compounds, and to pharmaceutical compositions comprising said compounds. embedded image

  15. Protocells and their use for targeted delivery of multicomponent cargos to cancer cells

    DOE Patents [OSTI]

    Brinker, C Jeffrey; Ashley, Carlee Erin; Jiang, Xingmao; Liu, Juewen; Peabody, David S; Wharton, Walker Richard; Carnes, Eric; Chackerian, Bryce; Willman, Cheryl L

    2015-03-31

    Various embodiments provide materials and methods for synthesizing protocells for use in targeted delivery of cargo components to cancer cells. In one embodiment, the lipid bilayer can be fused to the porous particle core to form a protocell. The lipid bilayer can be modified with targeting ligands or other ligands to achieve targeted delivery of cargo components that are loaded within the protocell to a target cell, e.g., a type of cancer. Shielding materials can be conjugated to the surface of the lipid bilayer to reduce undesired non-specific binding.

  16. Annexin A9 (ANXA9) biomarker and therapeutic target in epithelial cancer

    DOE Patents [OSTI]

    Hu, Zhi; Kuo, Wen-Lin; Neve, Richard M.; Gray, Joe W.

    2012-06-12

    Amplification of the ANXA9 gene in human chromosomal region 1q21 in epithelial cancers indicates a likelihood of both in vivo drug resistance and metastasis, and serves as a biomarker indicating these aspects of the disease. ANXA9 can also serve as a therapeutic target. Interfering RNAs (iRNAs) (such as siRNA and miRNA) and shRNA adapted to inhibit ANXA9 expression, when formulated in a therapeutic composition, and delivered to cells of the tumor, function to treat the epithelial cancer.

  17. Genetic linkage analysis in familial breast and ovarian cancer: Results from 214 families

    SciTech Connect (OSTI)

    Easton, D.F.; Ford, D. ); Bishop, D.T.; Crockford, G.P. )

    1993-04-01

    This paper reports the results of a collaborative linkage study involving 214 breast cancer families, including 57 breast-ovarian cancer families; this represents almost all the known families with 17q linkage data. Six markers on 17q, spanning approximately 30 cM, were typed in the families. The aims of the study were to define more precisely the localization of the disease gene, the extent of genetic heterogeneity and the characteristics of linked families and to estimate the penetrance of the 17q gene. Under the assumption of no genetic heterogeneity, the strongest linkage evidence was obtained with D17S588. Multipoint linkage analysis allowing for genetic heterogeneity provided evidence that the predisposing gene lies between the markers D17S588 and D17S250, an interval whose genetic length is estimated to be 8.3 cM in males and 18.0 cM in females. This position was supported over other intervals by odds of 66:1. The location of the gene with respect to D17S579 could not be determined unequivocally. Under the genetic model used in the analysis, the best estimate of the proportion of linked breast-ovarian cancer families was 1.0 (lower LOD -- 1 limit 0.79). In contrast, there was significant evidence of genetic heterogeneity among the families without ovarian cancer, with an estimated 45% being linked. These results suggest that a gene(s) on chromosome 17q accounts for the majority of families in which both early-onset breast cancer and ovarian cancer occur but that other genes predisposing to breast cancer exist. By examining the fit of the linkage data to different penetrance functions, the cumulative risk associated with the 17q gene was estimated to be 59% by age 50 years and 82% by age 70 years. The corresponding estimates for the breast-ovary families were 67% and 76%, and those for the families without ovarian cancer were 49% and 90%; these penetrance functions did not differ significantly from one another. 42 refs., 5 figs., 2 tabs.

  18. Cornell dots research collaboration leads to $10M cancer center > EMC2 News

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    > The Energy Materials Center at Cornell dots research collaboration leads to $10M cancer center September 24th, 2015 › Provided/Wiesner Lab A rendering of the molecular structure of a Cornell dot, which is smaller than 10 nanometers. Provided/Wiesner Lab A transmission electron microscope image of Cornell dots. C dots, which are injected into patients, are designed to either adhere to and light up cancer cells or quickly leave the body. Cornell University, in partnership with Memorial

  19. A reevaluation of cancer incidence near the Three Mile Island nuclear plant: The collision of evidence and assumptions

    SciTech Connect (OSTI)

    Wing, S.; Richardson, D.; Armstrong, D.; Crawford-Brown, D.

    1997-01-01

    Previous studies concluded that there was no evidence that the 1979 nuclear accident at Three Mile Island (TMI) affected cancer incidence in the surrounding area; however, there were logical and methodological problems in earlier reports that led us to reconsider data previously collected. A 10-mile area around TMI was divided into 69 study tracts, which were assigned radiation dose estimates based on radiation readings and models of atmospheric dispersion. Incident cancers from 1975 to 1985 were ascertained from hospital records and assigned to study tracts. Associations between accident doses and incidence rates of leukemia, lung cancer, and all cancer were assessed using relative dose estimates calculated by the earlier investigators. Adjustments were made for age, sex, socioeconomic characteristics, and preaccident variation in incidence. Considering a 2-year latency, the estimated percent increase per dose unit {plus_minus} standard error was 0.020 {plus_minus} 0.012 for all cancer, 0.082 {plus_minus} 0.032 for lung cancer, and 0.116 {plus_minus} 0.067 for leukemia. Adjustment for socioeconomic variables increased the estimates to 0.034 {plus_minus} 0.013, 0.103 {plus_minus} 0.035, and 0.139 {plus_minus} 0.073 for all cancer, lung cancer, and leukemia, respectively. Associations were generally larger considering a 5-year latency, but were based on smaller numbers of cases. Results support the hypothesis that radiation doses are related to increased cancer incidence around TMI. The analysis avoids medical detection bias, but suffers from inaccurate dose classification; therefore, results may underestimate the magnitude of the association between radiation and cancer incidence. These associations would not be expected, based on previous estimates of near-background levels of radiation exposure following the accident. 35 refs., 3 tabs.

  20. IL1{beta}-mediated Stromal COX-2 signaling mediates proliferation and invasiveness of colonic epithelial cancer cells

    SciTech Connect (OSTI)

    Zhu, Yingting; Tissue Tech Inc, Miami, FL 33173 ; Zhu, Min; Lance, Peter

    2012-11-15

    COX-2 is a major inflammatory mediator implicated in colorectal inflammation and cancer. However, the exact origin and role of COX-2 on colorectal inflammation and carcinogenesis are still not well defined. Recently, we reported that COX-2 and iNOS signalings interact in colonic CCD18Co fibroblasts. In this article, we investigated whether activation of COX-2 signaling by IL1{beta} in primary colonic fibroblasts obtained from normal and cancer patients play a critical role in regulation of proliferation and invasiveness of human colonic epithelial cancer cells. Our results demonstrated that COX-2 level was significantly higher in cancer associated fibroblasts than that in normal fibroblasts with or without stimulation of IL-1{beta}, a powerful stimulator of COX-2. Using in vitro assays for estimating proliferative and invasive potential, we discovered that the proliferation and invasiveness of the epithelial cancer cells were much greater when the cells were co-cultured with cancer associated fibroblasts than with normal fibroblasts, with or without stimulation of IL1{beta}. Further analysis indicated that the major COX-2 product, prostaglandin E{sub 2}, directly enhanced proliferation and invasiveness of the epithelial cancer cells in the absence of fibroblasts. Moreover, a selective COX-2 inhibitor, NS-398, blocked the proliferative and invasive effect of both normal and cancer associate fibroblasts on the epithelial cancer cells, with or without stimulation of IL-1{beta}. Those results indicate that activation of COX-2 signaling in the fibroblasts plays a major role in promoting proliferation and invasiveness of the epithelial cancer cells. In this process, PKC is involved in the activation of COX-2 signaling induced by IL-1{beta} in the fibroblasts.

  1. SU-E-J-115: Using Markov Chain Modeling to Elucidate Patterns in Breast Cancer Metastasis Over Time and Space

    SciTech Connect (OSTI)

    Comen, E; Mason, J; Kuhn, P; Nieva, J; Newton, P; Norton, L; Venkatappa, N; Jochelson, M

    2014-06-01

    Purpose: Traditionally, breast cancer metastasis is described as a process wherein cancer cells spread from the breast to multiple organ systems via hematogenous and lymphatic routes. Mapping organ specific patterns of cancer spread over time is essential to understanding metastatic progression. In order to better predict sites of metastases, here we demonstrate modeling of the patterned migration of metastasis. Methods: We reviewed the clinical history of 453 breast cancer patients from Memorial Sloan Kettering Cancer Center who were non-metastatic at diagnosis but developed metastasis over time. We used the variables of organ site of metastases as well as time to create a Markov chain model of metastasis. We illustrate the probabilities of metastasis occurring at a given anatomic site together with the probability of spread to additional sites. Results: Based on the clinical histories of 453 breast cancer patients who developed metastasis, we have learned (i) how to create the Markov transition matrix governing the probabilities of cancer progression from site to site; (ii) how to create a systemic network diagram governing disease progression modeled as a random walk on a directed graph; (iii) how to classify metastatic sites as sponges that tend to only receive cancer cells or spreaders that receive and release them; (iv) how to model the time-scales of disease progression as a Weibull probability distribution function; (v) how to perform Monte Carlo simulations of disease progression; and (vi) how to interpret disease progression as an entropy-increasing stochastic process. Conclusion: Based on our modeling, metastatic spread may follow predictable pathways. Mapping metastasis not simply by organ site, but by function as either a spreader or sponge fundamentally reframes our understanding of metastatic processes. This model serves as a novel platform from which we may integrate the evolving genomic landscape that drives cancer metastasis. PS-OC Trans-Network Project Grant Award for Data Assimilation and ensemble statistical forecasting methods applied to the MSKCC longitudinal metastatic breast cancer cohort..

  2. MicroRNA-320a suppresses human colon cancer cell proliferation by directly targeting {beta}-catenin

    SciTech Connect (OSTI)

    Sun, Jian-Yong; State Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, 710032 Xi'an ; Huang, Yi; Li, Ji-Peng; Zhang, Xiang; Wang, Lei; Meng, Yan-Ling; Yan, Bo; Bian, Yong-Qian; Zhao, Jing; Wang, Wei-Zhong; and others

    2012-04-20

    Highlights: Black-Right-Pointing-Pointer miR-320a is downregulated in human colorectal carcinoma. Black-Right-Pointing-Pointer Overexpression of miR-320a inhibits colon cancer cell proliferation. Black-Right-Pointing-Pointer {beta}-Catenin is a direct target of miR-320a in colon cancer cells. Black-Right-Pointing-Pointer miR-320a expression inversely correlates with mRNA expression of {beta}-catenin's target genes in human colon carcinoma. -- Abstract: Recent profile studies of microRNA (miRNA) expression have documented a deregulation of miRNA (miR-320a) in human colorectal carcinoma. However, its expression pattern and underlying mechanisms in the development and progression of colorectal carcinoma has not been elucidated clearly. Here, we performed real-time PCR to examine the expression levels of miR-320a in colon cancer cell lines and tumor tissues. And then, we investigated its biological functions in colon cancer cells by a gain of functional strategy. Further more, by the combinational approaches of bioinformatics and experimental validation, we confirmed target associations of miR-320a in colorectal carcinoma. Our results showed that miR-320a was frequently downregulated in cancer cell lines and colon cancer tissues. And we demonstrated that miR-320a restoration inhibited colon cancer cell proliferation and {beta}-catenin, a functionally oncogenic molecule was a direct target gene of miR-320a. Finally, the data of real-time PCR showed the reciprocal relationship between miR-320a and {beta}-catenin's downstream genes in colon cancer tissues. These findings indicate that miR-320a suppresses the growth of colon cancer cells by directly targeting {beta}-catenin, suggesting its application in prognosis prediction and cancer treatment.

  3. Bolus electron conformal therapy for the treatment of recurrent inflammatory breast cancer: a case report

    SciTech Connect (OSTI)

    Kim, Michelle M.; Kudchadker, Rajat J.; Kanke, James E.; Zhang, Sean; Perkins, George H.

    2012-07-01

    The treatment of locoregionally recurrent breast cancer in patients who have previously undergone radiation therapy is challenging. Special techniques are often required that both eradicate the disease and minimize the risks of retreatment. We report the case of a patient with an early-stage left breast cancer who developed inflammatory-type recurrence requiring re-irradiation of the chest wall using bolus electron conformal therapy with image-guided treatment delivery. The patient was a 51-year-old woman who had undergone lumpectomy, axillary lymph node dissection, and adjuvant whole-breast radiation therapy for a stage I left breast cancer in June 1998. In March 2009, she presented at our institution with biopsy-proven recurrent inflammatory carcinoma and was aggressively treated with multi-agent chemotherapy followed by mastectomy that left a positive surgical margin. Given the patient's prior irradiation and irregular chest wall anatomy, bolus electron conformal therapy was used to treat her chest wall and draining lymphatics while sparing the underlying soft tissue. The patient still had no evidence of disease 21 months after treatment. Our results indicate that bolus electron conformal therapy is an accessible, effective radiation treatment approach for recurrent breast cancer in patients with irregular chest wall anatomy as a result of surgery. This approach may complement standard techniques used to reduce locoregional recurrence in the postmastectomy setting.

  4. Distinct p53 genomic binding patterns in normal and cancer-derived human cells

    SciTech Connect (OSTI)

    Botcheva K.; McCorkle S. R.; McCombie W. R.; Dunn J. J.; Anderson C. W.

    2011-12-15

    We report here genome-wide analysis of the tumor suppressor p53 binding sites in normal human cells. 743 high-confidence ChIP-seq peaks representing putative genomic binding sites were identified in normal IMR90 fibroblasts using a reference chromatin sample. More than 40% were located within 2 kb of a transcription start site (TSS), a distribution similar to that documented for individually studied, functional p53 binding sites and, to date, not observed by previous p53 genome-wide studies. Nearly half of the high-confidence binding sites in the IMR90 cells reside in CpG islands, in marked contrast to sites reported in cancer-derived cells. The distinct genomic features of the IMR90 binding sites do not reflect a distinct preference for specific sequences, since the de novo developed p53 motif based on our study is similar to those reported by genome-wide studies of cancer cells. More likely, the different chromatin landscape in normal, compared with cancer-derived cells, influences p53 binding via modulating availability of the sites. We compared the IMR90 ChIPseq peaks to the recently published IMR90 methylome1 and demonstrated that they are enriched at hypomethylated DNA. Our study represents the first genome-wide, de novo mapping of p53 binding sites in normal human cells and reveals that p53 binding sites reside in distinct genomic landscapes in normal and cancer-derived human cells.

  5. EPA`s program for risk assessment guidelines: Cancer classification issues

    SciTech Connect (OSTI)

    Wiltse, J.

    1990-12-31

    Issues presented are related to classification of weight of evidence in cancer risk assessments. The focus in this paper is on lines of evidence used in constructing a conclusion about potential human carcinogenicity. The paper also discusses issues that are mistakenly addressed as classification issues but are really part of the risk assessment process. 2 figs.

  6. New Breast Cancer Recursive Partitioning Analysis Prognostic Index in Patients With Newly Diagnosed Brain Metastases

    SciTech Connect (OSTI)

    Niwinska, Anna; Murawska, Magdalena

    2012-04-01

    Purpose: The aim of the study was to present a new breast cancer recursive partitioning analysis (RPA) prognostic index for patients with newly diagnosed brain metastases as a guide in clinical decision making. Methods and Materials: A prospectively collected group of 441 consecutive patients with breast cancer and brain metastases treated between the years 2003 and 2009 was assessed. Prognostic factors significant for univariate analysis were included into RPA. Results: Three prognostic classes of a new breast cancer RPA prognostic index were selected. The median survival of patients within prognostic Classes I, II, and III was 29, 9, and 2.4 months, respectively (p < 0.0001). Class I included patients with one or two brain metastases, without extracranial disease or with controlled extracranial disease, and with Karnofsky performance status (KPS) of 100. Class III included patients with multiple brain metastases with KPS of {<=}60. Class II included all other cases. Conclusions: The breast cancer RPA prognostic index is an easy and valuable tool for use in clinical practice. It can select patients who require aggressive treatment and those in whom whole-brain radiotherapy or symptomatic therapy is the most reasonable option. An individual approach is required for patients from prognostic Class II.

  7. Berkeley Scientists Find New Way to Get Physical in the Fight Against Cancer

    SciTech Connect (OSTI)

    2010-01-01

    In these time lapse images, in the left panel an invasive cancer cell engages with ephrin-A1, in the center panel the fluorescently labeled ephrin-A1 is transported beneath the cell, and in the right panel, the ephrin-A1 has gathered into clusters that correspond to darkened areas within the cell.

  8. A high incidence of BRCA1 mutations in 20 breast-ovarian cancer families

    SciTech Connect (OSTI)

    Serova, O.; Montagna, M.; Sylla, B.

    1996-01-01

    We have analyzed 20 breast-ovarian cancer families, the majority of which show positive evidence of linkage to chromosome 17q12, for germ-line mutations in the BRCA1 gene. BRCA1 mutations cosegregating with breast and ovarian cancer susceptibility were identified in 16 families, including 1 family with a case of male breast cancer. Nine of these mutations have not been reported previously. The majority of mutations were found to generate a premature stop codon leading to the formation of a truncated BRCA1 protein of 2%-88% of the expected normal length. Two mutations altered the RING finger domain. Sequencing of genomic DNA led to the identification of a mutation in the coding region of BRCA1 in 12 families, and cDNA analysis revealed an abnormal or missing BRCA1 transcript in 4 of the 8 remaining families. A total of eight mutations were associated with a reduced quantity of BRCA1 transcript. We were unable to detect BRCA1 mutations in 4 of the 20 families, but only 1 of these was clearly linked to BRCA1. It is expected that the majority of clear examples of the breast-ovarian cancer syndrome will be associated with germ-line mutations in the coding region of BRCA1. 30 refs., 4 figs., 3 tabs.

  9. Early Detection of Melanoma and other Cancers in Residents of Nevada

    SciTech Connect (OSTI)

    David Ward, PhD and Nicholas Vogelzang, MD

    2006-10-30

    The overall goal of this project was to develop simple and inexpensive tests to screen for the presence of early stage cancer in the residents of Nevada with a particular emphasis on the membership of the Hotel Employee Restaurant Employee International Union (HEREIU) in Las Vegas. Our specific goals were: 1) to develop a clinical database of individuals with cancer and to create a biological specimen Collection and Storage Systems (the NVCI bio-bank); 2) to initiate screening of individuals for proteomic markers indicating susceptibility to or the presence of specific cancers, e.g. breast, ovarian, prostate and bladder. In addition, we proposed the implementation of novel digital imaging technologies to detect melanoma; 3) to genotype blood samples from individuals who consent to participate in IRB approved research studies using a high throughput single nucleotide polymorphisms (SNP) method based on optical thin-film biosensor chip technology; and 4) to conduct biostatistical analysis of clinical, demographic, genetic, proteomic and digital imaging data to stratify the population cohort into relative risk groups for cancers that are prevalent in Nevada.

  10. Health status of young children with cancer following discontinuation of therapy

    SciTech Connect (OSTI)

    Pastore, G.; Zurlo, M.G.; Acquaviva, A.; Calculli, G.; Castello, M.; Ceci, A.; Di Tullio, M.L.; Gandus, S.; Macchia, P.; Di Montezemolo, L.C.

    1987-01-01

    This paper reports late effects and health status of 198 children who had cancer or leukemia diagnosed under 2 years of age and their therapies electively withdrawn. This series (92 neuroblastoma (NBL), 57 Wilms' tumor (WT), 46 acute lymphoblastic leukemia (ALL), and 3 non-Hodgkin's lymphoma) was followed for 1-12 years after discontinuation of therapy. Thirty-three children were diagnosed before 1973, 92 between 1973 and 1977, and 73 after 1977 in 16 Italian Pediatric Oncology Centers. As of December 1983, 176 children were reported to be alive and without evidence of primary cancer by physicians responsible for their care. One child died from a second primary tumor, two from late recurrences of the primary cancer, and three from other causes; eight were alive with evidence of primary cancer; and eight were lost to follow-up. Kyphoscoliosis was found in 22 children and other musculoskeletal anomalies in 8. Neurological sequelae were observed in 8 of 35 children with ALL treated with radiotherapy (RT) and intrathecal methotrexate. All but one were in continuous complete remission when they developed seizures (three cases), leukoencephalopathy (three cases), or intracerebral calcifications (two cases). One child had cardiomyopathy and subsequently died from cardiac failure: he had received doxorubicin (400 mg/m2) and mediastinal RT (13 Gy) for NBL. Growth impairments were observed in children with NBL and WT.

  11. SU-E-T-208: Incidence Cancer Risk From the Radiation Treatment for Acoustic Neuroma Patient

    SciTech Connect (OSTI)

    Kim, D; Chung, W; Shin, D; Yoon, M

    2014-06-01

    Purpose: The present study aimed to compare the incidence risk of a secondary cancer from therapeutic doses in patients receiving intensitymodulated radiotherapy (IMRT), volumetric modulated arc therapy (VMAT), and stereotactic radiosurgery (SRS). Methods: Four acoustic neuroma patients were treated with IMRT, VMAT, or SRS. Their incidnece excess relative risk (ERR), excess absolute risk (EAR), and lifetime attributable risk (LAR) were estimated using the corresponding therapeutic doses measured at various organs by radio-photoluminescence glass dosimeters (RPLGD) placed inside a humanoid phantom. Results: When a prescription dose was delivered in the planning target volume of the 4 patients, the average organ equivalent doses (OED) at the thyroid, lung, normal liver, colon, bladder, prostate (or ovary), and rectum were measured. The OED decreased as the distance from the primary beam increased. The thyroid received the highest OED compared to other organs. A LAR were estimated that more than 0.03% of AN patients would get radiation-induced cancer. Conclusion: The tyroid was highest radiation-induced cancer risk after radiation treatment for AN. We found that LAR can be increased by the transmitted dose from the primary beam. No modality-specific difference in radiation-induced cancer risk was observed in our study.

  12. Tomsk Polytechnic University cyclotron as a source for neutron based cancer treatment

    SciTech Connect (OSTI)

    Lisin, V. A.; Tomsk Polytechnic University, 30 Lenina av., Tomsk 634050 ; Bogdanov, A. V.; Golovkov, V. M.; Sukhikh, L. G.; Verigin, D. A.; Musabaeva, L. I.

    2014-02-15

    In this paper we present our cyclotron based neutron source with average energy 6.3 MeV generated during the 13.6 MeV deuterons interactions with beryllium target, neutron field dosimetry, and dosimetry of attendant gamma fields. We also present application of our neutron source for cancer treatment.

