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Showing papers by "Fred Hutchinson Cancer Research Center published in 2010"



Journal ArticleDOI
TL;DR: This report documents the additions and revisions to the nomenclature of HLA specificities following the principles established in previous reports.
Abstract: The WHO Nomenclature Committee for Factors of the HLA System met following the 14th International HLA and Immunogenetics Workshop in Melbourne, Australia in December 2005 and Buzios, Brazil during the 15th International HLA and Immunogenetics Workshop in September 2008. This report documents the additions and revisions to the nomenclature of HLA specificities following the principles established in previous reports (1–18).

2,390 citations


Journal ArticleDOI
TL;DR: Semen quality of the reference population was superior to that of the men from the general population and normozoospermic men, and provide an appropriate tool in conjunction with clinical data to evaluate a patient's semen quality and prospects for fertility.
Abstract: BACKGROUND Semen quality is taken as a surrogate measure of male fecundity in clinical andrology, male fertility, reproductive toxicology, epidemiology and pregnancy risk assessments. Reference intervals for values of semen parameters from a fertile population could provide data from which prognosis of fertility or diagnosis of infertility can be extrapolated. METHODS Semen samples from over 4500 men in 14 countries on four continents were obtained from retrospective and prospective analyses on fertile men, men of unknown fertility status and men selected as normozoospermic. Men whose partners had a time-to-pregnancy (TTP) of < or =12 months were chosen as individuals to provide reference distributions for semen parameters. Distributions were also generated for a population assumed to represent the general population. RESULTS The following one-sided lower reference limits, the fifth centiles (with 95th percent confidence intervals), were generated from men whose partners had TTP < or = 12 months: semen volume, 1.5 ml (1.4-1.7); total sperm number, 39 million per ejaculate (33-46); sperm concentration, 15 million per ml (12-16); vitality, 58% live (55-63); progressive motility, 32% (31-34); total (progressive + non-progressive) motility, 40% (38-42); morphologically normal forms, 4.0% (3.0-4.0). Semen quality of the reference population was superior to that of the men from the general population and normozoospermic men. CONCLUSIONS The data represent sound reference distributions of semen characteristics of fertile men in a number of countries. They provide an appropriate tool in conjunction with clinical data to evaluate a patient's semen quality and prospects for fertility.

2,264 citations


Journal ArticleDOI
TL;DR: A substantial reduction in the hazard of death related to allogeneic hematopoietic-cell transplantation, as well as increased long-term survival, over the past decade is found.
Abstract: BACKGROUND Over the past decade, advances have been made in the care of patients undergoing transplantation. We conducted a study to determine whether these advances have improved the outcomes of transplantation. METHODS We analyzed overall mortality, mortality not preceded by relapse, recurrent malignant conditions, and the frequency and severity of major complications of transplantation, including graft-versus-host disease (GVHD) and hepatic, renal, pulmonary, and infectious complications, among 1418 patients who received their first allogeneic transplants at our center in Seattle in the period from 1993 through 1997 and among 1148 patients who received their first allogeneic transplants in the period from 2003 through 2007. Components of the Pretransplant Assessment of Mortality (PAM) score were used in regression models to adjust for the severity of illness at the time of transplantation. RESULTS In the 2003-2007 period, as compared with the 1993-1997 period, we observed significant decreases in mortality not preceded by relapse, both at day 200 (by 60%) and overall (by 52%), the rate of relapse or progression of a malignant condition (by 21%), and overall mortality (by 41%), after adjustment for components of the PAM score. The results were similar when the analyses were limited to patients who received myeloablative conditioning therapy. We also found significant decreases in the risk of severe GVHD; disease caused by viral, bacterial, and fungal infections; and damage to the liver, kidneys, and lungs. CONCLUSIONS We found a substantial reduction in the hazard of death related to allogeneic hematopoietic-cell transplantation, as well as increased long-term survival, over the past decade. Improved outcomes appear to be related to reductions in organ damage, infection, and severe acute GVHD. (Funded by the National Institutes of Health.).