  13. Cancer risk estimates from radiation therapy for heterotopic ossification prophylaxis after total hip arthroplasty

    SciTech Connect (OSTI)

    Mazonakis, Michalis; Berris, Theoharris; Damilakis, John; Lyraraki, Efrossyni

    2013-10-15

    Purpose: Heterotopic ossification (HO) is a frequent complication following total hip arthroplasty. This study was conducted to calculate the radiation dose to organs-at-risk and estimate the probability of cancer induction from radiotherapy for HO prophylaxis.Methods: Hip irradiation for HO with a 6 MV photon beam was simulated with the aid of a Monte Carlo model. A realistic humanoid phantom representing an average adult patient was implemented in Monte Carlo environment for dosimetric calculations. The average out-of-field radiation dose to stomach, liver, lung, prostate, bladder, thyroid, breast, uterus, and ovary was calculated. The organ-equivalent-dose to colon, that was partly included within the treatment field, was also determined. Organ dose calculations were carried out using three different field sizes. The dependence of organ doses upon the block insertion into primary beam for shielding colon and prosthesis was investigated. The lifetime attributable risk for cancer development was estimated using organ, age, and gender-specific risk coefficients.Results: For a typical target dose of 7 Gy, organ doses varied from 1.0 to 741.1 mGy by the field dimensions and organ location relative to the field edge. Blocked field irradiations resulted in a dose range of 1.4146.3 mGy. The most probable detriment from open field treatment of male patients was colon cancer with a high risk of 564.3 10{sup ?5} to 837.4 10{sup ?5} depending upon the organ dose magnitude and the patient's age. The corresponding colon cancer risk for female patients was (372.2541.0) 10{sup ?5}. The probability of bladder cancer development was more than 113.7 10{sup ?5} and 110.3 10{sup ?5} for males and females, respectively. The cancer risk range to other individual organs was reduced to (0.00368.5) 10{sup ?5}.Conclusions: The risk for cancer induction from radiation therapy for HO prophylaxis after total hip arthroplasty varies considerably by the treatment parameters, organ site in respect to treatment volume and patient's gender and age. The presented risk estimates may be useful in the follow-up studies of irradiated patients.

  14. Breast cancer drugs dampen vascular functions by interfering with nitric oxide signaling in endothelium

    SciTech Connect (OSTI)

    Gajalakshmi, Palanivel; Priya, Mani Krishna; Pradeep, Thangaraj; Behera, Jyotirmaya; Muthumani, Kandasamy; Madhuwanti, Srinivasan; Saran, Uttara; Chatterjee, Suvro

    2013-06-01

    Widely used chemotherapeutic breast cancer drugs such as Tamoxifen citrate (TC), Capecitabine (CP) and Epirubicin (EP) are known to cause various cardiovascular side-effects among long term cancer survivors. Vascular modulation warrants nitric oxide (NO) signal transduction, which targets the vascular endothelium. We hypothesize that TC, CP and EP interference with the nitric oxide downstream signaling specifically, could lead to cardiovascular dysfunctions. The results demonstrate that while all three drugs attenuate NO and cyclic guanosine mono-phosphate (cGMP) production in endothelial cells, they caused elevated levels of NO in the plasma and RBC. However, PBMC and platelets did not show any significant changes under treatment. This implies that the drug effects are specific to the endothelium. Altered eNOS and phosphorylated eNOS (Ser-1177) localization patterns in endothelial cells were observed following drug treatments. Similarly, the expression of phosphorylated eNOS (Ser-1177) protein was decreased under the treatment of drugs. Altered actin polymerization was also observed following drug treatment, while addition of SpNO and 8Br-cGMP reversed this effect. Incubation with the drugs decreased endothelial cell migration whereas addition of YC-1, SC and 8Br-cGMP recovered the effect. Additionally molecular docking studies showed that all three drugs exhibited a strong binding affinity with the catalytic domain of human sGC. In conclusion, results indicate that TC, CP and EP cause endothelial dysfunctions via the NOsGCcGMP pathway and these effects could be recovered using pharmaceutical agonists of NO signaling pathway. Further, the study proposes a combination therapy of chemotherapeutic drugs and cGMP analogs, which would confer protection against chemotherapy mediated vascular dysfunctions in cancer patients. - Highlights: NO production is reduced in endothelial cells under breast cancer drug treatment. Cellular cGMP level is decreased under the treatments of breast cancer drugs. Breast cancer drugs induce vasoconstriction by interfering with NO pathway. NO donors, cGMP analogs rescue breast cancer drug induced endothelial dysfunctions.

  15. Oestradiol reduces Liver Receptor Homolog-1 mRNA transcript stability in breast cancer cell lines

    SciTech Connect (OSTI)

    Lazarus, Kyren A.; Environmental and Biotechnology Centre, Swinburne University, Hawthorn, Victoria 3122 ; Zhao, Zhe; Knower, Kevin C.; To, Sarah Q.; Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria 3168 ; Chand, Ashwini L.; Clyne, Colin D.

    2013-08-30

    Highlights: LRH-1 is an orphan nuclear receptor that regulates tumor proliferation. In breast cancer, high mRNA expression is associated with ER+ status. In ER?ve cells, despite very low mRNA, we found abundant LRH-1 protein. Our data show distinctly different LRH-1 protein isoforms in ER? and ER+ breast cancer cells. This is due to differences in LRH-1 mRNA and protein stability rates. -- Abstract: The expression of orphan nuclear receptor Liver Receptor Homolog-1 (LRH-1) is elevated in breast cancer and promotes proliferation, migration and invasion in vitro. LRH-1 expression is regulated by oestrogen (E{sub 2}), with LRH-1 mRNA transcript levels higher in oestrogen receptor ? (ER?) positive (ER+) breast cancer cells compared to ER? cells. However, the presence of LRH-1 protein in ER? cells suggests discordance between mRNA transcript levels and protein expression. To understand this, we investigated the impact of mRNA and protein stability in determining LRH-1 protein levels in breast cancer cells. LRH-1 transcript levels were significantly higher in ER+ versus ER? breast cancer cells lines; however LRH-1 protein was expressed at similar levels. We found LRH-1 mRNA and protein was more stable in ER? compared to ER+ cell lines. The tumor-specific LRH-1 variant isoform, LRH-1v4, which is highly responsive to E{sub 2}, showed increased mRNA stability in ER? versus ER+ cells. In addition, in MCF-7 and T47-D cell lines, LRH-1 total mRNA stability was reduced with E{sub 2} treatment, this effect mediated by ER?. Our data demonstrates that in ER? cells, increased mRNA and protein stability contribute to the abundant protein expression levels. Expression and immunolocalisation of LRH-1 in ER? cells as well as ER? tumors suggests a possible role in the development of ER? tumors. The modulation of LRH-1 bioactivity may therefore be beneficial as a treatment option in both ER? and ER+ breast cancer.

  16. Low doses ionizing radiation enhances the invasiveness of breast cancer cells by inducing epithelial-mesenchymal transition

    SciTech Connect (OSTI)

    Zhang, Xin; Li, Xiaoyan; Zhang, Ning; Yang, Qifeng; Moran, Meena S.

    2011-08-19

    Highlights: {yields} Low doses ionizing irradiation would enhance the invasiveness of breast cancer cells by inducing EMT. {yields} Low doses ionizing radiation induced morphologic changes in breast cancer cells. {yields} Low doses ionizing radiation led to upregulation of mesenchymal markers and down-regulation of epithelial markers. {yields} Low doses ionizing radiation increased migration and invasion of breast cancer cells. -- Abstract: Epithelial-mesenchymal transition (EMT) is a process cellular morphologic and molecular alterations facilitate cell invasion. We hypothesized that low dose ionizing irradiation (LDIR) enhances the invasiveness of breast cancer cells by inducing EMT. The effects of LDIR on cellular morphology and the EMT markers of MCF-7 breast cancer cells were analyzed by western blot/RT-PCR and migration/invasion was examined using the transwell assay. We found that LDIR led to the phenotypic changes of EMT in MCF-7 cells and down-regulation of epithelial differentiation markers and transcriptional induction of mesenchymal markers. Furthermore, the radiated cells demonstrated enhanced migration/invasion MCF-7 cells compared with non-radiated cells. In summary, LDIR promotes the invasiveness of breast cancer cells through epithelial to mesenchymal transition. These findings may ultimately provide a new targeted approach for improving the therapeutic effectiveness of radiation in breast cancer.

  17. The oncoprotein HBXIP upregulates PDGFB via activating transcription factor Sp1 to promote the proliferation of breast cancer cells

    SciTech Connect (OSTI)

    Zhang, Yingyi; Zhao, Yu; Li, Leilei; Shen, Yu; Cai, Xiaoli; Zhang, Xiaodong; Ye, Lihong

    2013-05-03

    Highlights: HBXIP is able to upregulate the expression of PDGFB in breast cancer cells. HBXIP serves as a coactivator of activating transcription factor Sp1. HBXIP stimulates the PDGFB promoter via activating transcription factor Sp1. HBXIP promotes the proliferation of breast cancer cell via upregulating PDGFB. -- Abstract: We have reported that the oncoprotein hepatitis B virus X-interacting protein (HBXIP) acts as a novel transcriptional coactivator to promote proliferation and migration of breast cancer cells. Previously, we showed that HBXIP was able to activate nuclear factor-?B (NF-?B) in breast cancer cells. As an oncogene, the platelet-derived growth factor beta polypeptide (PDGFB) plays crucial roles in carcinogenesis. In the present study, we found that both HBXIP and PDGFB were highly expressed in breast cancer cell lines. Interestingly, HBXIP was able to increase transcriptional activity of NF-?B through PDGFB, suggesting that HBXIP is associated with PDGFB in the cells. Moreover, HBXIP was able to upregulate PDGFB at the levels of mRNA, protein and promoter in the cells. Then, we identified that HBXIP stimulated the promoter of PDGFB through activating transcription factor Sp1. In function, HBXIP enhanced the proliferation of breast cancer cells through PDGFB in vitro. Thus, we conclude that HBXIP upregulates PDGFB via activating transcription factor Sp1 to promote proliferation of breast cancer cells.

  18. Cell migration or cytokinesis and proliferation? Revisiting the go or grow hypothesis in cancer cells in vitro

    SciTech Connect (OSTI)

    Garay, Tams; Juhsz, va; Molnr, Eszter; Eisenbauer, Maria; Czirk, Andrs; Dekan, Barbara; Lszl, Viktria; Hoda, Mir Alireza; Dme, Balzs; Tmr, Jzsef; Klepetko, Walter; Berger, Walter; Heged?s, Balzs

    2013-12-10

    The mortality of patients with solid tumors is mostly due to metastasis that relies on the interplay between migration and proliferation. The go or grow hypothesis postulates that migration and proliferation spatiotemporally excludes each other. We evaluated this hypothesis on 35 cell lines (12 mesothelioma, 13 melanoma and 10 lung cancer) on both the individual cell and population levels. Following three-day-long videomicroscopy, migration, proliferation and cytokinesis-length were quantified. We found a significantly higher migration in mesothelioma cells compared to melanoma and lung cancer while tumor types did not differ in mean proliferation or duration of cytokinesis. Strikingly, we found in melanoma and lung cancer a significant positive correlation between mean proliferation and migration. Furthermore, non-dividing melanoma and lung cancer cells displayed slower migration. In contrast, in mesothelioma there were no such correlations. Interestingly, negative correlation was found between cytokinesis-length and migration in melanoma. FAK activation was higher in melanoma cells with high motility. We demonstrate that the cancer cells studied do not defer proliferation for migration. Of note, tumor cells from various organ systems may differently regulate migration and proliferation. Furthermore, our data is in line with the observation of pathologists that highly proliferative tumors are often highly invasive. - Highlights: We investigated the go or grow hypothesis in human cancer cells in vitro. Proliferation and migration positively correlate in melanoma and lung cancer cells. Duration of cytokinesis and migration shows inverse correlation. Increased FAK activation is present in highly motile melanoma cells.

  19. Uncertainty and sensitivity analysis of chronic exposure results with the MACCS reactor accident consequence model

    SciTech Connect (OSTI)

    Helton, J.C.; Johnson, J.D.; Rollstin, J.A.; Shiver, A.W.; Sprung, J.L.

    1995-01-01

    Uncertainty and sensitivity analysis techniques based on Latin hypercube sampling, partial correlation analysis and stepwise regression analysis are used in an investigation with the MACCS model of the chronic exposure pathways associated with a severe accident at a nuclear power station. The primary purpose of this study is to provide guidance on the variables to be considered in future review work to reduce the uncertainty in the important variables used in the calculation of reactor accident consequences. The effects of 75 imprecisely known input variables on the following reactor accident consequences are studied: crop growing season dose, crop long-term dose, water ingestion dose, milk growing season dose, long-term groundshine dose, long-term inhalation dose, total food pathways dose, total ingestion pathways dose, total long-term pathways dose, total latent cancer fatalities, area-dependent cost, crop disposal cost, milk disposal cost, population-dependent cost, total economic cost, condemnation area, condemnation population, crop disposal area and milk disposal area. When the predicted variables are considered collectively, the following input variables were found to be the dominant contributors to uncertainty: dry deposition velocity, transfer of cesium from animal feed to milk, transfer of cesium from animal feed to meat, ground concentration of Cs-134 at which the disposal of milk products will be initiated, transfer of Sr-90 from soil to legumes, maximum allowable ground concentration of Sr-90 for production of crops, fraction of cesium entering surface water that is consumed in drinking water, groundshine shielding factor, scale factor defining resuspension, dose reduction associated with decontamination, and ground concentration of 1-131 at which disposal of crops will be initiated due to accidents that occur during the growing season.

  20. Health and safety impacts related to the management of spent nuclear fuels

    SciTech Connect (OSTI)

    Jilek, D.C.

    1996-06-01

    Under the Nuclear Waste Policy Act of 1982, as amended, the U.S. Department of Energy is responsible for managing the disposal of spent nuclear fuel from civilian nuclear power plants. Deployment of a multipurpose canister (MPC) system for dry storage of commercial spent nuclear fuel at reactor sites was determined to be an option for managing spent nuclear fuel until either a permanent repository or interim central storage facility (commonly called a Monitored Retrievable Storage Facility, or MRS) becomes available. Routine health and safety impacts to workers from handling and storage operations at nuclear facilities for four separate scenarios were evaluated for the MPC system: an on-time repository with an MRS; an on-time repository with no MRS; a delayed repository with an MRS; and a delayed repository with no MRS. In addition to evaluating the MPC system, five alternatives were analyzed. These included the No Action Alternative (NAA), Current Technology (CTr), the Transposable Storage Cask (TSC), the Dual-Purpose Canister (DPC), and the Small MPC (SmMPC). Health effects are expressed as collective doses in person- rem per year and risks as latent cancer fatalities per year for incident-free operations for each alternative and scenario. Results show that both dose and risks to workers vary as much as 68{percent} among scenarios and alternatives. Although dose estimates and risks fall below limits for radiation dose to workers as specified in Title 10, Part 20, of the Code of Federal Regulations, additional measures could be applied to reduce potential doses and resultant health risk. 5 refs., 2 tabs.

  1. Targeting ceramide metabolic pathway induces apoptosis in human breast cancer cell lines

    SciTech Connect (OSTI)

    Vethakanraj, Helen Shiphrah; Babu, Thabraz Ahmed; Sudarsanan, Ganesh Babu; Duraisamy, Prabhu Kumar; Ashok Kumar, Sekar

    2015-08-28

    The sphingolipid ceramide is a pro apoptotic molecule of ceramide metabolic pathway and is hydrolyzed to proliferative metabolite, sphingosine 1 phosphate by the action of acid ceramidase. Being upregulated in the tumors of breast, acid ceramidase acts as a potential target for breast cancer therapy. We aimed at targeting this enzyme with a small molecule acid ceramidase inhibitor, Ceranib 2 in human breast cancer cell lines MCF 7 and MDA MB 231. Ceranib 2 effectively inhibited the growth of both the cell lines in dose and time dependant manner. Morphological apoptotic hallmarks such as chromatin condensation, fragmented chromatin were observed in AO/EtBr staining. Moreover, ladder pattern of fragmented DNA observed in DNA gel electrophoresis proved the apoptotic activity of Ceranib 2 in breast cancer cell lines. The apoptotic events were associated with significant increase in the expression of pro-apoptotic genes (Bad, Bax and Bid) and down regulation of anti-apoptotic gene (Bcl 2). Interestingly, increase in sub G1 population of cell cycle phase analysis and elevated Annexin V positive cells after Ceranib 2 treatment substantiated its apoptotic activity in MCF 7 and MDA MB 231 cell lines. Thus, we report Ceranib 2 as a potent therapeutic agent against both ER{sup +} and ER{sup −} breast cancer cell lines. - Highlights: • Acid Ceramidase inhibitor, Ceranib 2 induced apoptosis in Breast cancer cell lines (MCF 7 and MDA MB 231 cell lines). • Apoptosis is mediated by DNA fragmentation and cell cycle arrest. • Ceranib 2 upregulated the expression of pro-apoptotic genes and down regulated anti-apoptotic gene expression. • More potent compared to the standard drug Tamoxifen.

  2. Differences in serum concentrations of organochlorine compounds by occupational social class in pancreatic cancer

    SciTech Connect (OSTI)

    Porta, Miquel Bosch de Basea, Magda; Benavides, Fernando G.; Lopez, Tomas; Fernandez, Esteve; Marco, Esther; Alguacil, Juan; Grimalt, Joan O.; Puigdomenech, Elisa

    2008-11-15

    Background: The relationships between social factors and body concentrations of environmental chemical agents are unknown in many human populations. Some chemical compounds may play an etiopathogenic role in pancreatic cancer. Objective: To analyze the relationships between occupational social class and serum concentrations of seven selected organochlorine compounds (OCs) in exocrine pancreatic cancer: dichlorodiphenyltrichloroethane (p,p'-DDT), dichlorodiphenyldichloroethene (p,p'-DDE), 3 polychlorinated biphenyls (PCBs), hexachlorobenzene, and {beta}-hexachlorocyclohexane. Methods: Incident cases of exocrine pancreatic cancer were prospectively identified, and interviewed face-to-face during hospital admission (n=135). Serum concentrations of OCs were analyzed by high-resolution gas chromatography with electron-capture detection. Social class was classified according to occupation. Results: Multivariate-adjusted concentrations of all seven compounds were higher in occupational social classes IV-V (the less affluent) than in classes I-II; they were higher as well in class III than in classes I-II for four compounds. Concentrations of six OCs were higher in manual workers than in non-manual workers (p<0.05 for PCBs). Social class explained statistically between 3.7% and 5.7% of the variability in concentrations of PCBs, and 2% or less variability in the other OCs. Conclusions: Concentrations of most OCs were higher in the less affluent occupational social classes. In pancreatic cancer the putative causal role of these persistent organic pollutants may not be independent of social class. There is a need to integrate evidence on the contribution of different social processes and environmental chemical exposures to the etiology of pancreatic and other cancers.

  3. Adjuvant Radiation Therapy Treatment Time Impacts Overall Survival in Gastric Cancer

    SciTech Connect (OSTI)

    McMillan, Matthew T.; Ojerholm, Eric; Roses, Robert E.; Plastaras, John P.; Metz, James M.; Mamtani, Ronac; Stripp, Diana; Ben-Josef, Edgar; Datta, Jashodeep

    2015-10-01

    Purpose: Prolonged radiation therapy treatment time (RTT) is associated with worse survival in several tumor types. This study investigated whether delays during adjuvant radiation therapy impact overall survival (OS) in gastric cancer. Methods and Materials: The National Cancer Data Base was queried for patients with resected gastric cancer who received adjuvant radiation therapy with National Comprehensive Cancer Network–recommended doses (45 or 50.4 Gy) between 1998 and 2006. RTT was classified as standard (45 Gy: 33-36 days, 50.4 Gy: 38-41 days) or prolonged (45 Gy: >36 days, 50.4 Gy: >41 days). Cox proportional hazards models evaluated the association between the following factors and OS: RTT, interval from surgery to radiation therapy initiation, interval from surgery to radiation therapy completion, radiation therapy dose, demographic/pathologic and operative factors, and other elements of adjuvant multimodality therapy. Results: Of 1591 patients, RTT was delayed in 732 (46%). Factors associated with prolonged RTT were non-private health insurance (OR 1.3, P=.005) and treatment at non-academic facilities (OR 1.2, P=.045). Median OS and 5-year actuarial survival were significantly worse in patients with prolonged RTT compared with standard RTT (36 vs 51 months, P=.001; 39 vs 47%, P=.005); OS worsened with each cumulative week of delay (P<.0004). On multivariable analysis, prolonged RTT was associated with inferior OS (hazard ratio 1.2, P=.002); the intervals from surgery to radiation therapy initiation or completion were not. Prolonged RTT was particularly detrimental in patients with node positivity, inadequate nodal staging (<15 nodes examined), and those undergoing a cycle of chemotherapy before chemoradiation therapy. Conclusions: Delays during adjuvant radiation therapy appear to negatively impact survival in gastric cancer. Efforts to minimize cumulative interruptions to <7 days should be considered.

  4. Surgeons' Knowledge and Practices Regarding the Role of Radiation Therapy in Breast Cancer Management

    SciTech Connect (OSTI)

    Zhou, Jessica; Griffith, Kent A.; Hawley, Sarah T.; Zikmund-Fisher, Brian J.; Janz, Nancy K.; Sabel, Michael S.; Katz, Steven J.; Jagsi, Reshma

    2013-12-01

    Purpose: Population-based studies suggest underuse of radiation therapy, especially after mastectomy. Because radiation oncology is a referral-based specialty, knowledge and attitudes of upstream providers, specifically surgeons, may influence patients' decisions regarding radiation, including whether it is even considered. Therefore, we sought to evaluate surgeons' knowledge of pertinent risk information, their patterns of referral, and the correlates of surgeon knowledge and referral in specific breast cancer scenarios. Methods and Materials: We surveyed a national sample of 750 surgeons, with a 67% response rate. We analyzed responses from those who had seen at least 1 breast cancer patient in the past year (n=403), using logistic regression models to identify correlates of knowledge and appropriate referral. Results: Overall, 87% of respondents were general surgeons, and 64% saw >10 breast cancer patients in the previous year. In a scenario involving a 45-year-old undergoing lumpectomy, only 45% correctly estimated the risk of locoregional recurrence without radiation therapy, but 97% would refer to radiation oncology. In a patient with 2 of 20 nodes involved after mastectomy, 30% would neither refer to radiation oncology nor provide accurate information to make radiation decisions. In a patient with 4 of 20 nodes involved after mastectomy, 9% would not refer to radiation oncology. Fewer than half knew that the Oxford meta-analysis revealed a survival benefit from radiation therapy after lumpectomy (45%) or mastectomy (32%). Only 16% passed a 7-item knowledge test; female and more-experienced surgeons were more likely to pass. Factors significantly associated with appropriate referral to radiation oncology included breast cancer volume, tumor board participation, and knowledge. Conclusions: Many surgeons have inadequate knowledge regarding the role of radiation in breast cancer management, especially after mastectomy. Targeted educational interventions may improve the quality of care.

  5. Amplification of PVT1 contributes to the pathophysiology ofovarian and breast cancer

    SciTech Connect (OSTI)

    Guan, Yinghui; Kuo, Wen-Lin; Stilwell, Jackie; Takano, Hirokuni; Lapuk, Anna; Fridlyand, Jane; Mao, Jian-Hua; Yu, Mami; Ginzinger, David; Gray, Joe W.

    2007-10-09

    Purpose. This study was designed to elucidate the role of amplification at 8q24 in the pathophysiology of ovarian and breast cancer since increased copy number at this locus is one of the most frequent genomic abnormalities in these cancers. Experimental Design. To accomplish this, we assessed the association of amplification at 8q24 with outcome in ovarian cancers using FISH to tissue microarrays and measured responses of ovarian and breast cancer cell lines to specific small interfering RNAs (siRNA) against the oncogene, MYC, and a putative noncoding RNA, PVT1, both of which map to 8q24. Results. Amplification of 8q24 was associated with significantly reduced survival duration. In addition, siRNA-mediated reduction in either PVT1 or MYC expression inhibited proliferation in breast and ovarian cancer cell lines in which they were both amplified and over expressed but not in lines in which they were not amplified/over expressed. Inhibition of PVT1 expression also induced a strong apoptotic response in cell lines in which it was over expressed but not in lines in which it was not amplified/over expressed. Inhibition of MYC, on the other hand, did not induce an apoptotic response in cell lines in which MYC was amplified and over expressed. Conclusions. These results suggest that MYC and PVT1 contribute independently to ovarian and breast pathogenesis when over expressed because of genomic abnormalities. They also suggest that PVT1 mediated inhibition of apoptosis may explain why amplification of 8q24 is associated with reduced survival duration in patients treated with agents that act through apoptotic mechanisms.