1,311 citations


Journal ArticleDOI
Sushmita Roy1, Jason Ernst1, Peter V. Kharchenko2, Pouya Kheradpour1, Nicolas Nègre3, Matthew L. Eaton4, Jane M. Landolin5, Christopher A. Bristow1, Lijia Ma3, Michael F. Lin1, Stefan Washietl6, Bradley I. Arshinoff7, Ferhat Ay8, Patrick E. Meyer9, Nicolas Robine10, Nicole L. Washington5, Luisa Di Stefano2, Eugene Berezikov11, Christopher D. Brown3, Rogerio Candeias6, Joseph W. Carlson5, Adrian Carr12, Irwin Jungreis1, Daniel Marbach1, Rachel Sealfon1, Michael Y. Tolstorukov2, Sebastian Will6, Artyom A. Alekseyenko2, Carlo G. Artieri13, Benjamin W. Booth5, Angela N. Brooks14, Qi Dai10, Carrie A. Davis15, Michael O. Duff16, X. Feng, Andrey A. Gorchakov2, Tingting Gu17, Jorja G. Henikoff10, Philipp Kapranov18, Renhua Li13, Heather K. MacAlpine4, John H. Malone13, Aki Minoda5, Jared T. Nordman6, Katsutomo Okamura10, Marc D. Perry7, Sara K. Powell4, Nicole C. Riddle17, Akiko Sakai2, Anastasia Samsonova2, Jeremy E. Sandler5, Yuri B. Schwartz2, Noa Sher6, Rebecca Spokony3, David Sturgill13, Marijke J. van Baren17, Kenneth H. Wan5, Li Yang16, Charles Yu5, Elise A. Feingold13, Peter J. Good13, Mark S. Guyer13, Rebecca F. Lowdon13, Kami Ahmad2, Justen Andrews19, Bonnie Berger1, Steven E. Brenner14, Michael R. Brent17, Lucy Cherbas19, Sarah C. R. Elgin17, Thomas R. Gingeras18, Robert L. Grossman3, Roger A. Hoskins5, Thomas C. Kaufman19, W. J. Kent20, Mitzi I. Kuroda2, Terry L. Orr-Weaver6, Norbert Perrimon2, Vincenzo Pirrotta21, James W. Posakony22, Bing Ren22, Steven Russell12, Peter Cherbas19, Brenton R. Graveley16, Suzanna E. Lewis5, Gos Micklem12, Brian Oliver13, Peter J. Park2, Susan E. Celniker5, Steven Henikoff23, Gary H. Karpen14, Eric C. Lai10, David M. MacAlpine4, Lincoln Stein7, Kevin P. White3, Manolis Kellis1 
24 Dec 2010-Science
TL;DR: The Drosophila Encyclopedia of DNA Elements (modENCODE) project as mentioned in this paper has been used to map transcripts, histone modifications, chromosomal proteins, transcription factors, replication proteins and intermediates, and nucleosome properties across a developmental time course and in multiple cell lines.
Abstract: To gain insight into how genomic information is translated into cellular and developmental programs, the Drosophila model organism Encyclopedia of DNA Elements (modENCODE) project is comprehensively mapping transcripts, histone modifications, chromosomal proteins, transcription factors, replication proteins and intermediates, and nucleosome properties across a developmental time course and in multiple cell lines. We have generated more than 700 data sets and discovered protein-coding, noncoding, RNA regulatory, replication, and chromatin elements, more than tripling the annotated portion of the Drosophila genome. Correlated activity patterns of these elements reveal a functional regulatory network, which predicts putative new functions for genes, reveals stage- and tissue-specific regulators, and enables gene-expression prediction. Our results provide a foundation for directed experimental and computational studies in Drosophila and related species and also a model for systematic data integration toward comprehensive genomic and functional annotation.

1,102 citations


Journal ArticleDOI
01 Apr 2010-Methods
TL;DR: The procedure for qRT-PCR analysis of circulating miRNAs as biomarkers is described, and relevant issues of sample preparation, experimental design and data analysis are discussed.