  6. Second Solid Cancers After Radiation Therapy: A Systematic Review of the Epidemiologic Studies of the Radiation Dose-Response Relationship

    SciTech Connect (OSTI)

    Berrington de Gonzalez, Amy; Gilbert, Ethel; Curtis, Rochelle; Inskip, Peter; Kleinerman, Ruth; Morton, Lindsay; Rajaraman, Preetha; Little, Mark P.

    2013-06-01

    Rapid innovations in radiation therapy techniques have resulted in an urgent need for risk projection models for second cancer risks from high-dose radiation exposure, because direct observation of the late effects of newer treatments will require patient follow-up for a decade or more. However, the patterns of cancer risk after fractionated high-dose radiation are much less well understood than those after lower-dose exposures (0.1-5 Gy). In particular, there is uncertainty about the shape of the dose-response curve at high doses and about the magnitude of the second cancer risk per unit dose. We reviewed the available evidence from epidemiologic studies of second solid cancers in organs that received high-dose exposure (>5 Gy) from radiation therapy where dose-response curves were estimated from individual organ-specific doses. We included 28 eligible studies with 3434 second cancer patients across 11 second solid cancers. Overall, there was little evidence that the dose-response curve was nonlinear in the direction of a downturn in risk, even at organ doses of ≥60 Gy. Thyroid cancer was the only exception, with evidence of a downturn after 20 Gy. Generally the excess relative risk per Gray, taking account of age and sex, was 5 to 10 times lower than the risk from acute exposures of <2 Gy among the Japanese atomic bomb survivors. However, the magnitude of the reduction in risk varied according to the second cancer. The results of our review provide insights into radiation carcinogenesis from fractionated high-dose exposures and are generally consistent with current theoretical models. The results can be used to refine the development of second solid cancer risk projection models for novel radiation therapy techniques.

  7. Rare alleles of the HRAS polymorphism do not modify the risk of breast or ovarian cancer in BRCA1 carriers

    SciTech Connect (OSTI)

    Phelan, C.; Tonin, P.; Lynch, H.T.

    1994-09-01

    The presence of one of the rare alleles of a minisatellite polymorphism at the HRAS locus on chromosome 11p15 has been associated with a roughly two-fold increase in the risk of breast cancer. The BRCA1 gene on chromosome 17q12-21 is responsible for the majority of the families with the breast-ovarian cancer syndrome. It is estimated that 87% of BRCA1 carriers will be affected with breast cancer by age 70. The relative risk for premenopausal breast cancer in carriers, compared to non-carriers, is roughly 100. Because of the wide range in ages of onset of cancer among BRCA1 carriers, it is likely that additional factors modify the risk of cancer. The role of other modifying genetic loci has not been studied. Through haplotype analysis we have identified 199 female BRCA1 carriers above the age of 20 years in 25 linked families. 127 of these women have been diagnosed with cancer and 72 are currently healthy. DNA was available on 59 carriers. Each sample was typed for the HRAS polymorphism by PCR, using primers flanking the minisatellite. Rare alleles were identified in 18 carriers. The penetrance of the BRCA1 gene was not higher among those women who carried a rare HRAS allele (mean age of onset 49 years) than among those who carried two common alleles (mean age of onset 43 years) (p= 0.59; log rank test). Similar results were obtained for ovarian cancer. These data do not support the hypothesis that the HRAS locus modified the risk of cancer among carriers of mutations in BRCA1.

  8. SU-E-T-320: The Effect of Survivin Perturbation On the Radiation Response of Breast Cancer Cell Lines

    SciTech Connect (OSTI)

    Smith, D; Debeb, B; Woodward, W

    2014-06-01

    Purpose: Survivin is the smallest member of the inhibitor of apoptosis protein family and is well-known for its universal over-expression in human cancers. Due to its role in apoptosis and cellular proliferation, survivin is implicated in the radiation response in several cancer types, and antisurvivin treatments have had success as a radiation sensitizer in many preclinical cancer models. As no studies to date have reported survivin as a factor affecting radiation resistance in breast cancer models, we sought to evaluate the synergistic relationship between survivin function and irradiation in breast cancer cell lines. Methods: Information regarding survivin protein expression in breast cancer was retrieved from three public databases: Oncomine, Kaplan-Meier Plotter, and GOBO. For the in vitro studies, survivin function was compromised by transducing a non-functional mutant form (survivin-DN) into two breast cancer cell lines, the estrogen receptor-positive MCF7 and the triple-negative, inflammatory SUM149. Cell growth was compared in the survivin-DN and control populations with colony-formation assays. To assess how survivin affects radiation response, clonogenic assays were performed by irradiating the cell lines up to 6 Gy. Results: From the public databases, survivin is more highly expressed in triple-negative breast cancer compared to all other subtypes, and is prognostic of poor survival in all breast cancer patients. In MCF7, the survivin-DN population had decreased colony-formation potential; the opposite was true in SUM149. In the clonogenic assays, abrogation of survivin function radio-protected MCF7 cells in monolayer and 3D growth conditions, while SUM149 survivin-DN cells were radiosensitized in monolayer conditions. Conclusion: We observed synergy between survivin function and radiation, although the results between the two cell lines were disparate. Further investigation is required to identify the mechanism of this discrepancy, including evaluation of the potential role of estrogen receptor status, before proceeding with small-animal experiments.

  9. STAT3 signaling pathway is necessary for cell survival and tumorsphere forming capacity in ALDH{sup +}/CD133{sup +} stem cell-like human colon cancer cells

    SciTech Connect (OSTI)

    Lin, Li; Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030 ; Fuchs, James; Li, Chenglong; Olson, Veronica; Bekaii-Saab, Tanios; Lin, Jiayuh

    2011-12-16

    Highlights: Black-Right-Pointing-Pointer The phosphorylated or activated form of STAT3 was expressed in colon cancer stem-like cells. Black-Right-Pointing-Pointer STAT3 inhibitor, FLLL32 inhibits P-STAT3 and STAT3 target genes in colon cancer stem-like cells. Black-Right-Pointing-Pointer Inhibition of STAT3 resulted in decreased cell viability and reduced numbers of tumorspheres. Black-Right-Pointing-Pointer STAT3 is required for survival and tumorsphere forming capacity in colon cancer stem-like cells. Black-Right-Pointing-Pointer Targeting STAT3 in cancer stem-like cells may offer a novel treatment approach for colon cancer. -- Abstract: Persistent activation of Signal Transducers and Activators of Transcription 3 (STAT3) is frequently detected in colon cancer. Increasing evidence suggests the existence of a small population of colon cancer stem or cancer-initiating cells may be responsible for tumor initiation, metastasis, and resistance to chemotherapy and radiation. Whether STAT3 plays a role in colon cancer-initiating cells and the effect of STAT3 inhibition is still unknown. Flow cytometry was used to isolate colon cancer stem-like cells from three independent human colon cancer cell lines characterized by both aldehyde dehydrogenase (ALDH)-positive and CD133-positive subpopulation (ALDH{sup +}/CD133{sup +}). The effects of STAT3 inhibition in colon cancer stem-like cells were examined. The phosphorylated or activated form of STAT3 was expressed in colon cancer stem-like cells and was reduced by a STAT3-selective small molecular inhibitor, FLLL32. FLLL32 also inhibited the expression of potential STAT3 downstream target genes in colon cancer stem-like cells including survivin, Bcl-XL, as well as Notch-1, -3, and -4, which may be involved in stem cell function. Furthermore, FLLL32 inhibited cell viability and tumorsphere formation as well as induced cleaved caspase-3 in colon cancer stem-like cells. FLLL32 is more potent than curcumin as evidenced with lower IC50 in colon cancer stem-like cells. In summary, our results indicate that STAT3 is a novel therapeutic target in colon cancer stem-like cells and inhibition of STAT3 in cancer stem-like cells may offer a potential treatment for colorectal cancer.

  10. miR-196a targets netrin 4 and regulates cell proliferation and migration of cervical cancer cells

    SciTech Connect (OSTI)

    Zhang, Jie; Zheng, Fangxia; Yu, Gang; Yin, Yanhua; Lu, Qingyang

    2013-11-01

    Highlights: miR-196a was overexpressed in cervical cancer tissue compared to normal tissue. miR-196a expression elevated proliferation and migration of cervical cancer cells. miR-196a inhibited NTN4 expression by binding 3?-UTR region of NTN4 mRNA. NTN4 inversely correlated with miR-196a expression in cervical tissue and cell line. NTN4 expression was low in cervical cancer tissue compared to normal tissue. -- Abstract: Recent research has uncovered tumor-suppressive and oncogenic potential of miR-196a in various tumors. However, the expression and mechanism of its function in cervical cancer remains unclear. In this study, we assess relative expression of miR-196a in cervical premalignant lesions, cervical cancer tissues, and four cancer cell lines using quantitative real-time PCR. CaSki and HeLa cells were treated with miR-196a inhibitors, mimics, or pCDNA/miR-196a to investigate the role of miR-196a in cancer cell proliferation and migration. We demonstrated that miR-196a was overexpressed in cervical intraepithelial neoplasia 23 and cervical cancer tissue. Moreover, its expression contributes to the proliferation and migration of cervical cancer cells, whereas inhibiting its expression led to a reduction in proliferation and migration. Five candidate targets of miR-196a chosen by computational prediction and Cervical Cancer Gene Database search were measured for their mRNA in both miR-196a-overexpressing and -depleted cancer cells. Only netrin 4 (NTN4) expression displayed an inverse association with miR-196a. Fluorescent reporter assays revealed that miR-196a inhibited NTN4 expression by targeting one binding site in the 3?-untranslated region (3?-UTR) of NTN4 mRNA. Furthermore, qPCR and Western blot assays verified NTN4 expression was downregulated in cervical cancer tissues compared to normal controls, and in vivo mRNA level of NTN4 inversely correlated with miR-196a expression. In summary, our findings provide new insights about the functional role of miR-196a in cervical carcinogenesis and suggested a potential use of miR-196a for clinical diagnosis and as a therapeutic target.

  11. Snail/beta-catenin signaling protects breast cancer cells from hypoxia attack

    SciTech Connect (OSTI)

    Scherbakov, Alexander M.; Stefanova, Lidia B.; Sorokin, Danila V.; Semina, Svetlana E.; Berstein, Lev M.; Krasilnikov, Mikhail A.

    2013-12-10

    The tolerance of cancer cells to hypoxia depends on the combination of different factors from increase of glycolysis (Warburg Effect) to activation of intracellular growth/apoptotic pathways. Less is known about the influence of epithelialmesenchymal transition (EMT) and EMT-associated pathways on the cell sensitivity to hypoxia. The aim of this study was to explore the role of Snail signaling, one of the key EMT pathways, in the mediating of hypoxia response and regulation of cell sensitivity to hypoxia, using as a model in vitro cultured breast cancer cells. Earlier we have shown that estrogen-independent HBL-100 breast cancer cells differ from estrogen-dependent MCF-7 cells with increased expression of Snail1, and demonstrated Snail1 involvement into formation of hormone-resistant phenotype. Because Snail1 belongs to hypoxia-activated proteins, here we studied the influence of Snail1 signaling on the cell tolerance to hypoxia. We found that Snail1-enriched HBL-100 cells were less sensitive to hypoxia-induced growth suppression if compared with MCF-7 line (31% MCF-7 vs. 71% HBL-100 cell viability after 1% O{sub 2} atmosphere for 3 days). Snail1 knock-down enhanced the hypoxia-induced inhibition of cell proliferation giving the direct evidence of Snail1 involvement into cell protection from hypoxia attack. The protective effect of Snail1 was shown to be mediated, at least in a part, via beta-catenin which positively regulated expression of HIF-1-dependent genes. Finally, we found that cell tolerance to hypoxia was accompanied with the failure in the phosphorylation of AMPK the key energy sensor, and demonstrated an inverse relationship between AMPK and Snail/beta-catenin signaling. Totally, our data show that Snail1 and beta-catenin, besides association with loss of hormone dependence, protect cancer cells from hypoxia and may serve as an important target in the treatment of breast cancer. Moreover, we suggest that the level of these proteins as well the level of AMPK phosphorylation may be considered as predictors of the tumor sensitivity to anti-angiogenic drugs. - Highlights: Snail1 protects breast cancer cells from hypoxia. Protective effect of Snail1 is mediated via ?-catenin/HIF-1 pathway. Snail/?-catenin signaling is negatively controlled by the energy sensor AMPK. The failure in AMPK phosphorylation drives cells to the hypoxia-tolerant state.

  12. Differential effects of a complex organochlorine mixture on the proliferation of breast cancer cell lines

    SciTech Connect (OSTI)

    Aube, Michel; Larochelle, Christian; Ayotte, Pierre; Laboratoire de Toxicologie, Institut national de sante publique du Quebec, 945 avenue Wolfe, Quebec, QC, Canada G1V 5B3

    2011-04-15

    Organochlorine compounds (OCs) are a group of persistent chemicals that accumulate in fatty tissues with age. Although OCs has been tested individually for their capacity to induce breast cancer cell proliferation, few studies examined the effect of complex mixtures that comprise compounds frequently detected in the serum of women. We constituted such an OC mixture containing 15 different components in environmentally relevant proportions and assessed its proliferative effects in four breast cancer cell lines (MCF-7, T47D, CAMA-1, MDAMB231) and in non-cancerous CV-1 cells. We also determined the capacity of the mixture to modulate cell cycle stage of breast cancer cells and to induce estrogenic and antiandrogenic effects using gene reporter assays. We observed that low concentrations of the mixture (100x10{sup 3} and 50x10{sup 3} dilutions) stimulated the proliferation of MCF-7 cells while higher concentrations (10x10{sup 3} and 5x10{sup 3} dilutions) had the opposite effect. In contrast, the mixture inhibited the proliferation of non-hormone-dependent cell lines. The mixture significantly increased the number of MCF-7 cells entering the S phase, an effect that was blocked by the antiestrogen ICI 182,780. Low concentrations of the mixture also caused an increase in CAMA-1 cell proliferation but only in the presence estradiol and dihydrotestosterone (p<0.05 at the 50x10{sup 3} dilution). DDT analogs and polychlorinated biphenyls all had the capacity to stimulate the proliferation of CAMA-1 cells in the presence of sex steroids. Reporter gene assays further revealed that the mixture and several of its constituents (DDT analogs, aldrin, dieldrin, {beta}-hexachlorocyclohexane, toxaphene) induced estrogenic effects, whereas the mixture and several components (DDT analogs, aldrin, dieldrin and PCBs) inhibited the androgen signaling pathway. Our results indicate that the complex OC mixture increases the proliferation of MCF-7 cells due to its estrogenic potential. The proliferative effect of the mixture on CAMA-1 cells in the presence of sex steroids appears mostly due to the antiandrogenic properties of p,p'-DDE, a major constituent of the mixture. Other mixtures of contaminants that include emerging compounds of interest such as brominated flame retardants and perfluoroalkyl compounds should be tested for their capacity to induce breast cancer cell proliferation. - Research highlights: {yields} We studied effects of a complex organochlorine mixture on breast cancer cell growth. {yields} Weak xenoestrogens in the mixture stimulated the proliferation of MCF-7 cells. {yields} Antiandrogens increased the proliferation CAMA-1 cells grown with sex steroids. {yields} High concentrations of the mixture decreased the proliferation of all cell lines.

  13. TRASH TO TREASURE: CONVERTING COLD WAR LEGACY WASTE INTO WEAPONS AGAINST CANCER

    SciTech Connect (OSTI)

    Nicholas, R.G.; Lacy, N.H.; Butz, T.R.; Brandon, N.E.

    2004-10-06

    As part of its commitment to clean up Cold War legacy sites, the U.S. Department of Energy (DOE) has initiated an exciting and unique project to dispose of its inventory of uranium-233 (233U) stored at Oak Ridge National Laboratory (ORNL), and extract isotopes that show great promise in the treatment of deadly cancers. In addition to increasing the supply of potentially useful medical isotopes, the project will rid DOE of a nuclear concern and cut surveillance and security costs. For more than 30 years, DOE's ORNL has stored over 1,200 containers of fissile 233U, originally produced for several defense-related projects, including a pilot study that looked at using 233U as a commercial reactor fuel. This uranium, designated as special nuclear material, requires expensive security, safety, and environmental controls. It has been stored at an ORNL facility, Building 3019A, that dates back to the Manhattan Project. Down-blending the material to a safer form, rather than continuing to store it, will eliminate a $15 million a year financial liability for the DOE and increase the supply of medical isotopes by 5,700 percent. During the down-blending process, thorium-229 (229Th) will be extracted. The thorium will then be used to extract actinium-225 (225Ac), which will ultimately supply its progeny, bismuth-213 (213Bi), for on-going cancer research. The research includes Phase II clinical trials for the treatment of acute myelogenous leukemia at Sloan-Kettering Memorial Cancer Center in New York, as well as other serious cancers of the lungs, pancreas, and kidneys using a technique known as alpha-particle radioimmunotherapy. Alpha-particle radioimmunotherapy is based on the emission of alpha particles by radionuclides. 213Bi is attached to a monoclonal antibody that targets specific cells. The bismuth then delivers a high-powered but short-range radiation dose, effectively killing the cancerous cells but sparing the surrounding tissue. Production of the actinium and bismuth would be a private venture at no cost to the government. Isotek Systems, LLC, was commissioned by the DOE to execute the project, known as the 233U Disposition, Medical Isotope Production, and Building 3019 Complex Shutdown Project. Isotek is a partnership between Duratek Federal Services, Burns and Roe Enterprises, and Nuclear Fuel Services. By pooling their pioneering experiences in nuclear engineering and design, nuclear recycling, and waste management, the partnership has developed a novel process to meet this clean-up milestone. The project is not only important for its cancer treatment potential, but also for setting the stage for reducing global threats through the down-blending of materials.

  14. 70 Gy Versus 80 Gy in Localized Prostate Cancer: 5-Year Results of GETUG 06 Randomized Trial;Prostate cancer; Dose escalation; Conformal radiotherapy; Randomized trial

    SciTech Connect (OSTI)

    Beckendorf, Veronique; Guerif, Stephane; Le Prise, Elisabeth; Cosset, Jean-Marc; Bougnoux, Agnes; Chauvet, Bruno; Salem, Naji; Chapet, Olivier; Bourdain, Sylvain; Bachaud, Jean-Marc; Maingon, Philippe; Hannoun-Levi, Jean-Michel; Malissard, Luc; Simon, Jean-Marc; Pommier, Pascal; Hay, Men; Dubray, Bernard; Lagrange, Jean-Leon; Luporsi, Elisabeth; Bey, Pierre

    2011-07-15

    Purpose: To perform a randomized trial comparing 70 and 80 Gy radiotherapy for prostate cancer. Patients and Methods: A total of 306 patients with localized prostate cancer were randomized. No androgen deprivation was allowed. The primary endpoint was biochemical relapse according to the modified 1997-American Society for Therapeutic Radiology and Oncology and Phoenix definitions. Toxicity was graded using the Radiation Therapy Oncology Group 1991 criteria and the late effects on normal tissues-subjective, objective, management, analytic scales (LENT-SOMA) scales. The patients' quality of life was scored using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire 30-item cancer-specific and 25-item prostate-specific modules. Results: The median follow-up was 61 months. According to the 1997-American Society for Therapeutic Radiology and Oncology definition, the 5-year biochemical relapse rate was 39% and 28% in the 70- and 80-Gy arms, respectively (p = .036). Using the Phoenix definition, the 5-year biochemical relapse rate was 32% and 23.5%, respectively (p = .09). The subgroup analysis showed a better biochemical outcome for the higher dose group with an initial prostate-specific antigen level >15 ng/mL. At the last follow-up date, 26 patients had died, 10 of their disease and none of toxicity, with no differences between the two arms. According to the Radiation Therapy Oncology Group scale, the Grade 2 or greater rectal toxicity rate was 14% and 19.5% for the 70- and 80-Gy arms (p = .22), respectively. The Grade 2 or greater urinary toxicity was 10% at 70 Gy and 17.5% at 80 Gy (p = .046). Similar results were observed using the LENT-SOMA scale. Bladder toxicity was more frequent at 80 Gy than at 70 Gy (p = .039). The quality-of-life questionnaire results before and 5 years after treatment were available for 103 patients with no differences found between the 70- and 80-Gy arms. Conclusion: High-dose radiotherapy provided a better 5-year biochemical outcome with slightly greater toxicity.

  15. Second Malignant Neoplasms in Digestive Organs After Childhood Cancer: A Cohort-Nested Case-Control Study

    SciTech Connect (OSTI)

    Tukenova, Markhaba; Diallo, Ibrahima; Anderson, Harald; Hawkins, Mike; Garwicz, Stanislaw; Sankila, Risto; El Fayech, Chiraz; Winter, Dave; Rubino, Carole; Adjadj, Elisabeth; Haddy, Nadia; Oberlin, Odile; Moller, Torgil; Langmark, Froydis; and others

    2012-03-01

    Purpose: Cancers of the digestive system constitute a major risk for childhood cancer survivors treated with radiotherapy once they reach adulthood. The aim of this study was to determine therapy-related risk factors for the development of a second malignancy in the digestive organs (SMDO) after a childhood cancer. Methods and Materials: Among 4,568 2-year survivors of a childhood solid cancer diagnosed before 17 years of age at eight French and British centers, and among 25,120 patients diagnosed as having a malignant neoplasm before the age of 20 years, whose data were extracted from the Nordic Cancer Registries, we matched 58 case patients (41 men and 17 women) of SMDO and 167 controls, in their respective cohort, for sex, age at first cancer, calendar year of occurrence of the first cancer, and duration of follow-up. The radiation dose received at the site of each second malignancy and at the corresponding site of its matched control was estimated. Results: The risk of developing a SMDO was 9.7-fold higher in relation to the general populations in France and the United Kingdom. In the case-control study, a strong dose-response relationship was estimated, compared with that in survivors who had not received radiotherapy; the odds ratio was 5.2 (95% CI, 1.7-16.0) for local radiation doses between 10 and 29 Gy and 9.6 (95% CI, 2.6-35.2) for doses equal to or greater than 30 Gy. Chemotherapy was also found to increase the risk of developing SMDO. Conclusions: This study confirms that childhood cancer treatments strongly increase the risk of SMDO, which occur only after a very long latency period.

  16. Fibre Diffraction Analysis of Skin Offers a Very Early and Extremely Accurate Diagnostic Test for Prostate Cancer

    DOE Public Access Gateway for Energy & Science Beta (PAGES Beta)

    James, Veronica J.; O’Malley Ford, Judith M.

    2014-01-01

    Double blind analysis of a batch of thirty skin tissue samples from potential prostate cancer sufferers correctly identified all “control” patients, patients with high and low grade prostate cancers, the presence of benign prostate hyperplasia (BPH), perineural invasions, and the one lymphatic invasion. Identification was by analysis of fibre diffraction patterns interpreted using a schema developed from observations in nine previous studies. The method, schema, and specific experiment results are reported in this paper, with some implications then drawn.