1,086 citations


Journal ArticleDOI
TL;DR: Six months of high-intensity aerobic exercise had sex-specific effects on cognition, glucose metabolism, and hypothalamic-pituitary-adrenal axis and trophic activity despite comparable gains in cardiorespiratory fitness and body fat reduction.
Abstract: Objectives To examine the effects of aerobic exercise on cognition and other biomarkers associated with Alzheimer disease pathology for older adults with mild cognitive impairment, and assess the role of sex as a predictor of response. Design Six-month, randomized, controlled, clinical trial. Setting Veterans Affairs Puget Sound Health Care System clinical research unit. Participants Thirty-three adults (17 women) with amnestic mild cognitive impairment ranging in age from 55 to 85 years (mean age, 70 years). Intervention Participants were randomized either to a high-intensity aerobic exercise or stretching control group. The aerobic group exercised under the supervision of a fitness trainer at 75% to 85% of heart rate reserve for 45 to 60 min/d, 4 d/wk for 6 months. The control group carried out supervised stretching activities according to the same schedule but maintained their heart rate at or below 50% of their heart rate reserve. Before and after the study, glucometabolic and treadmill tests were performed and fat distribution was assessed using dual-energy x-ray absorptiometry. At baseline, month 3, and month 6, blood was collected for assay and cognitive tests were administered. Main Outcome Measures Performance measures on Symbol-Digit Modalities, Verbal Fluency, Stroop, Trails B, Task Switching, Story Recall, and List Learning. Fasting plasma levels of insulin, cortisol, brain-derived neurotrophic factor, insulinlike growth factor-I, and β-amyloids 40 and 42. Results Six months of high-intensity aerobic exercise had sex-specific effects on cognition, glucose metabolism, and hypothalamic-pituitary-adrenal axis and trophic activity despite comparable gains in cardiorespiratory fitness and body fat reduction. For women, aerobic exercise improved performance on multiple tests of executive function, increased glucose disposal during the metabolic clamp, and reduced fasting plasma levels of insulin, cortisol, and brain-derived neurotrophic factor. For men, aerobic exercise increased plasma levels of insulinlike growth factor I and had a favorable effect only on Trails B performance. Conclusions This study provides support, using rigorous controlled methodology, for a potent nonpharmacologic intervention that improves executive control processes for older women at high risk of cognitive decline. Moreover, our results suggest that a sex bias in cognitive response may relate to sex-based differences in glucometabolic and hypothalamic-pituitary-adrenal axis responses to aerobic exercise.

1,036 citations


Journal ArticleDOI
Mark Gerstein1, Zhi John Lu1, Eric L. Van Nostrand2, Chao Cheng1, Bradley I. Arshinoff3, Tao Liu4, Kevin Y. Yip1, R. Robilotto1, Andreas Rechtsteiner5, Kohta Ikegami6, P. Alves1, A. Chateigner, Marc D. Perry7, Mitzi Morris8, Raymond K. Auerbach1, X. Feng9, Jing Leng1, A. Vielle10, Wei Niu1, Kahn Rhrissorrakrai8, Ashish Agarwal1, Roger P. Alexander1, Galt P. Barber5, Cathleen M. Brdlik2, J. Brennan6, Jeremy Brouillet2, Adrian Carr, Ming Sin Cheung10, Hiram Clawson5, Sergio Contrino, Luke Dannenberg11, Abby F. Dernburg12, Arshad Desai13, L. Dick14, Andréa C. Dosé12, Jiang Du1, Thea A. Egelhofer5, Sevinc Ercan6, Ghia Euskirchen1, Brent Ewing15, Elise A. Feingold16, Reto Gassmann13, Peter J. Good16, Philip Green15, Francois Gullier, M. Gutwein8, Mark S. Guyer16, Lukas Habegger1, Ting Han17, Jorja G. Henikoff18, Stefan R. Henz19, Angie S. Hinrichs5, H. Holster11, Tony Hyman19, A. Leo Iniguez11, J. Janette1, M. Jensen6, Masaomi Kato1, W. James Kent5, E. Kephart7, Vishal Khivansara17, Ekta Khurana1, John Kim17, P. Kolasinska-Zwierz10, Eric C. Lai20, Isabel J. Latorre10, Amber Leahey15, Suzanna E. Lewis12, Paul Lloyd7, Lucas Lochovsky1, Rebecca F. Lowdon16, Yaniv Lubling21, Rachel Lyne, Michael J. MacCoss15, Sebastian D. Mackowiak22, Marco Mangone8, Sheldon J. McKay23, D. Mecenas8, Gennifer E. Merrihew15, David M. Miller24, A. Muroyama13, John I. Murray15, Siew Loon Ooi18, Hoang Pham12, T. Phippen5, Elicia Preston15, Nikolaus Rajewsky22, Gunnar Rätsch19, Heidi Rosenbaum11, Joel Rozowsky1, Kim Rutherford, P. Ruzanov7, Mihail Sarov19, Rajkumar Sasidharan1, Andrea Sboner1, P. Scheid8, Eran Segal21, Hyunjin Shin4, C. Shou1, Frank J. Slack1, C. Slightam2, Richard J.H. Smith, William C. Spencer24, Eo Stinson12, S. Taing4, Teruaki Takasaki5, D. Vafeados15, Ksenia Voronina13, Guilin Wang1, Nicole L. Washington12, Christina M. Whittle6, Beijing Wu2, Koon-Kiu Yan1, Georg Zeller, Z. Zha7, Mei Zhong1, Xingliang Zhou6, Julie Ahringer10, Susan Strome5, Kristin C. Gunsalus25, Gos Micklem, X. Shirley Liu4, Valerie Reinke1, Stuart K. Kim2, LaDeana W. Hillier15, Steven Henikoff18, Fabio Piano25, Michael Snyder1, Lincoln Stein23, Jason D. Lieb6, Robert H. Waterston15 
24 Dec 2010-Science
TL;DR: These studies identified regions of the nematode and fly genomes that show highly occupied targets (or HOT) regions where DNA was bound by more than 15 of the transcription factors analyzed and the expression of related genes were characterized, providing insights into the organization, structure, and function of the two genomes.
Abstract: We systematically generated large-scale data sets to improve genome annotation for the nematode Caenorhabditis elegans, a key model organism. These data sets include transcriptome profiling across a developmental time course, genome-wide identification of transcription factor-binding sites, and maps of chromatin organization. From this, we created more complete and accurate gene models, including alternative splice forms and candidate noncoding RNAs. We constructed hierarchical networks of transcription factor-binding and microRNA interactions and discovered chromosomal locations bound by an unusually large number of transcription factors. Different patterns of chromatin composition and histone modification were revealed between chromosome arms and centers, with similarly prominent differences between autosomes and the X chromosome. Integrating data types, we built statistical models relating chromatin, transcription factor binding, and gene expression. Overall, our analyses ascribed putative functions to most of the conserved genome.

978 citations


Journal ArticleDOI
TL;DR: In this article, the effect of ART use by patients infected with HIV-1 on risk of transmission to their uninfected partners was evaluated in a randomised placebo-controlled trial that enrolled heterosexual African adults who were seropositive for both HIV and herpes simplex virus type 2.

946 citations


Journal ArticleDOI
TL;DR: ChIPpeakAnno enables batch annotation of the binding sites identified from ChIP-seq, Chip-chip, CAGE or any technology that results in a large number of enriched genomic regions within the statistical programming environment R.
Abstract: Chromatin immunoprecipitation (ChIP) followed by high-throughput sequencing (ChIP-seq) or ChIP followed by genome tiling array analysis (ChIP-chip) have become standard technologies for genome-wide identification of DNA-binding protein target sites. A number of algorithms have been developed in parallel that allow identification of binding sites from ChIP-seq or ChIP-chip datasets and subsequent visualization in the University of California Santa Cruz (UCSC) Genome Browser as custom annotation tracks. However, summarizing these tracks can be a daunting task, particularly if there are a large number of binding sites or the binding sites are distributed widely across the genome. We have developed ChIPpeakAnno as a Bioconductor package within the statistical programming environment R to facilitate batch annotation of enriched peaks identified from ChIP-seq, ChIP-chip, cap analysis of gene expression (CAGE) or any experiments resulting in a large number of enriched genomic regions. The binding sites annotated with ChIPpeakAnno can be viewed easily as a table, a pie chart or plotted in histogram form, i.e., the distribution of distances to the nearest genes for each set of peaks. In addition, we have implemented functionalities for determining the significance of overlap between replicates or binding sites among transcription factors within a complex, and for drawing Venn diagrams to visualize the extent of the overlap between replicates. Furthermore, the package includes functionalities to retrieve sequences flanking putative binding sites for PCR amplification, cloning, or motif discovery, and to identify Gene Ontology (GO) terms associated with adjacent genes. ChIPpeakAnno enables batch annotation of the binding sites identified from ChIP-seq, ChIP-chip, CAGE or any technology that results in a large number of enriched genomic regions within the statistical programming environment R. Allowing users to pass their own annotation data such as a different Chromatin immunoprecipitation (ChIP) preparation and a dataset from literature, or existing annotation packages, such as GenomicFeatures and BSgenom e, provides flexibility. Tight integration to the biomaRt package enables up-to-date annotation retrieval from the BioMart database.