  17. Lung cancer-derived Dickkopf1 is associated with bone metastasis and the mechanism involves the inhibition of osteoblast differentiation

    SciTech Connect (OSTI)

    Chu, Tianqing; Teng, Jiajun; Jiang, Liyan; Zhong, Hua; Han, Baohui

    2014-01-17

    Highlights: DKK1 level was associated with NSCLC bone metastases. Lung tumor cells derived DKK1 inhibited osteoblast differentiation. Lung tumor cells derived DKK1 modulates ?-catenin and RUNX2. -- Abstract: Wnt/?-catenin signaling and Dickkopf1 (DKK1) play important roles in the progression of lung cancer, which preferably metastasizes to skeleton. But the role of them in bone dissemination is poorly understood. This study aims to define the role of DKK1 in lung cancer bone metastases and investigate the underlying mechanism. Our results demonstrated that DKK1 over-expression was a frequent event in non-small-cell lung cancer (NSCLC) blood samples, and serous DKK1 level was much higher in bone metastatic NSCLC compared to non-bone metastatic NSCLC. We also found that conditioned medium from DKK1 over-expressing lung cancer cells inhibited the differentiation of osteoblast, determined by alkaline phosphatase activity and osteocalcin secretion, whereas the conditioned medium from DKK1 silencing lung cancer cells exhibited the opposite effects. Mechanistically, DKK1 reduced the level of ?-catenin and RUNX2, as well as inhibiting the nuclear translocation of ?-catenin. Taken together, these results suggested that lung cancer-produced DKK1 may be an important mechanistic link between NSCLC and bone metastases, and targeting DKK1 may be an effective method to treat bone metastase of NSCLC.

  18. Role of the Technical Aspects of Hypofractionated Radiation Therapy Treatment of Prostate Cancer: A Review

    SciTech Connect (OSTI)

    Clemente, Stefania; Nigro, Roberta; Oliviero, Caterina; Marchioni, Chiara; Esposito, Marco; Giglioli, Francesca Romana; Mancosu, Pietro; Marino, Carmelo; Russo, Serenella; Stasi, Michele; Strigari, Lidia; Veronese, Ivan; Landoni, Valeria

    2015-01-01

    The increasing use of moderate (<35 fractions) and extreme (<5 fractions) hypofractionated radiation therapy in prostate cancer is yielding favorable results, both in terms of maintained biochemical response and toxicity. Several hypofractionation (HF) schemes for the treatment of prostate cancer are available, although there is considerable variability in the techniques used to manage intra-/interfraction motion and deliver radiation doses. We performed a review of the published studies on HF regimens as a topic of interest for the Stereotactic Ablative Radiotherapy working group, which is part of the Italian Association of Medical Physics. Aspects of organ motion management (imaging for contouring, target volume definition, and rectum/bladder preparation) and treatment delivery (prostate localization, image guided radiation therapy strategy and frequency) were evaluated and categorized to assess outcome relative to disease control and toxicity. Despite the heterogeneity of the data, some interesting trends that emerged from the review might be useful in identifying an optimum HF strategy.

  19. Nano-immunoassay with improved performance for detection of cancer biomarkers

    DOE Public Access Gateway for Energy & Science Beta (PAGES Beta)

    Krasnoslobodtsev, Alexey V.; Torres, Maria P.; Kaur, Sukhwinder; Vlassiouk, Ivan V.; Lipert, Robert J.; Jain, Maneesh; Batra, Surinder K.; Lyubchenko, Yuri L.

    2015-01-01

    Nano-immunoassay utilizing surface-enhanced Raman scattering (SERS) effect is a promising analytical technique for the early detection of cancer. In its current standing the assay is capable of discriminating samples of healthy individuals from samples of pancreatic cancer patients. Further improvements in sensitivity and reproducibility will extend practical applications of the SERS-based detection platforms to wider range of problems. In this report, we discuss several strategies designed to improve performance of the SERS-based detection system. We demonstrate that reproducibility of the platform is enhanced by using atomically smooth mica surface as a template for preparation of capture surface in SERS sandwichmore » immunoassay. Furthermore, the assay's stability and sensitivity can be further improved by using either polymer or graphene monolayer as a thin protective layer applied on top of the assay addresses. The protective layer renders the signal to be more stable against photo-induced damage and carbonaceous contamination.« less

  20. A stochastic model for tumor geometry evolution during radiation therapy in cervical cancer

    SciTech Connect (OSTI)

    Liu, Yifang; Lee, Chi-Guhn; Chan, Timothy C. Y.; Cho, Young-Bin; Islam, Mohammad K.; Department of Radiation Oncology, University of Toronto, 148-150 College Street, Toronto, Ontario M5S 3S2; Techna Institute for the Advancement of Technology for Health, 124-100 College Street, Toronto, Ontario M5G 1P5

    2014-02-15

    Purpose: To develop mathematical models to predict the evolution of tumor geometry in cervical cancer undergoing radiation therapy. Methods: The authors develop two mathematical models to estimate tumor geometry change: a Markov model and an isomorphic shrinkage model. The Markov model describes tumor evolution by investigating the change in state (either tumor or nontumor) of voxels on the tumor surface. It assumes that the evolution follows a Markov process. Transition probabilities are obtained using maximum likelihood estimation and depend on the states of neighboring voxels. The isomorphic shrinkage model describes tumor shrinkage or growth in terms of layers of voxels on the tumor surface, instead of modeling individual voxels. The two proposed models were applied to data from 29 cervical cancer patients treated at Princess Margaret Cancer Centre and then compared to a constant volume approach. Model performance was measured using sensitivity and specificity. Results: The Markov model outperformed both the isomorphic shrinkage and constant volume models in terms of the trade-off between sensitivity (target coverage) and specificity (normal tissue sparing). Generally, the Markov model achieved a few percentage points in improvement in either sensitivity or specificity compared to the other models. The isomorphic shrinkage model was comparable to the Markov approach under certain parameter settings. Convex tumor shapes were easier to predict. Conclusions: By modeling tumor geometry change at the voxel level using a probabilistic model, improvements in target coverage and normal tissue sparing are possible. Our Markov model is flexible and has tunable parameters to adjust model performance to meet a range of criteria. Such a model may support the development of an adaptive paradigm for radiation therapy of cervical cancer.

  1. Outcomes After Intensity-Modulated Versus Conformal Radiotherapy in Older Men With Nonmetastatic Prostate Cancer

    SciTech Connect (OSTI)

    Bekelman, Justin E.; Mitra, Nandita; Efstathiou, Jason; Liao Kaijun; Sunderland, Robert; Yeboa, Deborah N.; Armstrong, Katrina

    2011-11-15

    Purpose: There is little evidence comparing complications after intensity-modulated (IMRT) vs. three-dimensional conformal radiotherapy (CRT) for prostate cancer. The study objective was to test the hypothesis that IMRT, compared with CRT, is associated with a reduction in bowel, urinary, and erectile complications in elderly men with nonmetastatic prostate cancer. Methods and Materials: We undertook an observational cohort study using registry and administrative claims data from the SEER-Medicare database. We identified men aged 65 years or older diagnosed with nonmetastatic prostate cancer in the United States between 2002 and 2004 who received IMRT (n = 5,845) or CRT (n = 6,753). The primary outcome was a composite measure of bowel complications. Secondary outcomes were composite measures of urinary and erectile complications. We also examined specific subsets of bowel (proctitis/hemorrhage) and urinary (cystitis/hematuria) events within the composite complication measures. Results: IMRT was associated with reductions in composite bowel complications (24-month cumulative incidence 18.8% vs. 22.5%; hazard ratio [HR] 0.86; 95% confidence interval [CI], 0.79-0.93) and proctitis/hemorrhage (HR 0.78; 95% CI, 0.64-0.95). IMRT was not associated with rates of composite urinary complications (HR 0.93; 95% CI, 0.83-1.04) or cystitis/hematuria (HR 0.94; 95% CI, 0.83-1.07). The incidence of erectile complications involving invasive procedures was low and did not differ significantly between groups, although IMRT was associated with an increase in new diagnoses of impotence (HR 1.27, 95% CI, 1.14-1.42). Conclusion: IMRT is associated with a small reduction in composite bowel complications and proctitis/hemorrhage compared with CRT in elderly men with nonmetastatic prostate cancer.

  2. SL-01, an oral derivative of gemcitabine, inhibited human breast cancer growth through induction of apoptosis

    SciTech Connect (OSTI)

    Li, Yuan-Yuan; Qin, Yi-Zhuo; Wang, Rui-Qi; Li, Wen-Bao; Qu, Xian-Jun

    2013-08-23

    Highlights: SL-01 is an oral derivative of gemcitabine. SL-01 possessed activity against human breast cancer growth via apoptotic induction. SL-01s activity was more potently than that of gemcitabine. SL-01 inhibited cancer growth without toxicity to mice. -- Abstract: SL-01 is an oral derivative of gemcitabine that was synthesized by introducing the moiety of 3-(dodecyloxycarbonyl) pyrazine-2-carbonyl at N4-position on cytidine ring of gemcitabine. We aimed to evaluate the efficacy of SL-01 on human breast cancer growth. SL-01 significantly inhibited MCF-7 proliferation as estimated by colorimetric assay. Flow cytometry assay indicated the apoptotic induction and cell cycle arrest in G1 phase. SL-01 modulated the expressions of p-ATM, p53 and p21 and decrease of cyclin D1 in MCF-7 cells. Further experiments were performed in a MCF-7 xenografts mouse model. SL-01 by oral administration strongly inhibited MCF-7 xenografts growth. This effect of SL-01 might arise from its roles in the induction of apoptosis. Immunohistochemistry assay showed the increase of TUNEL staining cells. Western blotting indicated the modulation of apoptotic proteins in SL-01-treated xenografts. During the course of study, there was no evidence of toxicity to mice. In contrast, the decrease of neutrophil cells in peripheral and increase of AST and ALT levels in serum were observed in the gemcitabine-treated mice. Conclusion: SL-01 possessed similar activity against human breast cancer growth with gemcitabine, whereas, with lower toxicity to gemcitabine. SL-01 is a potent oral agent that may supplant the use of gemcitabine.

  3. Validated Competing Event Model for the Stage I-II Endometrial Cancer Population

    SciTech Connect (OSTI)

    Carmona, Ruben; Gulaya, Sachin; Murphy, James D.; Rose, Brent S.; Wu, John; Noticewala, Sonal; McHale, Michael T.; Yashar, Catheryn M.; Vaida, Florin; Mell, Loren K.

    2014-07-15

    Purpose/Objectives(s): Early-stage endometrial cancer patients are at higher risk of noncancer mortality than of cancer mortality. Competing event models incorporating comorbidity could help identify women most likely to benefit from treatment intensification. Methods and Materials: 67,397 women with stage I-II endometrioid adenocarcinoma after total hysterectomy diagnosed from 1988 to 2009 were identified in Surveillance, Epidemiology, and End Results (SEER) and linked SEER-Medicare databases. Using demographic and clinical information, including comorbidity, we sought to develop and validate a risk score to predict the incidence of competing mortality. Results: In the validation cohort, increasing competing mortality risk score was associated with increased risk of noncancer mortality (subdistribution hazard ratio [SDHR], 1.92; 95% confidence interval [CI], 1.60-2.30) and decreased risk of endometrial cancer mortality (SDHR, 0.61; 95% CI, 0.55-0.78). Controlling for other variables, Charlson Comorbidity Index (CCI)=1 (SDHR, 1.62; 95% CI, 1.45-1.82) and CCI >1 (SDHR, 3.31; 95% CI, 2.74-4.01) were associated with increased risk of noncancer mortality. The 10-year cumulative incidences of competing mortality within low-, medium-, and high-risk strata were 27.3% (95% CI, 25.2%-29.4%), 34.6% (95% CI, 32.5%-36.7%), and 50.3% (95% CI, 48.2%-52.6%), respectively. With increasing competing mortality risk score, we observed a significant decline in omega (?), indicating a diminishing likelihood of benefit from treatment intensification. Conclusion: Comorbidity and other factors influence the risk of competing mortality among patients with early-stage endometrial cancer. Competing event models could improve our ability to identify patients likely to benefit from treatment intensification.

  4. Coordination of Breast Cancer Care Between Radiation Oncologists and Surgeons: A Survey Study

    SciTech Connect (OSTI)

    Jagsi, Reshma; Abrahamse, Paul; Morrow, Monica; Hamilton, Ann S.; Katz, Steven J.

    2012-04-01

    Purpose: To assess whether radiation oncologists and surgeons differ in their attitudes regarding the local management of breast cancer, and to examine coordination of care between these specialists. Methods and Materials: We surveyed attending surgeons and radiation oncologists who treated a population-based sample of patients diagnosed with breast cancer in metropolitan Detroit and Los Angeles. We identified 419 surgeons, of whom 318 (76%) responded, and 160 radiation oncologists, of whom 117 (73%) responded. We assessed demographic, professional, and practice characteristics; challenges to coordinated care; and attitudes toward management in three scenarios. Results: 92.1% of surgeons and 94.8% of radiation oncologists indicated access to a multidisciplinary tumor board. Nevertheless, the most commonly identified challenge to radiation oncologists, cited by 27.9%, was failure of other providers to include them in the treatment decision process early enough. Nearly half the surgeons (49.7%) stated that few or almost none of the breast cancer patients they saw in the past 12 months had consulted with a radiation oncologist before undergoing definitive surgery. Surgeons and radiation oncologists differed in their recommendations in management scenarios. Radiation oncologists were more likely to favor radiation than were surgeons for a patient with 3/20 lymph nodes undergoing mastectomy (p = 0.03); surgeons were more likely to favor more widely clear margins after breast conservation than were radiation oncologists (p = 0.001). Conclusions: Despite the widespread availability of tumor boards, a substantial minority of radiation oncologists indicated other providers failed to include them in the breast cancer treatment decision-making process early enough. Earlier inclusion of radiation oncologists may influence patient decisions, and interventions to facilitate this should be considered.

  5. Rictor regulates FBXW7-dependent c-Myc and cyclin E degradation in colorectal cancer cells

    SciTech Connect (OSTI)

    Guo, Zheng; Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, 1838 Guangzhou Dadao Bei, Guangzhou 510515 ; Zhou, Yuning; Evers, B. Mark; Department of Surgery, The University of Kentucky, 800 Rose Street, Lexington, KY 40536 ; Wang, Qingding; Department of Surgery, The University of Kentucky, 800 Rose Street, Lexington, KY 40536

    2012-02-10

    Highlights: Black-Right-Pointing-Pointer Rictor associates with FBXW7 to form an E3 complex. Black-Right-Pointing-Pointer Knockdown of rictor decreases ubiquitination of c-Myc and cylin E. Black-Right-Pointing-Pointer Knockdown of rictor increases protein levels of c-Myc and cylin E. Black-Right-Pointing-Pointer Overexpression of rictor induces the degradation of c-Myc and cyclin E proteins. Black-Right-Pointing-Pointer Rictor regulation of c-Myc and cyclin E requires FBXW7. -- Abstract: Rictor (Rapamycin-insensitive companion of mTOR) forms a complex with mTOR and phosphorylates and activates Akt. Activation of Akt induces expression of c-Myc and cyclin E, which are overexpressed in colorectal cancer and play an important role in colorectal cancer cell proliferation. Here, we show that rictor associates with FBXW7 to form an E3 complex participating in the regulation of c-Myc and cyclin E degradation. The Rictor-FBXW7 complex is biochemically distinct from the previously reported mTORC2 and can be immunoprecipitated independently of mTORC2. Moreover, knocking down of rictor in serum-deprived colorectal cancer cells results in the decreased ubiquitination and increased protein levels of c-Myc and cyclin E while overexpression of rictor induces the degradation of c-Myc and cyclin E proteins. Genetic knockout of FBXW7 blunts the effects of rictor, suggesting that rictor regulation of c-Myc and cyclin E requires FBXW7. Our findings identify rictor as an important component of FBXW7 E3 ligase complex participating in the regulation of c-Myc and cyclin E protein ubiquitination and degradation. Importantly, our results suggest that elevated growth factor signaling may contribute to decrease rictor/FBXW7-mediated ubiquitination of c-Myc and cyclin E, thus leading to accumulation of cyclin E and c-Myc in colorectal cancer cells.

  6. Relationship Between HER2 Status and Prognosis in Women With Brain Metastases From Breast Cancer

    SciTech Connect (OSTI)

    Xu Zhiyuan; Marko, Nicholas F.; Chao, Sam T.; Angelov, Lilyana; Vogelbaum, Michael A.; Suh, John H.; Barnett, Gene H.; Weil, Robert J.

    2012-04-01

    Purpose: To analyze factors affecting outcomes in breast cancer patients with brain metastases (BM) and characterize the role of HER2 status. Methods and Materials: We identified 264 breast cancer patients treated between 1999 and 2008 for BM. HER2 status was known definitively for 172 patients and was used to define cohorts in which survival and risk factors were analyzed. Results: Kaplan-Meier survival analysis demonstrated improved mean overall survival (105.7 vs. 74.3 months, p < 0.02), survival after diagnosis of BM (neurologic survival, NS) (32.2 vs. 18.9 months, p < 0.01), and survival after treatment with stereotactic radiosurgery (RS) (31.3 vs. 14.1, p < 0.01) in HER2+ patients relative to those with HER2- breast cancer. HER2+ status was an independent, positive prognostic factor for survival on univariate and multivariate hazard analysis (hazard ratio: overall survival = 0.66, 0.18; NS = 0.50, 0.34). Additionally, subgroup analysis suggests that stereotactic radiosurgery may be of particular benefit in patients with HER2+ tumors. Conclusions: Overall survival, NS, and RS are improved in patients with HER2+ tumors, relative to those with HER2- lesions, and HER2 amplification is independently associated with increased survival in patients with BM from breast cancer. Our findings suggest that the prognosis of HER2+ patients may be better than that of otherwise similar patients who are HER2- and that stereotactic radiosurgery may be beneficial for some patients with HER2+ lesions.

  7. Expression and potential role of the peptide orexin-A in prostate cancer

    SciTech Connect (OSTI)

    Valiante, Salvatore; Liguori, Giovanna; Tafuri, Simona; Pavone, Luigi Michele; Campese, Roberto; Monaco, Roberto; Iachetta, Giuseppina; Assisi, Loredana; Mirabella, Nicola; Forte, Maurizio; Costagliola, Anna; Vittoria, Alfredo

    2015-09-04

    The peptides orexin-A and orexin-B and their G protein-coupled OX1 and OX2 receptors are involved in multiple physiological processes in the central nervous system and peripheral organs. Altered expression or signaling dysregulation of orexins and their receptors have been associated with a wide range of human diseases including narcolepsy, obesity, drug addiction, and cancer. Although orexin-A, its precursor molecule prepro-orexin and OX1 receptor have been detected in the human normal and hyperplastic prostate tissues, their expression and function in the prostate cancer (PCa) remains to be addressed. Here, we demonstrate for the first time the immunohistochemical localization of orexin-A in human PCa specimens, and the expression of prepro-orexin and OX1 receptor at both protein and mRNA levels in these tissues. Orexin-A administration to the human androgen-dependent prostate carcinoma cells LNCaP up-regulates OX1 receptor expression resulting in a decrease of cell survival. Noteworthy, nanomolar concentrations of the peptide counteract the testosterone-induced nuclear translocation of the androgen receptor in the cells: the orexin-A action is prevented by the addition of the OX1 receptor antagonist SB-408124 to the test system. These findings indicate that orexin-A/OX1 receptor interaction interferes with the activity of the androgen receptor which regulates PCa onset and progression, thus suggesting that orexin-A and its receptor might represent novel therapeutic targets to challenge this aggressive cancer. - Highlights: • Orexin-A and OX1 receptor are present in human cancer prostate tissues. • Orexin-A up-regulates OX1 receptor expression in LNCaP cells. • Orexin-A inhibits testosterone-induced nuclear translocation of androgen receptor.

  8. SU-E-T-221: Investigation of Lower Energy (< 6 MV) Photon Beams for Cancer Radiotherapy

    SciTech Connect (OSTI)

    Zhang, Y; Ming, X; Feng, Y; Zhou, L; Ahmad, M; Deng, J; Nguyen, K; Griffin, M

    2014-06-01

    Purpose: To study the potential applications of the lower energy (< 6MV) photon beams in the radiotherapeutic management of pediatric cancer and lung cancer patients. Methods: Photon beams of 2, 3, 4, 5 and 6MV were first simulated with EGS4/BEAM and then used for Monte-Carlo dose calculations. For four pediatric patients with abdominal and brain lesions, six 3D-conformal radiotherapy (3DCRT) plans were generated using single photon energy (2 to 6MV) or mixed energies (3 and 6MV). Furthermore, a virtual machine of 3 and 6MV was commissioned in a treatment planning system (TPS) based on Monte-Carlo simulated data. Three IMRT plans of a lung cancer patient were generated on this virtual machine. All plans were normalized to D95% of target dose for 6MV plan and then compared in terms of integral dose and OAR sparing. Results: For the four pediatric patients, the integral dose for the 2, 3, 4 and 5MV plans increased by 9%, 5%, 3.5%, 1.7%, respectively as compared to 6MV. Almost all OARs in the 2MV plan received more than 10% more doses than 6MV. Mixed energy 3DCRT plans were of the same quality as 6MV plans. For the lung IMRT plans, both the 3MV plan and the mixed beam plan showed better OAR sparing in comparison to 6MV plan. Specifically, the maximum and mean doses to the spinal cord in the mixed energy plan were lower by 21% and 16%, respectively. Conclusion: Single lower energy photon beam was found to be inferior to 6MV in the radiotherapy of pediatric patients and lung cancer patients when the integral doses and the doses to the OARs were considered. However, mixed energy plans combining low with high energy beams showed significant OAR sparing while maintaining the same PTV coverage. Investigation with more patient data is ongoing for further confirmation.

  9. SPARCL1 Expression Increases With Preoperative Radiation Therapy and Predicts Better Survival in Rectal Cancer Patients

    SciTech Connect (OSTI)

    Kotti, Angeliki Holmqvist, Annica; Albertsson, Maria; Sun, Xiao-Feng

    2014-04-01

    Purpose: The secreted protein acidic and rich in cysteine-like 1 (SPARCL1) is expressed in various normal tissues and many types of cancers. The function of SPARCL1 and its relationship to a patient's prognosis have been studied, whereas its relationship to radiation therapy (RT) is not known. Our aim was to investigate the expression of SPARCL1 in rectal cancer patients who participated in a clinical trial of preoperative RT. Methods and Materials: The study included 136 rectal cancer patients who were randomized to undergo preoperative RT and surgery (n=63) or surgery alone (n=73). The expression levels of SPARCL1 in normal mucosa (n=29), primary tumor (n=136), and lymph node metastasis (n=35) were determined by immunohistochemistry. Results: Tumors with RT had stronger SPARCL1 expression than tumors without RT (P=.003). In the RT group, strong SPARCL1 expression was related to better survival than weak expression in patients with stage III tumors, independent of sex, age, differentiation, and margin status (P=.022; RR = 18.128; 95% confidence interval, 1.512-217.413). No such relationship was found in the non-RT group (P=.224). Further analysis of interactions among SPARCL1 expression, RT, and survival showed statistical significance (P=.024). In patients with metastases who received RT, strong SPARCL1 expression was related to better survival compared to weak expression (P=.041) but not in the non-RT group (P=.569). Conclusions: SPARCL1 expression increases with RT and is related to better prognosis in rectal cancer patients with RT but not in patients without RT. This result may help us to select the patients best suited for preoperative RT.

  10. Radiotherapy for Rectal Cancer Is Associated With Reduced Serum Testosterone and Increased FSH and LH

    SciTech Connect (OSTI)

    Bruheim, Kjersti [Cancer Center, Ullevaal University Hospital, Oslo (Norway)], E-mail: Kjersti.Bruheim@medisin.uio.no; Svartberg, Johan [Institute of Clinical Medicine, University of Tromso, Tromso (Norway); Department of Medicine, University Hospital of North Norway, Tromso (Norway); Carlsen, Erik [Department of Gastrointestinal Surgery, Ullevaal University Hospital, Oslo (Norway); Dueland, Svein [Department of Oncology, Norwegian Radium Hospital, Oslo (Norway); Haug, Egil [Hormone Laboratory, Aker University Hospital, Oslo (Norway); Skovlund, Eva [School of Pharmacy, University of Oslo, Oslo (Norway); Tveit, Kjell Magne; Guren, Marianne G. [Cancer Center, Ullevaal University Hospital, Oslo (Norway)

    2008-03-01

    Purpose: It is known that scattered radiation to the testes during pelvic radiotherapy can affect fertility, but there is little knowledge on its effects on male sex hormones. The aim of this study was to determine whether radiotherapy for rectal cancer affects testosterone production. Methods and Materials: All male patients who had received adjuvant radiotherapy for rectal cancer from 1993 to 2003 were identified from the Norwegian Rectal Cancer Registry. Patients treated with surgery alone were randomly selected from the same registry as control subjects. Serum levels of follicle stimulating hormone (FSH), luteinizing hormone (LH), testosterone, and sex hormone binding globulin (SHBG) were analyzed, and free testosterone was calculated (N = 290). Information about the radiotherapy treatment was collected from the patient hospital charts. Results: Serum FSH was 3 times higher in the radiotherapy group than in the control group (median, 18.8 vs. 6.3 IU/L, p <0.001), and serum LH was 1.7 times higher (median, 7.5 vs. 4.5 IU/l, p <0.001). In the radiotherapy group, 27% of patients had testosterone levels below the reference range (8-35 nmol/L), compared with 10% of the nonirradiated patients (p <0.001). Irradiated patients had lower serum testosterone (mean, 11.1 vs. 13.4 nmol/L, p <0.001) and lower calculated free testosterone (mean, 214 vs. 235 pmol/L, p <0.05) than control subjects. Total testosterone, calculated free testosterone, and gonadotropins were related to the distance from the bony pelvic structures to the caudal field edge. Conclusions: Increased serum levels of gonadotropins and subnormal serum levels of testosterone indicate that curative radiotherapy for rectal cancer can result in permanent testicular dysfunction.

  11. Radioisotopes for Medical Diagnostics and Cancer Therapy at BNL | U.S. DOE

    Office of Science (SC) Website

    Office of Science (SC) Radioisotopes for Medical Diagnostics and Cancer Therapy at BNL Nuclear Physics (NP) NP Home About Research Facilities Science Highlights Benefits of NP Applications of Nuclear Science Applications of Nuclear Science Archives Small Business Innovation Research / Small Business Technology Transfer Funding Opportunities Nuclear Science Advisory Committee (NSAC) Community Resources Contact Information Nuclear Physics U.S. Department of Energy SC-26/Germantown Building

  12. SU-E-J-31: Biodynamic Imaging of Cancer Tissue and Response to Chemotherapy

    SciTech Connect (OSTI)

    Nolte, D; Turek, J; Childress, M; An, R; Merrill, D; Matei, D

    2014-06-01

    Purpose: To measure intracellular motions inside three-dimensional living cancer tissue samples to establish a novel set of biodynamic biomarkers that assess tissue proliferative activity and sensitivity or resistance to chemotherapy. Methods: Biodynamic imaging (BDI) uses digital holography with low-coherence low-intensity light illumination to construct 3D holograms from depths up to a millimeter deep inside cancer tissue models that include multicellular tumor spheroids and ex vivo cancer biopsies from canine non-Hodgkins lymphoma and epithelial ovarian cancer (EOC) mouse explants. Intracellular motions modulate the holographic intensity with frequencies related to the Doppler effect caused by the motions of a wide variety of intracellular components. These motions are affected by applied therapeutic agents, and BDI produces unique fingerprints of the action of specific drugs on the motions in specific cell types. In this study, chemotherapeutic agents (doxorubicin for canine lymphoma and oxoplatin for ovarian) are applied to the living tissue models and monitored over 10 hours by BDI. Results: Multicellular spheroids and patient biopsies are categorized as either sensitive or insensitive to applied therapeutics depending on the intracellular Doppler signatures of chemotherapy response. For both lymphoma and EOC there is strong specificity to the two types of sensitivities, with sensitive cell lines and biopsies exhibiting a global cessation of proliferation and strong suppression of metabolic activity, while insensitive cell lines and biopsies show moderate activation of Doppler frequencies associated with membrane processes and possible membrane trafficking. Conclusion: This work supports the hypothesis that biodynamic biomarkers from three-dimensional living tumor tissue, that includes tissue heterogeneity and measured within 24 hours of surgery, is predictive of near-term patient response to therapy. Future work will correlate biodynamic biomarkers with progression free survival times. This work is supported by NIH 1R01EB016582 and NSF 1263753-CBET. Nolte, Turek and An have a financial interest in Animated Dynamics, Inc. that will be licensing technology from Purdue University.

  13. PES1 regulates sensitivity of colorectal cancer cells to anticancer drugs

    SciTech Connect (OSTI)

    Xie, Wei; Qu, Like; Meng, Lin; Liu, Caiyun; Wu, Jian; Shou, Chengchao

    2013-02-15

    Highlights: ? PES1 was overexpressed in diverse cancer cell lines. ? PES1-ablation enhances DNA damage response by decreasing DNA repair. ? PES1-ablation increases the sensitivity of HCT116 cells to chemotherapeutic agents. ? PES1-ablation is associated with diminished nuclear entry of RAD51. -- Abstract: PES1 (also known as Pescadillo), a nucleolar protein, was involved in biogenesis of ribosomal RNA. Up-regulation of PES1 has been documented in some human cancers, indicating that PES1 may play some crucial roles in tumorigenesis. In our previous study, it was found that silencing of PES1 resulted in decreased proliferation of colorectal cancer cells. We also noticed that depletion of PES1 altered expression profiles of diverse genes. In the present study, we validated the expression changes of a subset of genotoxic stress-related genes in PES1-silenced HCT116 cells by quantitative RT-PCR. The steady and etoposide-induced phosphorylated H2AX (?-H2AX) were higher in PES1-silenced cells than in control cells. Besides, etoposide-induced ?-H2AX persisted longer in PES1-silenced cells after removing the etoposide. Next, results of comet assay revealed decreased DNA repair after PES1-ablation. PES1-ablated cells were more sensitive to chemotherapeutic agents, which could be reversed by reconstitution with exogenous PES1. Furthermore, deletion of PES1 diminished steady and DNA damage-induced levels of nuclear RAD51. Our results uncover a potential role of PES1 in chemoresistance by regulating DNA damage response in colorectal cancer cells.

  14. Variation in Use of Androgen Suppression With External-Beam Radiotherapy for Nonmetastatic Prostate Cancer

    SciTech Connect (OSTI)

    Swisher-McClure, Samuel; Pollack, Craig E.; Christodouleas, John P.; Guzzo, Thomas J.; Haas, Naomi B.; Vapiwala, Neha; Bekelman, Justin E.

    2012-05-01

    Purpose: To describe practice patterns associated with androgen suppression (AS) stratified by disease risk group in patients undergoing external-beam radiotherapy (EBRT) for localized prostate cancer. Methods and Materials: We identified 2,184 low-risk, 2,339 intermediate-risk, and 2,897 high-risk patients undergoing EBRT for nonmetastatic prostate cancer diagnosed between January 1, 2004, and December 31, 2005, in the linked Surveillance, Epidemiology, and End Results-Medicare database. We examined the association of patient, clinical, and demographic characteristics with AS use by multivariate logistic regression. Results: The proportions of patients receiving AS for low-risk, intermediate-risk, and high-risk prostate cancer were 32.2%, 56.3%, and 81.5%, respectively. AS use among men in the low-risk disease category varied widely, ranging from 13.6% in Detroit to 47.8% in Kentucky. We observed a significant decline in AS use between 2004 and 2005 within all three disease risk categories. Men aged {>=}75 years or with elevated comorbidity levels were more likely to receive AS. Conclusion: Our results identified apparent overuse and underuse of AS among men within the low-risk and high-risk disease categories, respectively. These results highlight the need for clinician and patient education regarding the appropriate use of AS. Practice patterns among intermediate-risk patients reflect the clinical heterogeneity of this population and underscore the need for better evidence to guide the treatment of these patients.

  15. Accelerated Partial Breast Irradiation Using Only Intraoperative Electron Radiation Therapy in Early Stage Breast Cancer

    SciTech Connect (OSTI)

    Maluta, Sergio; Dall'Oglio, Stefano; Marciai, Nadia; Gabbani, Milena; Franchini, Zeno; Pietrarota, Paolo; Meliado, Gabriele; Guariglia, Stefania; Cavedon, Carlo

    2012-10-01

    Background: We report the results of a single-institution, phase II trial of accelerated partial breast irradiation (APBI) using a single dose of intraoperative electron radiation therapy (IOERT) in patients with low-risk early stage breast cancer. Methods and Materials: A cohort of 226 patients with low-risk, early stage breast cancer were treated with local excision and axillary management (sentinel node biopsy with or without axillary node dissection). After the surgeon temporarily reapproximated the excision cavity, a dose of 21 Gy using IOERT was delivered to the tumor bed, with a margin of 2 cm laterally. Results: With a mean follow-up of 46 months (range, 28-63 months), only 1 case of local recurrence was reported. The observed toxicity was considered acceptable. Conclusions: APBI using a single dose of IOERT can be delivered safely in women with early, low-risk breast cancer in carefully selected patients. A longer follow-up is needed to ascertain its efficacy compared to that of the current standard treatment of whole-breast irradiation.

  16. Fractionated changes in prostate cancer radiotherapy using cone-beam computed tomography

    SciTech Connect (OSTI)

    Huang, Tzung-Chi; Chou, Kuei-Ting; Yang, Shih-Neng; Chang, Chih-Kai; Liang, Ji-An; Zhang, Geoffrey

    2015-10-01

    The high mobility of the bladder and the rectum causes uncertainty in radiation doses prescribed to patients with prostate cancer who undergo radiotherapy (RT) multifraction treatments. The purpose of this study was to estimate the dose received by the bladder, rectum, and prostate from multifraction treatments using daily cone-beam computed tomography (CBCT). Overall, 28 patients with prostate cancer who planned to receive radiation treatments were enrolled in the study. The acquired CBCT before the treatment delivery was registered with the planning CT to map the dose distribution used in the treatment plan for estimating the received dose during clinical treatment. For all 28 patients with 112 data sets, the mean percentage differences (± standard deviation) in the volume and radiation dose were 44% (± 41) and 18% (± 17) for the bladder, 20% (± 21) and 2% (± 2) for the prostate, and 36% (± 29) and 22% (± 15) for the rectum, respectively. Substantial differences between the volumes and radiation dose and those specified in treatment plans were observed. Besides the use of image-guided RT to improve patient setup accuracy, further consideration of large changes in bladder and rectum volumes is strongly suggested when using external beam radiation for prostate cancer.

  17. Enhancement of neurite outgrowth in neuron cancer stem cells by growth on 3-D collagen scaffolds

    SciTech Connect (OSTI)

    Chen, Chih-Hao; Neurosurgery, Department of Surgery, Kaohsiung Veterans General Hospital, Taiwan, ROC; Department of Biomedical Engineering, I-Shou University, Taiwan, ROC ; Kuo, Shyh Ming; Liu, Guei-Sheung; Chen, Wan-Nan U.; Chuang, Chin-Wen; Liu, Li-Feng

    2012-11-09

    Highlights: Black-Right-Pointing-Pointer Neuron cancer stem cells (NCSCs) behave high multiply of growth on collagen scaffold. Black-Right-Pointing-Pointer Enhancement of NCSCs neurite outgrowth on porous collagen scaffold. Black-Right-Pointing-Pointer 3-D collagen culture of NCSCs shows an advance differentiation than 2-D culture. -- Abstract: Collagen is one component of the extracellular matrix that has been widely used for constructive remodeling to facilitate cell growth and differentiation. The 3-D distribution and growth of cells within the porous scaffold suggest a clinical significance for nerve tissue engineering. In the current study, we investigated proliferation and differentiation of neuron cancer stem cells (NCSCs) on a 3-D porous collagen scaffold that mimics the natural extracellular matrix. We first generated green fluorescence protein (GFP) expressing NCSCs using a lentiviral system to instantly monitor the transitions of morphological changes during growth on the 3-D scaffold. We found that proliferation of GFP-NCSCs increased, and a single cell mass rapidly grew with unrestricted expansion between days 3 and 9 in culture. Moreover, immunostaining with neuronal nuclei (NeuN) revealed that NCSCs grown on the 3-D collagen scaffold significantly enhanced neurite outgrowth. Our findings confirmed that the 80 {mu}m porous collagen scaffold could enhance attachment, viability and differentiation of the cancer neural stem cells. This result could provide a new application for nerve tissue engineering and nerve regeneration.

  18. Feasibility study of volumetric modulated arc therapy with constant dose rate for endometrial cancer

    SciTech Connect (OSTI)

    Yang, Ruijie; Wang, Junjie; Xu, Feng; Li, Hua; Zhang, Xile

    2013-10-01

    To investigate the feasibility, efficiency, and delivery accuracy of volumetric modulated arc therapy with constant dose rate (VMAT-CDR) for whole-pelvic radiotherapy (WPRT) of endometrial cancer. The nine-field intensity-modulated radiotherapy (IMRT), VMAT with variable dose-rate (VMAT-VDR), and VMAT-CDR plans were created for 9 patients with endometrial cancer undergoing WPRT. The dose distribution of planning target volume (PTV), organs at risk (OARs), and normal tissue (NT) were compared. The monitor units (MUs) and treatment delivery time were also evaluated. For each VMAT-CDR plan, a dry run was performed to assess the dosimetric accuracy with MatriXX from IBA. Compared with IMRT, the VMAT-CDR plans delivered a slightly greater V{sub 20} of the bowel, bladder, pelvis bone, and NT, but significantly decreased the dose to the high-dose region of the rectum and pelvis bone. The MUs decreased from 1105 with IMRT to 628 with VMAT-CDR. The delivery time also decreased from 9.5 to 3.2 minutes. The average gamma pass rate was 95.6% at the 3%/3 mm criteria with MatriXX pretreatment verification for 9 patients. VMAT-CDR can achieve comparable plan quality with significant shorter delivery time and smaller number of MUs compared with IMRT for patients with endometrial cancer undergoing WPRT. It can be accurately delivered and be an alternative to IMRT on the linear accelerator without VDR capability.

  19. Prevalence and Treatment Management of Oropharyngeal Candidiasis in Cancer Patients: Results of the French Candidoscope Study

    SciTech Connect (OSTI)

    Gligorov, Joseph; Bastit, Laurent; Gervais, Honorine; Henni, Mehdi; Kahila, Widad; Lepille, Daniel; Luporsi, Elisabeth; Sasso, Giuseppe; Varette, Charles; Azria, David

    2011-06-01

    Purpose: The aim of this pharmaco-epidemiological study was to evaluate the prevalence of oropharyngeal candidiasis (OPC) in cancer patients treated with chemotherapy and/or radiotherapy. Methods and Materials: Signs and symptoms of OPC were noted for all patients. Antifungal therapeutic management was recorded in OPC patients. Patients receiving local antifungal treatments were monitored until the end of treatment. Results: Enrolled in the study were 2,042 patients with solid tumor and/or lymphoma treated with chemotherapy and/or another systemic cancer treatment and/or radiotherapy. The overall prevalence of OPC was 9.6% (95% confidence interval, 8.4%-11.0%]in this population. It was most frequent in patients treated with combined chemoradiotherapy (22.0%) or with more than two cytotoxic agents (16.9%). Local antifungal treatments were prescribed in 75.0% of OPC patients as recommended by guidelines. The compliance to treatment was higher in patients receiving once-daily miconazole mucoadhesive buccal tablet (MBT; 88.2%) than in those treated with several daily mouthwashes of amphotericin B (40%) or nystatin (18.8%). Conclusion: OPC prevalence in treated cancer patients was high. Local treatments were usually prescribed as per guidelines. Compliance to local treatments was better with once-daily drugs.

  20. Linkage studies with 17q and 18q markers in a breast/ovarian cancer family

    SciTech Connect (OSTI)

    Milner, B.J.; Allan, L.A.; Kelly, K.F.; Johnston, A.; Haites, N. ); Cruickshank, D.; Hall, M.; Kitchener, H.; Parkin, D. )

    1993-04-01

    Genes on chromosomes 17q and 18q have been shown to code for putative tumor suppressors. By a combination of allele-loss studies on sporadic ovarian carcinomas and linkage analysis on a breast/ovarian cancer family, the authors have investigated the involvement of such genes in these diseases. Allele loss occurred in sporadic tumors from both chromosome 17p, in 18/26 (69%) cases, and chromosome 17q, in 15/22 (68%) cases. In the three familial tumors studied, allele loss also occurred on chromosome 17 (in 2/3 cases for 17p markers and in 2/2 cases for a 17q allele). Allele loss on chromosome 18q, at the DCC (deleted in colorectal carcinomas) locus, was not as common (6/16 cases [38%]) in sporadic ovarian tumors but had occurred in all three familial tumors. The results of linkage analysis on the breast/ovarian cancer family suggested linkage between the disease locus and 17q markers, with a maximum lod score of 1.507 obtained with Mfd188 (D17S579) polymorphism at 5% recombination. The maximum lod score for DCC was 0.323 at 0.1% recombination. In this family the results are consistent with a predisposing gene for breast/ovarian cancer being located at chromosome 17q21. 24 refs., 1 fig., 3 tabs.

  1. Amplifications and deletions in clinical ovarian cancer detected by Comparative Genomic Hybridization (CGH)

    SciTech Connect (OSTI)

    Sakunaga, H.; Sakamoto, M.; Kallioniemi, A.; Kallioniemi, O.; Sudar, D.; Pinkel, D.; Gray, I.W. ); Yang-Feng, T. )

    1993-01-01

    CGH is a new powerful method for surveying the whole genome for DNA sequence copy number changes in a single hybridization. The method is based on the competition between biotinylated total tumor DNA and a digoxigenin-labeled normal genomic reference DNA during hybridization to normal metaphase chromosomes. After immunofluorescent staining with avidin-FITC and antidigoxigenin Rhodamine, variation of DNA sequence copy numbers in the tumor are detected as variations in the ratios of green and red fluorescence along each chromosome. The authors applied CGH analysis to DNA extracted from surgically removed ovarian cancer specimens (27 cases). Seven amplified regions were identified by CGH analysis. Three loci, 1p32-p34 (most likely, MYCL), 8q23-q24 (MYC), 12q12 (KRAS2), were known to be amplified in solid tumors and four other loci (3q26, 6p22, 9q31-q33, 17q22) were previously unknown to be amplified. Many regions indicating physical deletions were also identified by the analysis. Chromosomal regions showing frequent deletion were 1p, 3p, 17p, 17q, 19p, 19q and Xp. There were also significant similarities of the regions with amplifications and deletions between bilateral ovarian tumors or among several different tumors form the same ovarian cancer cases, suggesting that the genetic changes observed might be relatively early events during the progression of ovarian cancer.

  2. Radiation-induced complications in prostate cancer patients treated with radiotherapy

    SciTech Connect (OSTI)

    Azuddin, A. Yusof; Rahman, I. Abdul; Mohamed, F.; Siah, N. J.; Saadc, M.; Ismail, F.

    2014-09-03

    The purpose of the study is to determine the relationship between radiation-induced complications with dosimetric and radiobiological parameters for prostate cancer patients that underwent the conformal radiotherapy treatment. 17 prostate cancer patients that have been treated with conformal radiotherapy were retrospectively analysed. The dosimetric data was retrieved in the form of dose-volume histogram (DVH) from Radiotherapy Treatment Planning System. The DVH was utilised to derived Normal Tissue Complication Probability (NTCP) in radiobiological data. Follow-up data from medical records were used to grade the occurrence of acute gastrointestinal (GI) and genitourinary (GU) complications using Radiation Therapy Oncology Group (RTOG) scoring system. The chi-square test was used to determine the relationship between radiation-induced complication with dosimetric and radiobiological parameters. 8 (47%) and 7 (41%) patients were having acute GI and GU complications respectively. The acute GI complication can be associated with V60{sub rectum}, rectal mean dose and NTCP{sub rectum} with p-value of 0.016, 0.038 and 0.049 respectively. There are no significant relationships of acute GU complication with dosimetric and radiobiological variables. Further study can be done by increase the sample size and follow up duration for deeper understanding of the factors that effecting the GU and GI complication in prostate cancer radiotherapy.

  3. Combined Treatment Effects of Radiation and Immunotherapy: Studies in an Autochthonous Prostate Cancer Model

    SciTech Connect (OSTI)

    Wada, Satoshi; Harris, Timothy J.; Tryggestad, Erik; Yoshimura, Kiyoshi; Zeng, Jing; Yen, Hung-Rong; Getnet, Derese; Grosso, Joseph F.; Bruno, Tullia C.; De Marzo, Angelo M.; and others

    2013-11-15

    Purpose: To optimize the combination of ionizing radiation and cellular immunotherapy using a preclinical autochthonous model of prostate cancer. Methods and Materials: Transgenic mice expressing a model antigen under a prostate-specific promoter were treated using a platform that integrates cone-beam CT imaging with 3-dimensional conformal therapy. Using this technology we investigated the immunologic and therapeutic effects of combining ionizing radiation with granulocyte/macrophage colony-stimulating factor-secreting cellular immunotherapy for prostate cancer in mice bearing autochthonous prostate tumors. Results: The combination of ionizing radiation and immunotherapy resulted in a significant decrease in pathologic tumor grade and gross tumor bulk that was not evident with either single-modality therapy. Furthermore, combinatorial therapy resulted in improved overall survival in a preventive metastasis model and in the setting of established micrometastases. Mechanistically, combined therapy resulted in an increase of the ratio of effector-to-regulatory T cells for both CD4 and CD8 tumor-infiltrating lymphocytes. Conclusions: Our preclinical model establishes a potential role for the use of combined radiation-immunotherapy in locally advanced prostate cancer, which warrants further exploration in a clinical setting.

  4. Phase-based x-ray scatteringA possible method to detect cancer cells in a very early stage

    SciTech Connect (OSTI)

    Feye-Treimer, U. Treimer, W.