911 citations


Journal ArticleDOI
TL;DR: Pplacer as discussed by the authors is a software package for phylogenetic placement and subsequent visualization, which can place twenty thousand short reads on a reference tree of one thousand taxa per hour per processor, and is easy to run in parallel.
Abstract: Likelihood-based phylogenetic inference is generally considered to be the most reliable classification method for unknown sequences. However, traditional likelihood-based phylogenetic methods cannot be applied to large volumes of short reads from next-generation sequencing due to computational complexity issues and lack of phylogenetic signal. "Phylogenetic placement," where a reference tree is fixed and the unknown query sequences are placed onto the tree via a reference alignment, is a way to bring the inferential power offered by likelihood-based approaches to large data sets. This paper introduces pplacer, a software package for phylogenetic placement and subsequent visualization. The algorithm can place twenty thousand short reads on a reference tree of one thousand taxa per hour per processor, has essentially linear time and memory complexity in the number of reference taxa, and is easy to run in parallel. Pplacer features calculation of the posterior probability of a placement on an edge, which is a statistically rigorous way of quantifying uncertainty on an edge-by-edge basis. It also can inform the user of the positional uncertainty for query sequences by calculating expected distance between placement locations, which is crucial in the estimation of uncertainty with a well-sampled reference tree. The software provides visualizations using branch thickness and color to represent number of placements and their uncertainty. A simulation study using reads generated from 631 COG alignments shows a high level of accuracy for phylogenetic placement over a wide range of alignment diversity, and the power of edge uncertainty estimates to measure placement confidence. Pplacer enables efficient phylogenetic placement and subsequent visualization, making likelihood-based phylogenetics methodology practical for large collections of reads; it is freely available as source code, binaries, and a web service.

Journal ArticleDOI
TL;DR: Differences among histone variants in their stability, DNA wrapping, specialized domains that regulate access to DNA, and post-translational modifications, underlie the diverse functions that histones have acquired in evolution.
Abstract: Histones wrap DNA to form nucleosome particles that compact eukaryotic genomes. Variant histones have evolved crucial roles in chromosome segregation, transcriptional regulation, DNA repair, sperm packaging and other processes. 'Universal' histone variants emerged early in eukaryotic evolution and were later displaced for bulk packaging roles by the canonical histones (H2A, H2B, H3 and H4), the synthesis of which is coupled to DNA replication. Further specializations of histone variants have evolved in some lineages to perform additional tasks. Differences among histone variants in their stability, DNA wrapping, specialized domains that regulate access to DNA, and post-translational modifications, underlie the diverse functions that histones have acquired in evolution.