    2014-05-15

    Purpose: This theoretical work contains a detailed investigation of the potential and sensitivity of phase-based x-ray scattering for cancer detection in biopsies if cancer is in a very early stage of development. Methods: Cancer cells in their early stage of development differ from healthy ones mainly due to their faster growing cell nuclei and the enlargement of their densities. This growth is accompanied by an altered nucleusplasma relation for the benefit of the cell nuclei, that changes the physical properties especially the index of refraction of the cell and the one of the cell nuclei. Interaction of radiation with matter is known to be highly sensitive to small changes of the index of refraction of matter; therefore a detection of such changes of volume and density of cell nuclei by means of high angular resolved phase-based scattering of x rays might provide a technique to distinguish malignant cells from healthy ones ifthe cellcell nucleus system is considered as a coherent phase shifting object. Then one can observe from a thin biopsy which represents a monolayer of cells (no multiple scattering) that phase-based x-ray scattering curves from healthy cells differ from those of cancer cells in their early stage of development. Results: Detailed calculations of x-ray scattering patterns from healthy and cancer cell nuclei yield graphs and numbers with which one can distinguish healthy cells from cancer ones, taking into account that both kinds of cells occur in a tissue within a range of size and density. One important result is the role and the influence of the (lateral) coherence width of the radiation on the scattering curves and the sensitivity of phase-based scattering for cancer detection. A major result is that a larger coherence width yields a larger sensitivity for cancer detection. Further import results are calculated limits for critical sizes and densities of cell nuclei in order to attribute the investigated tissue to be healthy or diseased. Conclusions: With this proposed method it should be in principle possible to detect cancer cells in apparently healthy tissues in biopsies and/or in samples of the far border region of abscised or excised tissues. Thus this method could support established methods in diagnostics of cancer-suspicious samples.

  5. Causes of Mortality After Dose-Escalated Radiation Therapy and Androgen Deprivation for High-Risk Prostate Cancer

    SciTech Connect (OSTI)

    Tendulkar, Rahul D.; Hunter, Grant K.; Reddy, Chandana A.; Stephans, Kevin L.; Ciezki, Jay P.; Abdel-Wahab, May; Stephenson, Andrew J.; Klein, Eric A.; Mahadevan, Arul; Kupelian, Patrick A.

    2013-09-01

    Purpose: Men with high-risk prostate cancer have other competing causes of mortality; however, current risk stratification schema do not account for comorbidities. We aim to identify the causes of death and factors predictive for mortality in this population. Methods and Materials: A total of 660 patients with high-risk prostate cancer were treated with definitive high-dose external beam radiation therapy (?74 Gy) and androgen deprivation (AD) between 1996 and 2009 at a single institution. Cox proportional hazards regression analysis was conducted to determine factors predictive of survival. Results: The median radiation dose was 78 Gy, median duration of AD was 6 months, and median follow-up was 74 months. The 10-year overall survival (OS) was 60.6%. Prostate cancer was the leading single cause of death, with 10-year mortality of 14.1% (95% CI 10.7-17.6), compared with other cancers (8.4%, 95% CI 5.7-11.1), cardiovascular disease (7.3%, 95% CI 4.7-9.9), and all other causes (10.4%, 95% CI 7.2-13.6). On multivariate analysis, older age (HR 1.55, P=.002) and Charlson comorbidity index score (CS) ?1 (HR 2.20, P<.0001) were significant factors predictive of OS, whereas Gleason score, T stage, prostate-specific antigen, duration of AD, radiation dose, smoking history, and body mass index were not. Men younger than 70 years of age with CS = 0 were more likely to die of prostate cancer than any other cause, whereas older men or those with CS ?1 more commonly suffered non-prostate cancer death. The cumulative incidences of prostate cancer-specific mortality were similar regardless of age or comorbidities (P=.60). Conclusions: Men with high-risk prostate cancer are more likely to die of causes other than prostate cancer, except for the subgroup of men younger than 70 years of age without comorbidities. Only older age and presence of comorbidities significantly predicted for OS, whereas prostate cancer- and treatment-related factors did not.

  6. Hydroxychavicol, a betel leaf component, inhibits prostate cancer through ROS-driven DNA damage and apoptosis

    SciTech Connect (OSTI)

    Gundala, Sushma Reddy; Yang, Chunhua; Mukkavilli, Rao; Paranjpe, Rutugandha; Brahmbhatt, Meera; Pannu, Vaishali; Cheng, Alice; Reid, Michelle D.; Aneja, Ritu

    2014-10-01

    Dietary phytochemicals are excellent ROS-modulating agents and have been shown to effectively enhance ROS levels beyond toxic threshold in cancer cells to ensure their selective killing while leaving normal cells unscathed. Here we demonstrate that hydroxychavicol (HC), extracted and purified from Piper betel leaves, significantly inhibits growth and proliferation via ROS generation in human prostate cancer, PC-3 cells. HC perturbed cell-cycle kinetics and progression, reduced clonogenicity and mediated cytotoxicity by ROS-induced DNA damage leading to activation of several pro-apoptotic molecules. In addition, HC treatment elicited a novel autophagic response as evidenced by the appearance of acidic vesicular organelles and increased expression of autophagic markers, LC3-IIb and beclin-1. Interestingly, quenching of ROS with tiron, an antioxidant, offered significant protection against HC-induced inhibition of cell growth and down regulation of caspase-3, suggesting the crucial role of ROS in mediating cell death. The collapse of mitochondrial transmembrane potential by HC further revealed the link between ROS generation and induction of caspase-mediated apoptosis in PC-3 cells. Our data showed remarkable inhibition of prostate tumor xenografts by ∼ 72% upon daily oral administration of 150 mg/kg bw HC by quantitative tumor volume measurements and non-invasive real-time bioluminescent imaging. HC was well-tolerated at this dosing level without any observable toxicity. This is the first report to demonstrate the anti-prostate cancer efficacy of HC in vitro and in vivo, which is perhaps attributable to its selective prooxidant activity to eliminate cancer cells thus providing compelling grounds for future preclinical studies to validate its potential usefulness for prostate cancer management. - Highlights: • HC perturbs cell-cycle progression by induction of reactive oxygen species (ROS). • HC mediated cytotoxicity by ROS-induced DNA damage leading to apoptosis. • HC induced ROS-mediated autophagic response. • It inhibited prostate tumor growth by ∼ 72% without any observable toxicity. • Its anticancer efficacy is likely due to its selective prooxidant activity.

  7. Role of Positron Emission Tomography-Computed Tomography in the Management of Anal Cancer

    SciTech Connect (OSTI)

    Mistrangelo, Massimiliano; Pelosi, Ettore; Bello, Marilena; Ricardi, Umberto; Milanesi, Enrica; Cassoni, Paola; Baccega, Massimo; Filippini, Claudia; Racca, Patrizia; Lesca, Adriana; Munoz, Fernando H.; Fora, Gianluca; Skanjeti, Andrea; Cravero, Francesca; Morino, Mario

    2012-09-01

    Purpose: Pre- and post-treatment staging of anal cancer are often inaccurate. The role of positron emission tomograpy-computed tomography (PET-CT) in anal cancer is yet to be defined. The aim of the study was to compare PET-CT with CT scan, sentinel node biopsy results of inguinal lymph nodes, and anal biopsy results in staging and in follow-up of anal cancer. Methods and Materials: Fifty-three consecutive patients diagnosed with anal cancer underwent PET-CT. Results were compared with computed tomography (CT), performed in 40 patients, and with sentinel node biopsy (SNB) (41 patients) at pretreatment workup. Early follow-up consisted of a digital rectal examination, an anoscopy, a PET-CT scan, and anal biopsies performed at 1 and 3 months after the end of treatment. Data sets were then compared. Results: At pretreatment assessment, anal cancer was identified by PET-CT in 47 patients (88.7%) and by CT in 30 patients (75%). The detection rates rose to 97.9% with PET-CT and to 82.9% with CT (P=.042) when the 5 patients who had undergone surgery prior to this assessment and whose margins were positive at histological examination were censored. Perirectal and/or pelvic nodes were considered metastatic by PET-CT in 14 of 53 patients (26.4%) and by CT in 7 of 40 patients (17.5%). SNB was superior to both PET-CT and CT in detecting inguinal lymph nodes. PET-CT upstaged 37.5% of patients and downstaged 25% of patients. Radiation fields were changed in 12.6% of patients. PET-CT at 3 months was more accurate than PET-CT at 1 month in evaluating outcomes after chemoradiation therapy treatment: sensitivity was 100% vs 66.6%, and specificity was 97.4% vs 92.5%, respectively. Median follow-up was 20.3 months. Conclusions: In this series, PET-CT detected the primary tumor more often than CT. Staging of perirectal/pelvic or inguinal lymph nodes was better with PET-CT. SNB was more accurate in staging inguinal lymph nodes.

  8. Global identification of genes regulated by estrogen signaling and demethylation in MCF-7 breast cancer cells

    SciTech Connect (OSTI)

    Putnik, Milica; Zhao, Chunyan; Gustafsson, Jan-Ake; Department of Biology and Biochemistry, Science and Engineering Research Center Bldg, University of Houston, Houston, TX 77204-5056 ; Dahlman-Wright, Karin

    2012-09-14

    Highlights: Black-Right-Pointing-Pointer Estrogen signaling and demethylation can both control gene expression in breast cancers. Black-Right-Pointing-Pointer Cross-talk between these mechanisms is investigated in human MCF-7 breast cancer cells. Black-Right-Pointing-Pointer 137 genes are influenced by both 17{beta}-estradiol and demethylating agent 5-aza-2 Prime -deoxycytidine. Black-Right-Pointing-Pointer A set of genes is identified as targets of both estrogen signaling and demethylation. Black-Right-Pointing-Pointer There is no direct molecular interplay of mediators of estrogen and epigenetic signaling. -- Abstract: Estrogen signaling and epigenetic modifications, in particular DNA methylation, are involved in regulation of gene expression in breast cancers. Here we investigated a potential regulatory cross-talk between these two pathways by identifying their common target genes and exploring underlying molecular mechanisms in human MCF-7 breast cancer cells. Gene expression profiling revealed that the expression of approximately 140 genes was influenced by both 17{beta}-estradiol (E2) and a demethylating agent 5-aza-2 Prime -deoxycytidine (DAC). Gene ontology (GO) analysis suggests that these genes are involved in intracellular signaling cascades, regulation of cell proliferation and apoptosis. Based on previously reported association with breast cancer, estrogen signaling and/or DNA methylation, CpG island prediction and GO analysis, we selected six genes (BTG3, FHL2, PMAIP1, BTG2, CDKN1A and TGFB2) for further analysis. Tamoxifen reverses the effect of E2 on the expression of all selected genes, suggesting that they are direct targets of estrogen receptor. Furthermore, DAC treatment reactivates the expression of all selected genes in a dose-dependent manner. Promoter CpG island methylation status analysis revealed that only the promoters of BTG3 and FHL2 genes are methylated, with DAC inducing demethylation, suggesting DNA methylation directs repression of these genes in MCF-7 cells. In a further analysis of the potential interplay between estrogen signaling and DNA methylation, E2 treatment showed no effect on the methylation status of these promoters. Additionally, we show that the ER{alpha} recruitment occurs at the FHL2 promoter in an E2- and DAC-independent fashion. In conclusion, we identified a set of genes regulated by both estrogen signaling and DNA methylation. However, our data does not support a direct molecular interplay of mediators of estrogen and epigenetic signaling at promoters of regulated genes.

  9. Development of a High Latent Effectiveness Energy Recovery Ventilator with Integration into Rooftop Package Equipment

    SciTech Connect (OSTI)

    Gregory M. Dobbs; Norberto O. Lemcoff; Frederick J. Cogswell; Jeffrey T. Benolt

    2006-03-01

    This Final Report covers the Cooperative Program carried out to design and optimize an enhanced flat-plate energy recovery ventilator and integrate it into a packaged unitary (rooftop) air conditioning unit. The project objective was to optimize the design of a flat plate energy recovery ventilator (ERV) core that compares favorably to flat plate air-to-air heat exchanger cores on the market and to cost wise to small enthalpy wheel devices. The benefits of an integrated unit incorporating an enhanced ERV core and a downsized heating/cooling unit were characterized and the design of an integrated unit considering performance and cost was optimized. Phase I was to develop and optimize the design of a membrane based heat exchanger core. Phase II was the creation and observation of a system integrated demonstrator unit consisting of the Enhanced Energy Recovery Ventilator (EERV) developed in Phase I coupled to a standard Carrier 50HJ rooftop packaged unitary air conditioning unit. Phase III was the optimization of the system prior to commercialization based on the knowledge gained in Phase II. To assure that the designs chosen have the possibility of meeting cost objectives, a preliminary manufacturability and production cost study was performed by the Center for Automation Technologies at RPI. Phase I also included a preliminary design for the integrated unit to be further developed in Phase II. This was to assure that the physical design of the heat exchanger designed in Phase I would be acceptable for use in Phase II. An extensive modeling program was performed by the Center for Building Performance & Diagnostics of CMU. Using EnergyPlus as the software, a typical office building with multiple system configurations in multiple climatic zones in the US was simulated. The performance of energy recovery technologies in packaged rooftop HVAC equipment was evaluated. The experimental program carried out in Phases II and III consisted of fabricating and testing a demonstrator unit using Carrier Comfort Network (CCN) based controls. Augmenting the control signals, CCN was also used to monitor and record additional performance data that supported modeling and conceptual understanding. The result of the testing showed that the EERV core developed in Phase I recovered energy in the demonstrator unit at the expected levels based on projections. In fact, at near-ARI conditions the core recovered about one ton of cooling enthalpy when operating with a three-ton rooftop packaged unit.

  10. Project Profile: Heat Transfer and Latent Heat Storage in Inorganic Molten Salts for CSP Plants

    Broader source: Energy.gov [DOE]

    Terrafore, under the Thermal Storage FOA, is developing an economically feasible thermal energy storage (TES) system based on phase change materials (PCMs), for CSP plants.

  11. Plant cyclopeptide RA-V kills human breast cancer cells by inducing mitochondria-mediated apoptosis through blocking PDK1AKT interaction

    SciTech Connect (OSTI)

    Fang, Xian-Ying; Chen, Wei; Fan, Jun-Ting; Song, Ran; Wang, Lu; Gu, Yan-Hong; Zeng, Guang-Zhi; Shen, Yan; Wu, Xue-Feng; Tan, Ning-Hua; Xu, Qiang; Sun, Yang

    2013-02-15

    In the present paper, we examined the effects of a natural cyclopeptide RA-V on human breast cancer cells and the underlying mechanisms. RA-V significantly inhibited the growth of human breast cancer MCF-7, MDA-MB-231 cells and murine breast cancer 4T1 cells. In addition, RA-V triggered mitochondrial apoptotic pathway which was indicated by the loss of mitochondrial membrane potential, the release of cytochrome c, and the activation of caspase cascade. Further study showed that RA-V dramatically inhibited phosphorylation of AKT and 3-phosphoinositide dependent protein kinase 1 (PDK1) in MCF-7 cells. Moreover, RA-V disrupted the interaction between PDK1 and AKT in MCF-7 cells. Furthermore, RA-V-induced apoptosis could be enhanced by phosphatidylinositol 3-kinase inhibitor or attenuated by over-expression of AKT in all the three kinds of breast cancer cells. Taken together, this study shows that RA-V, which can induce mitochondria-mediated apoptosis, exerts strong anti-tumor activity against human breast cancer. The underlying anti-cancer mechanism of RA-V is related to the blockage of the interaction between PDK1 and AKT. - Highlights: ? Plant cyclopeptide RA-V kills human breast cancer cells. ? RA-V triggered mitochondrial apoptotic pathway in human breast cancer cells. ? RA-V inhibited phosphorylation of AKT and PDK1 in breast cancer MCF-7 cells. ? Its mechanism is related to the blockage of the interaction between PDK1 and AKT.

  12. Mitochondrial calcium uniporter silencing potentiates caspase-independent cell death in MDA-MB-231 breast cancer cells

    SciTech Connect (OSTI)

    Curry, Merril C.; Peters, Amelia A.; Kenny, Paraic A.; Roberts-Thomson, Sarah J.; Monteith, Gregory R.

    2013-05-10

    Highlights: Some clinical breast cancers are associated with MCU overexpression. MCU silencing did not alter cell death initiated with the Bcl-2 inhibitor ABT-263. MCU silencing potentiated caspase-independent cell death initiated by ionomycin. MCU silencing promoted ionomycin-mediated cell death without changes in bulk Ca{sup 2+}. -- Abstract: The mitochondrial calcium uniporter (MCU) transports free ionic Ca{sup 2+} into the mitochondrial matrix. We assessed MCU expression in clinical breast cancer samples using microarray analysis and the consequences of MCU silencing in a breast cancer cell line. Our results indicate that estrogen receptor negative and basal-like breast cancers are characterized by elevated levels of MCU. Silencing of MCU expression in the basal-like MDA-MB-231 breast cancer cell line produced no change in proliferation or cell viability. However, distinct consequences of MCU silencing were seen on cell death pathways. Caspase-dependent cell death initiated by the Bcl-2 inhibitor ABT-263 was not altered by MCU silencing; whereas caspase-independent cell death induced by the calcium ionophore ionomycin was potentiated by MCU silencing. Measurement of cytosolic Ca{sup 2+} levels showed that the promotion of ionomycin-induced cell death by MCU silencing occurs independently of changes in bulk cytosolic Ca{sup 2+} levels. This study demonstrates that MCU overexpression is a feature of some breast cancers and that MCU overexpression may offer a survival advantage against some cell death pathways. MCU inhibitors may be a strategy to increase the effectiveness of therapies that act through the induction of caspase-independent cell death pathways in estrogen receptor negative and basal-like breast cancers.

  13. Decreased expression of RNA interference machinery, Dicer and Drosha, is associated with poor outcome in ovarian cancer patients

    SciTech Connect (OSTI)

    Merritt, William M.; Lin, Yvonne G.; Han, Liz Y.; Kamat, Aparna A.; Spannuth, Whitney A.; Schmandt, Rosemarie; Urbauer, Diana; Pennacchio, Len A.; Cheng, Jan-Fang; Zeidan, Alexandra; Wang, Hua; Mueller, Peter; Lenburg, Marc E.; Gray, Joe W.; Mok, Samuel; Birrer, Michael J.; Lopez-Berestein, Gabriel; Coleman, Robert L.; Bar-Eli, Menashe; Sood, Anil K.

    2008-05-06

    The clinical and functional significance of RNA interference (RNAi) machinery, Dicer and Drosha, in ovarian cancer is not known and was examined. Dicer and Drosha expression was measured in ovarian cancer cell lines (n=8) and invasive epithelial ovarian cancer specimens (n=111) and correlated with clinical outcome. Validation was performed with previously published cohorts of ovarian, breast, and lung cancer patients. Anti-Galectin-3 siRNA and shRNA transfections were used for in vitro functional studies. Dicer and Drosha mRNA and protein levels were decreased in 37% to 63% of ovarian cancer cell lines and in 60% and 51% of human ovarian cancer specimens, respectively. Low Dicer was significantly associated with advanced tumor stage (p=0.007), and low Drosha with suboptimal surgical cytoreduction (p=0.02). Tumors with both high Dicer and Drosha were associated with increased median patient survival (>11 years vs. 2.66 years for other groups; p<0.001). In multivariate analysis, high Dicer (HR=0.48; p=0.02), high-grade histology (HR=2.46; p=0.03), and poor chemoresponse (HR=3.95; p<0.001) were identified as independent predictors of disease-specific survival. Findings of poor clinical outcome with low Dicer expression were validated in separate cohorts of cancer patients. Galectin-3 silencing with siRNA transfection was superior to shRNA in cell lines with low Dicer (78-95% vs. 4-8% compared to non-targeting sequences), and similar in cell lines with high Dicer. Our findings demonstrate the clinical and functional impact of RNAi machinery alterations in ovarian carcinoma and support the use of siRNA constructs that do not require endogenous Dicer and Drosha for therapeutic applications.

  14. Five-year Results of Whole Breast Intensity Modulated Radiation Therapy for the Treatment of Early Stage Breast Cancer: The Fox Chase Cancer Center Experience

    SciTech Connect (OSTI)

    Keller, Lanea M.M.; Sopka, Dennis M.; Li Tianyu; Klayton, Tracy; Li Jinsheng; Anderson, Penny R.; Bleicher, Richard J.; Sigurdson, Elin R.; Freedman, Gary M.

    2012-11-15

    Purpose: To report the 5-year outcomes using whole-breast intensity-modulated radiation therapy (IMRT) for the treatment of early-stage-breast cancer at the Fox Chase Cancer Center. Methods and Materials: A total of 946 women with early-stage breast cancer (stage 0, I, or II) were treated with IMRT after surgery with or without systemic therapy from 2003-2010. Whole-breast radiation was delivered via an IMRT technique with a median whole-breast radiation dose of 46 Gy and median tumor bed boost of 14 Gy. Endpoints included local-regional recurrence, cosmesis, and late complications. Results: With a median follow-up of 31 months (range, 1-97 months), there were 12 ipsilateral breast tumor recurrences (IBTR) and one locoregional recurrence. The 5-year actuarial IBTR and locoregional recurrence rates were 2.0% and 2.4%. Physician-reported cosmestic outcomes were available for 645 patients: 63% were considered 'excellent', 33% 'good', and <1.5% 'fair/poor'. For physician-reported cosmesis, boost doses {>=}16 Gy, breast size >900 cc, or boost volumes >34 cc were significantly associated with a 'fair/poor' cosmetic outcome. Fibrosis, edema, erythema, and telangectasia were also associated with 'fair/poor' physician-reported cosmesis; erythema and telangectasia remained significant on multivariate analysis. Patient-reported cosmesis was available for 548 patients, and 33%, 50%, and 17% of patients reported 'excellent', 'good', and 'fair/poor' cosmesis, respectively. The use of a boost and increased boost volume: breast volume ratio were significantly associated with 'fair/poor' outcomes. No parameter for patient-reported cosmesis was significant on multivariate analysis. The chances of experiencing a treatment related effect was significantly associated with a boost dose {>=}16 Gy, receipt of chemotherapy and endocrine therapy, large breast size, and electron boost energy. Conclusions: Whole-breast IMRT is associated with very low rates of local recurrence at 5 years, 83%-98% 'good/excellent' cosmetic outcomes, and minimal chronic toxicity, including late fibrosis.

  15. The founder mutations 185delAG and 5382insC in BRCA1 and 6174delT in BRCA2 appear in 60% of ovarian cancer and 30% of early-onset breast cancer patients among Ashkenazi women

    SciTech Connect (OSTI)

    Abeliovich, D.; Lerer, I.; Weinberg, N.

    1997-03-01

    The mutations 185delAG, 188del11, and 5382insC in the BRCA1 gene and 6174delT in the BRCA2 gene were analyzed in 199 Ashkenazi and 44 non-Ashkenazi Jewish unrelated patients with breast and/or ovarian cancer. Of the Jewish Ashkenazi women with ovarian cancer, 62% (13/21) had one of the target mutations, as did 30% (13/43) of women with breast cancer alone diagnosed before the age 40 years and 10% (15/141) of those with breast cancer diagnosed after the age 40 years. Age at ovarian cancer diagnosis was not associated with carrier status. Of 99 Ashkenazi patients with no family history of breast and/or ovarian cancer, 10% carried one of the mutations; in two of them the mutation was proved to be paternally transmitted. One non-Ashkenazi Jewish ovarian cancer patient from Iraq carried the 185delAG mutation. Individual mutation frequencies among breast cancer Ashkenazi patients were 6.7% for 185delAG, 2.2% for 5382insC, and 4.5% for 6174delT, among ovarian cancer patients; 185delAG and 6174delT were about equally common (33% and 29%, respectively), but no ovarian cancer patient carried the 5382insC. More mutations responsible for inherited breast and ovarian cancer probably remain to be found in this population, since 79% of high-incidence breast cancer families and 35% of high-incidence breast/ovarian cancer families had none of the three known founder mutations. 25 refs., 3 figs., 6 tabs.

  16. The expression level of HJURP has an independent prognostic impact and predicts the sensitivity to radiotherapy in breast cancer

    SciTech Connect (OSTI)

    Hu, Zhi; Huang, Ge; Sadanandam, Anguraj; Gu, Shenda; Lenburg, Marc E; Pai, Melody; Bayani, Nora; Blakely, Eleanor A; Gray, Joe W; Mao, Jian-Hua

    2010-06-25

    Introduction: HJURP (Holliday Junction Recognition Protein) is a newly discovered gene reported to function at centromeres and to interact with CENPA. However its role in tumor development remains largely unknown. The goal of this study was to investigate the clinical significance of HJURP in breast cancer and its correlation with radiotherapeutic outcome. Methods: We measured HJURP expression level in human breast cancer cell lines and primary breast cancers by Western blot and/or by Affymetrix Microarray; and determined its associations with clinical variables using standard statistical methods. Validation was performed with the use of published microarray data. We assessed cell growth and apoptosis of breast cancer cells after radiation using high-content image analysis. Results: HJURP was expressed at higher level in breast cancer than in normal breast tissue. HJURP mRNA levels were significantly associated with estrogen receptor (ER), progesterone receptor (PR), Scarff-Bloom-Richardson (SBR) grade, age and Ki67 proliferation indices, but not with pathologic stage, ERBB2, tumor size, or lymph node status. Higher HJURP mRNA levels significantly decreased disease-free and overall survival. HJURP mRNA levels predicted the prognosis better than Ki67 proliferation indices. In a multivariate Cox proportional-hazard regression, including clinical variables as covariates, HJURP mRNA levels remained an independent prognostic factor for disease-free and overall survival. In addition HJURP mRNA levels were an independent prognostic factor over molecular subtypes (normal like, luminal, Erbb2 and basal). Poor clinical outcomes among patients with high HJURP expression werevalidated in five additional breast cancer cohorts. Furthermore, the patients with high HJURP levels were much more sensitive to radiotherapy. In vitro studies in breast cancer cell lines showed that cells with high HJURP levels were more sensitive to radiation treatment and had a higher rate of apoptosis than those with low levels. Knock down of HJURP in human breast cancer cells using shRNA reduced the sensitivity to radiation treatment. HJURP mRNA levels were significantly correlated with CENPA mRNA levels. Conclusions: HJURP mRNA level is a prognostic factor for disease-free and overall survival in patients with breast cancer and is a predictive biomarker for sensitivity to radiotherapy.

  17. PPAR{gamma} ligands induce growth inhibition and apoptosis through p63 and p73 in human ovarian cancer cells

    SciTech Connect (OSTI)

    Kim, Soyeon; Innovative Research Institute for Cell Therapy, Seoul National University College of Medicine and Hospital, Seoul ; Lee, Jae-Jung; Heo, Dae Seog

    2011-03-18

    Research highlights: {yields} PPAR{gamma} ligands increased the rate of apoptosis and inhibition of proliferation in ovarian cancer cells. {yields} PPAR{gamma} ligands induced p63 and p73 expression, but not p53. {yields} p63 and p73 leads to an increase in p21 expression and apoptosis in ovarian cancer cells with treatment PPAR{gamma} ligands. {yields} These findings suggest that PPAR{gamma} ligands suppressed growth of ovarian cancer cells through upregulation of p63 and p73. -- Abstract: Peroxisome proliferator-activated receptor gamma (PPAR{gamma}) agonists, including thiazolidinediones (TZDs), can induce anti-proliferation, differentiation, and apoptosis in various cancer cell types. This study investigated the mechanism of the anticancer effect of TZDs on human ovarian cancer. Six human ovarian cancer cell lines (NIH:OVCAR3, SKOV3, SNU-251, SNU-8, SNU-840, and 2774) were treated with the TZD, which induced dose-dependent inhibition of cell growth. Additionally, these cell lines exhibited various expression levels of PPAR{gamma} protein as revealed by Western blotting. Flow cytometry showed that the cell cycle was arrested at the G1 phase, as demonstrated by the appearance of a sub-G1 peak. This observation was corroborated by the finding of increased levels of Bax, p21, PARP, and cleaved caspase 3 in TGZ-treated cells. Interestingly, when we determined the effect of p53-induced growth inhibition in these three human ovarian cancer cells, we found that they either lacked p53 or contained a mutant form of p53. Furthermore, TGZ induced the expression of endogenous or exogenous p63 and p73 proteins and p63- or p73-directed short hairpin (si) RNAs inhibited the ability of TGZ to regulate expression of p21 in these cells. Thus, our results suggest that PPAR{gamma} ligands can induce growth suppression of ovarian cancer cells and mediate p63 and p73 expression, leading to enhanced growth inhibition and apoptosis. The tumor suppressive effects of PPAR{gamma} ligands may have applications for the treatment of ovarian cancer.

  18. Perceptions of Radiation Oncologists and Urologists on Sources and Type of Evidence to Inform Prostate Cancer Treatment Decisions

    SciTech Connect (OSTI)

    Han, Leona C.; Delpe, Sophia; Shah, Nilay D.; Ziegenfuss, Jeanette Y.; Tilburt, Jon C.; Karnes, R. Jeffrey; Nguyen, Paul L.; Gross, Cary P.; Yu, James B.; Trinh, Quoc-Dien; Sun, Maxine; Ranasinghe, Weranja K.B.; Kim, Simon P.

    2014-06-01

    Purpose: To perform a national survey of radiation oncologists and urologists about the type of resources used and the level of evidence needed to change clinical practice in localized prostate cancer. Methods and Materials: From a random sample, 1422 physicians were mailed a survey assessing the types of information used and what level of evidence could alter their clinical practice in prostate cancer. Multivariable logistic regression models were used to identify differences in physician characteristics for each outcome. Results: Survey response rates were similar for radiation oncologists and urologists (44% vs 46%; P=.46). Specialty-specific journals represented the most commonly used resource for informing the clinical practice for radiation oncologists (65%) and urologists (70%). Relative to radiation oncologists, urologists were less likely to report utilizing top-tier medical journals (25% vs 39%; adjusted odds ratio [OR] 0.50; P=.01) or cancer journals (22% vs 51%; adjusted OR 0.50; P<.001) but more likely to rely on clinical guidelines (46% vs 38%; adjusted OR 1.6; P=.006). Both radiation oncologists and urologists most commonly reported large randomized, clinical trials as the level of evidence to change treatment recommendations for localized prostate cancer (85% vs 77%; P=.009). Conclusions: Both specialties rely on their own specialty-specific journals and view randomized, clinical trials as the level of evidence needed to change clinical practice. Our study provides a context on meaningful ways of disseminating evidence for localized prostate cancer.

  19. The depletion of Interleukin-8 causes cell cycle arrest and increases the efficacy of docetaxel in breast cancer cells

    SciTech Connect (OSTI)

    Shao, Nan; Chen, Liu-Hua; Ye, Run-Yi; Lin, Ying; Wang, Shen-Ming

    2013-02-15

    Highlights: ? IL-8 depletion affects cell cycle distribution. ? Intrinsic IL-8 mediates breast cancer cell migration and invasion. ? IL-8 siRNA down regulates key factors that control survival and metastatic pathway. ? IL-8 depletion reduces integrin ?3 expression. ? IL-8 depletion increases the chemosensitivity to docetaxel. -- Abstract: IL-8 is a multi-functional pro-inflammatory chemokine, which is highly expressed in cancers, such as ER-negative breast cancer. The present study demonstrates the pervasive role of IL-8 in the malignant progression of ER-negative breast cancer. IL-8 siRNA inhibited proliferation and delayed the G1 to S cell cycle progression in MDA-MB-231 and BT549 cells. IL-8 silencing resulted in the upregulation of the CDK inhibitor p27, the downregulation of cyclin D1, and the reduction of phosphorylated-Akt and NF-?B activities. IL-8 depletion also increased the chemosensitivity to docetaxel. These results indicate a role for IL-8 in promoting tumor cell survival and resistance to docetaxel and highlight the potential therapeutic significance of IL-8 depletion in ER-negative breast cancer patients.

  20. Concanavalin A: A potential anti-neoplastic agent targeting apoptosis, autophagy and anti-angiogenesis for cancer therapeutics

    SciTech Connect (OSTI)

    Li, Wen-wen; Yu, Jia-ying; Xu, Huai-long; Bao, Jin-ku

    2011-10-22

    Highlights: {yields} ConA induces cancer cell death targeting apoptosis and autophagy. {yields} ConA inhibits cancer cell angiogenesis. {yields} ConA is utilized in pre-clinical and clinical trials. -- Abstract: Concanavalin A (ConA), a Ca{sup 2+}/Mn{sup 2+}-dependent and mannose/glucose-binding legume lectin, has drawn a rising attention for its remarkable anti-proliferative and anti-tumor activities to a variety of cancer cells. ConA induces programmed cell death via mitochondria-mediated, P73-Foxo1a-Bim apoptosis and BNIP3-mediated mitochondrial autophagy. Through IKK-NF-{kappa}B-COX-2, SHP-2-MEK-1-ERK, and SHP-2-Ras-ERK anti-angiogenic pathways, ConA would inhibit cancer cell survival. In addition, ConA stimulates cell immunity and generates an immune memory, resisting to the same genotypic tumor. These biological findings shed light on new perspectives of ConA as a potential anti-neoplastic agent targeting apoptosis, autophagy and anti-angiogenesis in pre-clinical or clinical trials for cancer therapeutics.

  1. The Y-located gonadoblastoma gene TSPY amplifies its own expression through a positive feedback loop in prostate cancer cells

    SciTech Connect (OSTI)

    Kido, Tatsuo; Lau, Yun-Fai Chris

    2014-03-28

    Highlights: • Y-encoded proto-oncoprotein TSPY amplifies its expression level via a positive feedback loop. • TSPY binds to the chromatin/DNA at exon 1 of TSPY gene. • TSPY enhances the gene expression in a TSPY exon 1 sequence dependent manner. • The conserved SET/NAP-domain is essential for TSPY transactivation. • Insights on probable mechanisms on TSPY exacerbation on cancer development in men. - Abstract: The testis-specific protein Y-encoded (TSPY) is a repetitive gene located on the gonadoblastoma region of the Y chromosome, and has been considered to be the putative gene for this oncogenic locus on the male-only chromosome. It is expressed in spermatogonial cells and spermatocytes in normal human testis, but abundantly in gonadoblastoma, testicular germ cell tumors and a variety of somatic cancers, including melanoma, hepatocellular carcinoma and prostate cancer. Various studies suggest that TSPY accelerates cell proliferation and growth, and promotes tumorigenesis. In this report, we show that TSPY could bind directly to the chromatin/DNA at exon 1 of its own gene, and greatly enhance the transcriptional activities of the endogenous gene in the LNCaP prostate cancer cells. Domain mapping analyses of TSPY have localized the critical and sufficient domain to the SET/NAP-domain. These results suggest that TSPY could efficiently amplify its expression and oncogenic functions through a positive feedback loop, and contribute to the overall tumorigenic processes when it is expressed in various human cancers.

  2. Tumor suppressor KAI1 affects integrin {alpha}v{beta}3-mediated ovarian cancer cell adhesion, motility, and proliferation

    SciTech Connect (OSTI)

    Ruseva, Zlatna; Geiger, Pamina Xenia Charlotte; Hutzler, Peter; Kotzsch, Matthias; Luber, Birgit; Schmitt, Manfred; Gross, Eva; Reuning, Ute

    2009-06-10

    The tetraspanin KAI1 had been described as a metastasis suppressor in many different cancer types, a function for which associations of KAI1 with adhesion and signaling receptors of the integrin superfamily likely play a role. In ovarian cancer, integrin {alpha}v{beta}3 correlates with tumor progression and its elevation in vitro provoked enhanced cell adhesion accompanied by significant increases in cell motility and proliferation in the presence of its major ligand vitronectin. In the present study, we characterized integrin {alpha}v{beta}3-mediated tumor biological effects as a function of cellular KAI1 restoration and proved for the first time that KAI1, besides its already known physical crosstalk with {beta}1-integrins, also colocalizes with integrin {alpha}v{beta}3. Functionally, elevated KAI1 levels drastically increased integrin {alpha}v{beta}3/vitronectin-dependent ovarian cancer cell adhesion. Since an intermediate level of cell adhesive strength is required for optimal cell migration, we next studied ovarian cancer cell motility as a function of KAI1 restoration. By time lapse video microscopy, we found impaired integrin {alpha}v{beta}3/vitronectin-mediated cell migration most probably due to strongly enhanced cellular immobilization onto the adhesion-supporting matrix. Moreover, KAI1 reexpression significantly diminished cell proliferation. These data strongly indicate that KAI1 may suppress ovarian cancer progression by inhibiting integrin {alpha}v{beta}3/vitronectin-provoked tumor cell motility and proliferation as important hallmarks of the oncogenic process.

  3. LARG at chromosome 11q23 has functional characteristics of a tumor suppressor in human breast cancer

    SciTech Connect (OSTI)

    Ong, Danny C.T.; Rudduck, Christina; Chin, Koei; Kuo, Wen-Lin; Lie, Daniel K.H.; Chua, Constance L.M.; Wong, Chow Yin; Hong, Ga Sze; Gray, Joe; Lee, Ann S.G.

    2008-05-06

    Deletion of 11q23-q24 is frequent in a diverse variety of malignancies, including breast and colorectal carcinoma, implicating the presence of a tumor suppressor gene at that chromosomal region. We show here that LARG, from 11q23, has functional characteristics of a tumor suppressor. We examined a 6-Mb region on 11q23 by high-resolution deletion mapping, utilizing both loss of heterozygosity (LOH) analysis and microarray comparative genomic hybridization (CGH). LARG (also called ARHGEF12), identified from the analyzed region, was underexpressed in 34% of primary breast carcinomas and 80% of breast cancer cell lines including the MCF-7 line. Multiplex ligation-dependent probe amplification on 30 primary breast cancers and six breast cancer cell lines showed that LARG had the highest frequency of deletion compared to the BCSC-1 and TSLC1 genes, two known candidate tumor suppressor genes from 11q. In vitro analysis of breast cancer cell lines that underexpress LARG showed that LARG could be reactivated by trichostatin A, a histone deacetylase inhibitor, but not by 5-Aza-2{prime}-deoxycytidine, a demethylating agent. Bisulfite sequencing and quantitative high-throughput analysis of DNA methylation confirmed the lack of CpG island methylation in LARG in breast cancer. Restoration of LARG expression in MCF-7 cells by stable transfection resulted in reduced proliferation and colony formation, suggesting that LARG has functional characteristics of a tumor suppressor gene.

  4. Silencing of poly(ADP-ribose) glycohydrolase sensitizes lung cancer cells to radiation through the abrogation of DNA damage checkpoint

    SciTech Connect (OSTI)

    Nakadate, Yusuke; Department of Bioengineering, Graduate School of Engineering, Osaka City University, 3-3-138 Sugimoto, Sumiyoshi-ku, Osaka 558-8585 ; Kodera, Yasuo; Kitamura, Yuka; Tachibana, Taro; Tamura, Tomohide; Koizumi, Fumiaki

    2013-11-29

    Highlights: Radiosensitization by PARG silencing was observed in multiple lung cancer cells. PAR accumulation was enhanced by PARG silencing after DNA damage. Radiation-induced G2/M arrest and checkpoint activation were impaired by PARG siRNA. -- Abstract: Poly(ADP-ribose) glycohydrolase (PARG) is a major enzyme that plays a role in the degradation of poly(ADP-ribose) (PAR). PARG deficiency reportedly sensitizes cells to the effects of radiation. In lung cancer, however, it has not been fully elucidated. Here, we investigated whether PARG siRNA contributes to an increased radiosensitivity using 8 lung cancer cell lines. Among them, the silencing of PARG induced a radiosensitizing effect in 5 cell lines. Radiation-induced G2/M arrest was largely suppressed by PARG siRNA in PC-14 and A427 cells, which exhibited significantly enhanced radiosensitivity in response to PARG knockdown. On the other hand, a similar effect was not observed in H520 cells, which did not exhibit a radiosensitizing effect. Consistent with a cell cycle analysis, radiation-induced checkpoint signals were not well activated in the PC-14 and A427 cells when treated with PARG siRNA. These results suggest that the increased sensitivity to radiation induced by PARG knockdown occurs through the abrogation of radiation-induced G2/M arrest and checkpoint activation in lung cancer cells. Our findings indicate that PARG could be a potential target for lung cancer treatments when used in combination with radiotherapy.

  5. Impact of Concomitant Chemotherapy on Outcomes of Radiation Therapy for Head-and-Neck Cancer: A Population-Based Study

    SciTech Connect (OSTI)

    Gupta, Shlok; Kong, Weidong; Booth, Christopher M.; Mackillop, William J.

    2014-01-01

    Purpose: Clinical trials have shown that the addition of chemotherapy to radiation therapy (RT) improves survival in advanced head-and-neck cancer. The objective of this study was to describe the effectiveness of concomitant chemoradiation therapy (C-CRT) in routine practice. Methods and Materials: This was a population-based cohort study. Electronic records of treatment from all provincial cancer centers were linked to a population--based cancer registry to describe the adoption of C-CRT for head-and-neck cancer patients in Ontario, Canada. The study population was then divided into pre- and postadoption cohorts, and their outcomes were compared. Results: Between 1992 and 2008, 18,867 patients had diagnoses of head-and-neck cancer in Ontario, of whom 7866 (41.7%) were treated with primary RT. The proportion of primary RT cases that received C-CRT increased from 2.2% in the preadoption cohort (1992-1998) to 39.3% in the postadoption cohort (2003-2008). Five-year survival among all primary RT cases increased from 43.6% in the preadoption cohort to 51.8% in the postadoption cohort (P<.001). Over the same period, treatment-related hospital admissions increased significantly, but there was no significant increase in treatment-related deaths. Conclusions: C-CRT was widely adopted in Ontario after 2003, and its adoption was temporally associated with an improvement in survival.

  6. Knockdown of dual specificity phosphatase 4 enhances the chemosensitivity of MCF-7 and MCF-7/ADR breast cancer cells to doxorubicin

    SciTech Connect (OSTI)

    Liu, Yu; Du, Feiya; Chen, Wei; Yao, Minya; Lv, Kezhen; Fu, Peifen

    2013-12-10

    Background: Breast cancer is the major cause of cancer-related deaths in females world-wide. Doxorubicin-based therapy has limited efficacy in breast cancer due to drug resistance, which has been shown to be associated with the epithelial-to-mesenchymal transition (EMT). However, the molecular mechanisms linking the EMT and drug resistance in breast cancer cells remain unclear. Dual specificity phosphatase 4 (DUSP4), a member of the dual specificity phosphatase family, is associated with cellular proliferation and differentiation; however, its role in breast cancer progression is controversial. Methods: We used cell viability assays, Western blotting and immunofluorescent staining, combined with siRNA interference, to evaluate chemoresistance and the EMT in MCF-7 and adriamycin-resistant MCF-7/ADR breast cancer cells, and investigate the underlying mechanisms. Results: Knockdown of DUSP4 significantly increased the chemosensitivity of MCF-7 and MCF-7/ADR breast cancer cells to doxorubicin, and MCF-7/ADR cells which expressed high levels of DUSP4 had a mesenchymal phenotype. Furthermore, knockdown of DUSP4 reversed the EMT in MCF-7/ADR cells, as demonstrated by upregulation of epithelial biomarkers and downregulation of mesenchymal biomarkers, and also increased the chemosensitivity of MCF-7/ADR cells to doxorubicin. Conclusions: DUSP4 might represent a potential drug target for inhibiting drug resistance and regulating the process of the EMT during the treatment of breast cancer. - Highlights: We used different technologies to prove our conclusion. DUSP4 knockdown increased doxorubicin chemosensitivity in breast cancer cells. DUSP4 is a potential target for combating drug resistance in breast cancer. DUSP4 is a potential target for regulating the EMT in breast cancer.

  7. Inhibition of Hsp27 Radiosensitizes Head-and-Neck Cancer by Modulating Deoxyribonucleic Acid Repair

    SciTech Connect (OSTI)

    Guttmann, David M.; Hart, Lori; Du, Kevin; Seletsky, Andrew; Koumenis, Constantinos

    2013-09-01

    Purpose: To present a novel method of tumor radiosensitization through Hsp27 knockdown using locked nucleic acid (LNA) and to investigate the role of Hsp27 in DNA double strand break (DSB) repair. Methods and Materials: Clonogenic survival assays, immunoblotting, the proximity ligation assay, and ?H2AX foci analysis were conducted in SQ20B and FaDu human head-and-neck cancer cell lines treated with Hsp27 LNA and Hsp27 short hairpin RNA (shRNA). Additionally, nude mice with FaDu flank tumors were treated with fractionated radiation therapy after pretreatment with Hsp27 LNA and monitored for tumor growth. Results: Hsp27 LNA and Hsp27 shRNA radiosensitized head-and-neck cancer cell lines in an Hsp27-dependent manner. Ataxia-Telangectasia Mutated-mediated DNA repair signaling was impaired in irradiated cells with Hsp27 knockdown. ATM kinase inhibition abrogated the radiosensitizing effect of Hsp27. Furthermore, Hsp27 LNA and shRNA both attenuated DNA repair kinetics after radiation, and Hsp27 was found to colocalize with ATM in both untreated and irradiated cells. Last, combined radiation and Hsp27 LNA treatment in tumor xenografts in nude mice suppressed tumor growth compared with either treatment alone. Conclusions: These results support a radiosensitizing property of Hsp27 LNA in vitro and in vivo, implicate Hsp27 in double strand break repair, and suggest that Hsp27 LNA might eventually serve as an effective clinical agent in the radiotherapy of head-and-neck cancer.

  8. On the Development of a Miniature Neutron Generator for the Brachytherapy Treatment of Cancer

    SciTech Connect (OSTI)

    Forman, L.

    2009-03-10

    Brachytherapy refers to application of an irradiation source within a tumor. {sup 252}Cf needles used in brachytherapy have been successfully applied to treatment of some of the most virulent cancers but it is doubtful that it will be widely used because of difficulty in dealing with unwanted dose (source cannot be turned off) and in adhering to stringent NRC regulations that have been exacerbated in our post 911 environment. We have been working on the development of a miniature neutron generator with the reaction target placed at the end of a needle (tube) for brachytherapy applications. Orifice geometries are most amenable, e.g. rectum and cervix, but interstitial use is possible with microsurgery. This paper dicusses the results of a 30 watt DD neutron generator SBU project that demonstrates that sufficient hydrogen isotope current can be delivered down a small diameter needle required for a DT neutron treatment device, and, will summarize the progress of building a commercial device pursued by the All Russian Institute for Automatics (VNIIA) supported by the DOE's Industrial Proliferation Prevention Program (IPP). It is known that most of the fast neutron (FN) beam cancer treatment facilities have been closed down. It appears that the major limitation in the use of FN beams has been damage to healthy tissue, which is relatively insensitive to photons, but this problem is alleviated by brachytherapy. Moreover, recent clinical results indicate that fast neutrons in the boost mode are most highly effective in treating large, hypoxic, and rapidly repopulating diseases. It appears that early boost application of FN may halt angiogenesis (development and repair of tumor vascular system) and shrink the tumor resulting in lower hypoxia. The boost brachytherapy application of a small, low cost neutron generator holds promise of significant contribution to the treatment of cancer.

  9. Insulin like growth factor 2 regulation of aryl hydrocarbon receptor in MCF-7 breast cancer cells

    SciTech Connect (OSTI)

    Tomblin, Justin K.; Salisbury, Travis B.

    2014-01-17

    Highlights: IGF-2 stimulates concurrent increases in AHR and CCND1 expression. IGF-2 promotes the binding of AHR to the endogenous cyclin D1 promoter. AHR knockdown inhibits IGF-2 stimulated increases in CCND1 mRNA and protein. AHR knockdown inhibits IGF-2 stimulated increases in MCF-7 proliferation. -- Abstract: Insulin like growth factor (IGF)-1 and IGF-2 stimulate normal growth, development and breast cancer cell proliferation. Cyclin D1 (CCND1) promotes cell cycle by inhibiting retinoblastoma protein (RB1). The aryl hydrocarbon receptor (AHR) is a major xenobiotic receptor that also regulates cell cycle. The purpose of this study was to investigate whether IGF-2 promotes MCF-7 breast cancer proliferation by inducing AHR. Western blot and quantitative real time PCR (Q-PCR) analysis revealed that IGF-2 induced an approximately 2-fold increase (P < .001) in the expression of AHR and CCND1. Chromatin immunoprecipitation (ChIP), followed by Q-PCR indicated that IGF-2 promoted (P < .001) a 7-fold increase in AHR binding on the CCND1 promoter. AHR knockdown significantly (P < .001) inhibited IGF-2 stimulated increases in CCND1 mRNA and protein. AHR knockdown cells were less (P < .001) responsive to the proliferative effects of IGF-2 than control cells. Collectively, our findings have revealed a new regulatory mechanism by which IGF-2 induction of AHR promotes the expression of CCND1 and the proliferation of MCF-7 cells. This previously uncharacterized pathway could be important for the proliferation of IGF responsive cancer cells that also express AHR.

  10. Tobacco Smoking During Radiation Therapy for Head-and-Neck Cancer Is Associated With Unfavorable Outcome

    SciTech Connect (OSTI)

    Chen, Allen M.; Chen, Leon M.; Vaughan, Andrew; Sreeraman, Radhika; Farwell, D. Gregory; Luu, Quang; Lau, Derick H.; Stuart, Kerri; Purdy, James A.; Vijayakumar, Srinivasan

    2011-02-01

    Purpose: To evaluate the effect of continued cigarette smoking among patients undergoing radiation therapy for head-and-neck cancer by comparing the clinical outcomes among active smokers and quitters. Methods and Materials: A review of medical records identified 101 patients with newly diagnosed squamous cell carcinoma of the head and neck who continued to smoke during radiation therapy. Each active smoker was matched to a control patient who had quit smoking before initiation of radiation therapy. Matching was based on tobacco history (pack-years), primary site, age, sex, Karnofsky Performance Status, disease stage, radiation dose, chemotherapy use, year of treatment, and whether surgical resection was performed. Outcomes were compared by use of Kaplan-Meier analysis. Normal tissue effects were graded according to the Radiation Therapy Oncology Group/European Organization for the Treatment of Cancer toxicity criteria. Results: With a median follow-up of 49 months, active smokers had significantly inferior 5-year overall survival (23% vs. 55%), locoregional control (58% vs. 69%), and disease-free survival (42% vs. 65%) compared with the former smokers who had quit before radiation therapy (p < 0.05 for all). These differences remained statistically significant when patients treated by postoperative or definitive radiation therapy were analyzed separately. The incidence of Grade 3 or greater late complications was also significantly increased among active smokers compared with former smokers (49% vs. 31%, p = 0.01). Conclusions: Tobacco smoking during radiation therapy for head-and-neck cancer is associated with unfavorable outcomes. Further studies analyzing the biologic and molecular reasons underlying these differences are planned.

  11. Influence of Antiflatulent Dietary Advice on Intrafraction Motion for Prostate Cancer Radiotherapy

    SciTech Connect (OSTI)

    Lips, Irene M.; Kotte, Alexis N.T.J.; Gils, Carla H. van; Leerdam, Monique E. van; Heide, Uulke A. van der; Vulpen, Marco van

    2011-11-15

    Purpose: To evaluate the effect of an antiflatulent dietary advice on the intrafraction prostate motion in patients treated with intensity-modulated radiotherapy (IMRT) for prostate cancer. Methods and Materials: Between February 2002 and December 2009, 977 patients received five-beam IMRT for prostate cancer to a dose of 76 Gy in 35 fractions combined with fiducial markers for position verification. In July 2008, the diet, consisting of dietary guidelines to obtain regular bowel movements and to reduce intestinal gas by avoiding certain foods and air swallowing, was introduced to reduce the prostate motion. The intrafraction prostate movement was determined from the portal images of the first segment of all five beams. Clinically relevant intrafraction motion was defined as {>=}50% of the fractions with an intrafraction motion outside a range of 3 mm. Results: A total of 739 patients were treated without the diet and 105 patients were treated with radiotherapy after introduction of the diet. The median and interquartile range of the average intrafraction motion per patient was 2.53 mm (interquartile range, 2.2-3.0) without the diet and 3.00 mm (interquartile range, 2.4-3.5) with the diet (p < .0001). The percentage of patients with clinically relevant intrafraction motion increased statistically significant from 19.1% without diet to 42.9% with a diet (odds ratio, 3.18; 95% confidence interval, 2.07-4.88; p < .0001). Conclusions: The results of the present study suggest that antiflatulent dietary advice for patients undergoing IMRT for prostate cancer does not reduce the intrafraction movement of the prostate. Therefore, antiflatulent dietary advice is not recommended in clinical practice for this purpose.

  12. Oxidative phosphorylation-dependent regulation of cancer cell apoptosis in response to anticancer agents

    SciTech Connect (OSTI)

    Yadav, N.; Kumar, S.; Marlowe, T.; Chaudhary, A. K.; Kumar, R.; Wang, J.; O'Malley, J.; Boland, P. M.; Jayanthi, S.; Kumar, T. K. S.; Yadava, N.; Chandra, D.

    2015-11-05

    Cancer cells tend to develop resistance to various types of anticancer agents, whether they adopt similar or distinct mechanisms to evade cell death in response to a broad spectrum of cancer therapeutics is not fully defined. Current study concludes that DNA-damaging agents (etoposide and doxorubicin), ER stressor (thapsigargin), and histone deacetylase inhibitor (apicidin) target oxidative phosphorylation (OXPHOS) for apoptosis induction, whereas other anticancer agents including staurosporine, taxol, and sorafenib induce apoptosis in an OXPHOS-independent manner. DNA-damaging agents promoted mitochondrial biogenesis accompanied by increased accumulation of cellular and mitochondrial ROS, mitochondrial protein-folding machinery, and mitochondrial unfolded protein response. Induction of mitochondrial biogenesis occurred in a caspase activation-independent mechanism but was reduced by autophagy inhibition and p53-deficiency. Abrogation of complex-I blocked DNA-damage-induced caspase activation and apoptosis, whereas inhibition of complex-II or a combined deficiency of OXPHOS complexes I, III, IV, and V due to impaired mitochondrial protein synthesis did not modulate caspase activity. Mechanistic analysis revealed that inhibition of caspase activation in response to anticancer agents associates with decreased release of mitochondrial cytochrome c in complex-I-deficient cells compared with wild type (WT) cells. Gross OXPHOS deficiencies promoted increased release of apoptosis-inducing factor from mitochondria compared with WT or complex-I-deficient cells, suggesting that cells harboring defective OXPHOS trigger caspase-dependent as well as caspase-independent apoptosis in response to anticancer agents. Interestingly, DNA-damaging agent doxorubicin showed strong binding to mitochondria, which was disrupted by complex-I-deficiency but not by complex-II-deficiency. Thapsigargin-induced caspase activation was reduced upon abrogation of complex-I or gross OXPHOS deficiency whereas a reverse trend was observed with apicidin. Together, these finding provide a new strategy for differential mitochondrial targeting in cancer therapy.

  13. SU-E-J-193: Feasibility of MRI-Only Based IMRT Planning for Pancreatic Cancer

    SciTech Connect (OSTI)

    Prior, P; Botros, M; Chen, X; Paulson, E; Erickson, B; Li, X

    2014-06-01

    Purpose: With the increasing use of MRI simulation and the advent of MRI-guided delivery, it is desirable to use MRI only for treatment planning. In this study, we assess the dosimetric difference between MRI- and CTbased IMRT planning for pancreatic cancer. Methods: Planning CTs and MRIs acquired for a representative pancreatic cancer patient were used. MRI-based planning utilized forced relative electron density (rED) assignment of organ specific values from IRCU report 46, where rED = 1.029 for PTV and a rED = 1.036 for non-specified tissue (NST). Six IMRT plans were generated with clinical dose-volume (DV) constraints using a research Monaco planning system employing Monte Carlo dose calculation with optional perpendicular magnetic field (MF) of 1.5T. The following five plans were generated and compared with the planning CT: 1.) CT plan with MF and dose recalculation without optimization; 2.) MRI (T2) plan with target and OARs redrawn based on MRI, forced rED, no MF, and recalculation without optimization; 3.) Similar as in 2 but with MF; 4.) MRI plan with MF but without optimization; and 5.) Similar as in 4 but with optimization. Results: Generally, noticeable differences in PTV point doses and DV parameters (DVPs) between the CT-and MRI-based plans with and without the MF were observed. These differences between the optimized plans were generally small, mostly within 2%. Larger differences were observed in point doses and mean doses for certain OARs between the CT and MRI plan, mostly due to differences between image acquisition times. Conclusion: MRI only based IMRT planning for pancreatic cancer is feasible. The differences observed between the optimized CT and MRI plans with or without the MF were practically negligible if excluding the differences between MRI and CT defined structures.

  14. Redox Protein Expression Predicts Radiotherapeutic Response in Early-Stage Invasive Breast Cancer Patients

    SciTech Connect (OSTI)

    Woolston, Caroline M.; Al-Attar, Ahmad; Storr, Sarah J.; Ellis, Ian O.; Morgan, David A.L.; Martin, Stewart G.

    2011-04-01

    Purpose: Early-stage invasive breast cancer patients have commonly undergone breast-conserving surgery and radiotherapy. In a large majority of these patients, the treatment is effective; however, a proportion will develop local recurrence. Deregulated redox systems provide cancer cells protection from increased oxidative stress, such as that induced by ionizing radiation. Therefore, the expression of redox proteins was examined in tumor specimens from this defined cohort to determine whether such expression could predict response. Methods and Materials: The nuclear and cytoplasmic expression of nine redox proteins (glutathione, glutathione reductase, glutaredoxin, glutathione peroxidase 1, 3, and 4, and glutathione S-transferase-{theta}, -{pi}, and -{alpha}) was assessed using conventional immunohistochemistry on a tissue microarray of 224 tumors. Results: A high cytoplasmic expression of glutathione S-transferase-{theta} significantly correlated with a greater risk of local recurrence (p = .008) and, when combined with a low nuclear expression (p = .009), became an independent predictive factor (p = .002) for local recurrence. High cytoplasmic expression of glutathione S-transferase-{theta} also correlated with a worse overall survival (p = .009). Low nuclear and cytoplasmic expression of glutathione peroxidase 3 (p = .002) correlated with a greater risk of local recurrence and was an independent predictive factor (p = .005). These proteins did not correlate with tumor grade, suggesting their function might be specific to the regulation of oxidative stress rather than alterations of tumor phenotype. Only nuclear (p = .005) and cytoplasmic (p = .001) expression of glutathione peroxidase 4 correlated with the tumor grade. Conclusions: Our results support the use of redox protein expression, namely glutathione S-transferase-{theta} and glutathione peroxidase 3, to predict the response to radiotherapy in early-stage breast cancer patients. If incorporated into routine diagnostic tests, they have the potential to aid clinicians in their stratification of patients into more tailored treatment regimens. Future targeted therapies to these systems might improve the efficacy of reactive oxygen species-inducing therapies, such as radiotherapy.

  15. Oxidative phosphorylation-dependent regulation of cancer cell apoptosis in response to anticancer agents

    DOE Public Access Gateway for Energy & Science Beta (PAGES Beta)

    Yadav, N.; Kumar, S.; Marlowe, T.; Chaudhary, A. K.; Kumar, R.; Wang, J.; O'Malley, J.; Boland, P. M.; Jayanthi, S.; Kumar, T. K. S.; et al

    2015-11-05

    Cancer cells tend to develop resistance to various types of anticancer agents, whether they adopt similar or distinct mechanisms to evade cell death in response to a broad spectrum of cancer therapeutics is not fully defined. Current study concludes that DNA-damaging agents (etoposide and doxorubicin), ER stressor (thapsigargin), and histone deacetylase inhibitor (apicidin) target oxidative phosphorylation (OXPHOS) for apoptosis induction, whereas other anticancer agents including staurosporine, taxol, and sorafenib induce apoptosis in an OXPHOS-independent manner. DNA-damaging agents promoted mitochondrial biogenesis accompanied by increased accumulation of cellular and mitochondrial ROS, mitochondrial protein-folding machinery, and mitochondrial unfolded protein response. Induction of mitochondrialmore » biogenesis occurred in a caspase activation-independent mechanism but was reduced by autophagy inhibition and p53-deficiency. Abrogation of complex-I blocked DNA-damage-induced caspase activation and apoptosis, whereas inhibition of complex-II or a combined deficiency of OXPHOS complexes I, III, IV, and V due to impaired mitochondrial protein synthesis did not modulate caspase activity. Mechanistic analysis revealed that inhibition of caspase activation in response to anticancer agents associates with decreased release of mitochondrial cytochrome c in complex-I-deficient cells compared with wild type (WT) cells. Gross OXPHOS deficiencies promoted increased release of apoptosis-inducing factor from mitochondria compared with WT or complex-I-deficient cells, suggesting that cells harboring defective OXPHOS trigger caspase-dependent as well as caspase-independent apoptosis in response to anticancer agents. Interestingly, DNA-damaging agent doxorubicin showed strong binding to mitochondria, which was disrupted by complex-I-deficiency but not by complex-II-deficiency. Thapsigargin-induced caspase activation was reduced upon abrogation of complex-I or gross OXPHOS deficiency whereas a reverse trend was observed with apicidin. Together, these finding provide a new strategy for differential mitochondrial targeting in cancer therapy.« less

  16. Proteogenomic strategies for identification of aberrant cancer peptides using large-scale Next Generation Sequencing data

    SciTech Connect (OSTI)

    Woo, Sunghee; Cha, Seong Won; Na, Seungjin; Guest, Clark; Liu, Tao; Smith, Richard D.; Rodland, Karin D.; Payne, Samuel H.; Bafna, Vineet

    2014-11-17

    Cancer is driven by the acquisition of somatic DNA lesions. Distinguishing the early driver mutations from subsequent passenger mutations is key to molecular sub-typing of cancers, and the discovery of novel biomarkers. The availability of genomics technologies (mainly wholegenome and exome sequencing, and transcript sampling via RNA-seq, collectively referred to as NGS) have fueled recent studies on somatic mutation discovery. However, the vision is challenged by the complexity, redundancy, and errors in genomic data, and the difficulty of investigating the proteome using only genomic approaches. Recently, combination of proteomic and genomic technologies are increasingly employed. However, the complexity and redundancy of NGS data remains a challenge for proteogenomics, and various trade-offs must be made to allow for the searches to take place. This paperprovides a discussion of two such trade-offs, relating to large database search, and FDR calculations, and their implication to cancer proteogenomics. Moreover, it extends and develops the idea of a unified genomic variant database that can be searched by any mass spectrometry sample. A total of 879 BAM files downloaded from TCGA repository were used to create a 4.34 GB unified FASTA database which contained 2,787,062 novel splice junctions, 38,464 deletions, 1105 insertions, and 182,302 substitutions. Proteomic data from a single ovarian carcinoma sample (439,858 spectra) was searched against the database. By applying the most conservative FDR measure, we have identified 524 novel peptides and 65,578 known peptides at 1% FDR threshold. The novel peptides include interesting examples of doubly mutated peptides, frame-shifts, and non-sample-recruited mutations, which emphasize the strength of our approach.

  17. Expression analysis and prognostic significance of the SRA1 gene, in ovarian cancer

    SciTech Connect (OSTI)

    Leoutsakou, Theoni; Talieri, Maroulio; Scorilas, Andreas . E-mail: ascorilas@biol.uoa.gr

    2006-06-02

    The SR-related-CTD-associated-factors (SCAFs) have the ability to interact with the C-terminal domain of the RNA polymerase II, linking this way transcription to splicing. SRA1 (SR-A1) gene, encoding for a human high-molecular weight SCAF protein, is located on chromosome 19, between the IRF3 and the R-RAS oncogene and it has been demonstrated from members of our group that SRA1 is constitutively expressed in most of the human tissues, while it is overexpressed in a subset of ovarian tumors. In this study, we examine the expression of SRA1 gene in 111 ovarian malignant tissues and in the human ovarian carcinoma cell lines OVCAR-3, TOV21-G, and ES-2, using a semi-quantitative RT-PCR method. SRA1 gene was overexpressed in 61/111 (55%) of ovarian carcinomas. This higher expression was positively associated to the size of the tumor (p < 0.001), the grade and the stage of the disease (p = 0.003 and p = 0.006, respectively), and the debulking success (p < 0.001). Kaplan-Meier survival analysis revealed that lower SRA1 expression increases the probability of both the longer overall and the progression free survival of the patients. Multivariate Cox regression analysis revealed that SRA1 may be used as an independent prognostic biomarker in ovarian cancer. Our results suggest that SRA1 is associated with cancer progression and may possibly be characterized as a new marker of unfavorable prognosis for ovarian cancer.

  18. Identification of NDRG1-regulated genes associated with invasive potential in cervical and ovarian cancer cells

    SciTech Connect (OSTI)

    Zhao, Gang; Department of Pathology, Tianjin Cancer Hospital, Tianjin Medical University, Tianjin ; Chen, Jiawei; Deng, Yanqiu; Gao, Feng; Zhu, Jiwei; Feng, Zhenzhong; Lv, Xiuhong; Zhao, Zheng

    2011-04-29

    Highlights: {yields} NDRG1 was knockdown in cervical and ovarian cancer cell lines by shRNA technology. {yields} NDRG1 knockdown resulted in increased cell invasion activities. {yields} Ninety-six common deregulated genes in both cell lines were identified by cDNA microarray. {yields} Eleven common NDRG1-regulated genes might enhance cell invasive activity. {yields} Regulation of invasion by NDRG1 is an indirect and complicated process. -- Abstract: N-myc downstream regulated gene 1 (NDRG1) is an important gene regulating tumor invasion. In this study, shRNA technology was used to suppress NDRG1 expression in CaSki (a cervical cancer cell line) and HO-8910PM (an ovarian cancer cell line). In vitro assays showed that NDRG1 knockdown enhanced tumor cell adhesion, migration and invasion activities without affecting cell proliferation. cDNA microarray analysis revealed 96 deregulated genes with more than 2-fold changes in both cell lines after NDRG1 knockdown. Ten common upregulated genes (LPXN, DDR2, COL6A1, IL6, IL8, FYN, PTP4A3, PAPPA, ETV5 and CYGB) and one common downregulated gene (CLCA2) were considered to enhance tumor cell invasive activity. BisoGenet network analysis indicated that NDRG1 regulated these invasion effector genes/proteins in an indirect manner. Moreover, NDRG1 knockdown also reduced pro-invasion genes expression such as MMP7, TMPRSS4 and CTSK. These results suggest that regulation of invasion and metastasis by NDRG1 is a highly complicated process.

  19. Decision Regret in Men Undergoing Dose-Escalated Radiation Therapy for Prostate Cancer

    SciTech Connect (OSTI)

    Steer, Anna N.; Aherne, Noel J.; Gorzynska, Karen; Hoffman, Matthew; Last, Andrew; Hill, Jacques; Shakespeare, Thomas P.; Rural Clinical School Faculty of Medicine, University of New South Wales, Coffs Harbour

    2013-07-15

    Purpose: Decision regret (DR) is a negative emotion associated with medical treatment decisions, and it is an important patient-centered outcome after therapy for localized prostate cancer. DR has been found to occur in up to 53% of patients treated for localized prostate cancer, and it may vary depending on treatment modality. DR after modern dose-escalated radiation therapy (DE-RT) has not been investigated previously, to our knowledge. Our primary aim was to evaluate DR in a cohort of patients treated with DE-RT. Methods and Materials: We surveyed 257 consecutive patients with localized prostate cancer who had previously received DE-RT, by means of a validated questionnaire. Results: There were 220 responses (85.6% response rate). Image-guided intensity modulated radiation therapy was given in 85.0% of patients and 3-dimensional conformal radiation therapy in 15.0%. Doses received included 73.8 Gy (34.5% patients), 74 Gy (53.6%), and 76 Gy (10.9%). Neoadjuvant androgen deprivation (AD) was given in 51.8% of patients and both neoadjuvant and adjuvant AD in 34.5%. The median follow-up time was 23 months (range, 12-67 months). In all, 3.8% of patients expressed DR for their choice of treatment. When asked whether they would choose DE-RT or AD again, only 0.5% probably or definitely would not choose DE-RT again, compared with 8.4% for AD (P<.01). Conclusion: Few patients treated with modern DE-RT express DR, with regret appearing to be lower than in previously published reports of patients treated with radical prostatectomy or older radiation therapy techniques. Patients experienced more regret with the AD component of treatment than with the radiation therapy component, with implications for informed consent. Further research should investigate regret associated with individual components of modern therapy, including AD, radiation therapy and surgery.

  20. SU-E-T-460: Comparison of Proton and IMRT Planning for Head and Neck Cancer

    SciTech Connect (OSTI)

    Fontenla, S; Zhou, Y; Kowalski, A; Mah, D; Leven, T; Cahlon, O; Lee, N; Hunt, M; Mechalakos, J

    2014-06-01

    Purpose: A retrospective study comparing proton and intensity-modulated radiation therapy (IMRT) for head and neck cancer Methods: This study consists of six H and N cancer patients that underwent proton as well as IMRT planning. Patients analyzed had unilateral target volumes, one had prior RT. 3D-conformal proton therapy (3D-CPT) plans with multiple field uniform scanning were generated for delivery on the inclined beam line. IMRT was planned using fixed field sliding window. Final plan evaluations were performed by a radiation oncologist and a physicist. Metrics for comparison included tumor coverage, organ sparing with respect to spinal cord, brainstem, parotids, submandibulars, oral cavity, larynx, brachial plexus, cochleas, normal brain tissue, and skin using relevant indices for these structures. Dose volume histograms were generated as well as a qualitative comparison of isodose distributions between the two modalities. Planning and treatment delivery times were compared. Results: Results showed that IMRT plans offered better conformality in the high dose region as demonstrated by the conformality index for each plan. Ipsilateral cochlea, submandibular gland, and skin doses were lower with IMRT than proton therapy. There was significant sparing of larynx, oral cavity, and brainstem with proton therapy compared to IMRT. This translated into direct patient benefit with no evidence of hoarseness, mucositis, or nausea. Contralateral parotid and submandibular glands were equally spared. IMRT had shorter planning/parts fabrication and treatment times which needs to be taken into account when deciding modality. Conclusion: Sparing of clinically significant normal tissue structures such as oral cavity and larynx for unilateral H and N cancers was seen with 3D-CPT versus IMRT. However, this is at the expense of less conformality at the high dose region and higher skin dose. Future studies are needed with full gantry systems and pencil beam scanning as these deliveries would be expected to further improve conformality and normal tissue sparing.