Journal ArticleDOI
TL;DR: It is recommended that asymptomatic men who have at least a 10‐year life expectancy have an opportunity to make an informed decision with their health care provider about screening for prostate cancer after they receive information about the uncertainties, risks, and potential benefits associated with prostate cancer screening.
Abstract: In 2009, the American Cancer Society (ACS) Prostate Cancer Advisory Committee began the process of a complete update of recommendations for early prostate cancer detection. A series of systematic evidence reviews was conducted focusing on evidence related to the early detection of prostate cancer, test performance, harms of therapy for localized prostate cancer, and shared and informed decision making in prostate cancer screening. The results of the systematic reviews were evaluated by the ACS Prostate Cancer Advisory Committee, and deliberations about the evidence occurred at committee meetings and during conference calls. On the basis of the evidence and a consensus process, the Prostate Cancer Advisory Committee developed the guideline, and a writing committee drafted a guideline document that was circulated to the entire committee for review and revision. The document was then circulated to peer reviewers for feedback, and finally to the ACS Mission Outcomes Committee and the ACS Board of Directors for approval. The ACS recommends that asymptomatic men who have at least a 10-year life expectancy have an opportunity to make an informed decision with their health care provider about screening for prostate cancer after they receive information about the uncertainties, risks, and potential benefits associated with prostate cancer screening. Prostate cancer screening should not occur without an informed decision-making process. Men at average risk should receive this information beginning at age 50 years. Men in higher risk groups should receive this information before age 50 years. Men should either receive this information directly from their health care providers or be referred to reliable and culturally appropriate sources. Patient decision aids are helpful in preparing men to make a decision whether to be tested.

Journal ArticleDOI
16 Jul 2010-Science
TL;DR: The design of enzymes that catalyze the bimolecular Diels-Alder reaction, a carbon-carbon bond formation reaction that is central to organic synthesis but unknown in natural metabolism, is described.
Abstract: The Diels-Alder reaction is a cornerstone in organic synthesis, forming two carbon-carbon bonds and up to four new stereogenic centers in one step. No naturally occurring enzymes have been shown to catalyze bimolecular Diels-Alder reactions. We describe the de novo computational design and experimental characterization of enzymes catalyzing a bimolecular Diels-Alder reaction with high stereoselectivity and substrate specificity. X-ray crystallography confirms that the structure matches the design for the most active of the enzymes, and binding site substitutions reprogram the substrate specificity. Designed stereoselective catalysts for carbon-carbon bond-forming reactions should be broadly useful in synthetic chemistry.

Journal ArticleDOI
TL;DR: This is the first instance of rapid engraftment derived from ex vivo expanded stem/progenitor cells in humans, and when cord blood progenitors expanded ex vivo in the presence of Notch ligand were infused in a clinical setting after a myeloablative preparative regimen for stem cell transplantation, the time to neutrophil recovery was substantially shortened.
Abstract: Delayed myeloid engraftment after cord blood transplantation (CBT) is thought to result from inadequate numbers of progenitor cells in the graft and is associated with increased early transplant-related morbidity and mortality. New culture strategies that increase the number of cord blood progenitors capable of rapid myeloid engraftment after CBT would allow more widespread use of this stem cell source for transplantation. Here we report the development of a clinically relevant Notch-mediated ex vivo expansion system for human CD34(+) cord blood progenitors that results in a marked increase in the absolute number of stem/progenitor cells, including those capable of enhanced repopulation in the marrow of immunodeficient nonobese diabetic-severe combined immunodeficient (NOD-SCID) mice. Furthermore, when cord blood progenitors expanded ex vivo in the presence of Notch ligand were infused in a clinical setting after a myeloablative preparative regimen for stem cell transplantation, the time to neutrophil recovery was substantially shortened. To our knowledge, this is the first instance of rapid engraftment derived from ex vivo expanded stem/progenitor cells in humans.

Posted Content
TL;DR: Pplacer enables efficient phylogenetic placement and subsequent visualization, making likelihood-based phylogenetics methodology practical for large collections of reads; it is freely available as source code, binaries, and a web service.
Abstract: Likelihood-based phylogenetic inference is generally considered to be the most reliable classification method for unknown sequences. However, traditional likelihood-based phylogenetic methods cannot be applied to large volumes of short reads from next-generation sequencing due to computational complexity issues and lack of phylogenetic signal. "Phylogenetic placement," where a reference tree is fixed and the unknown query sequences are placed onto the tree via a reference alignment, is a way to bring the inferential power of likelihood-based approaches to large data sets. This paper introduces pplacer, a software package for phylogenetic placement and subsequent visualization. The algorithm can place twenty thousand short reads on a reference tree of one thousand taxa per hour per processor, has essentially linear time and memory complexity in the number of reference taxa, and is easy to run in parallel. Pplacer features calculation of the posterior probability of a placement on an edge, which is a statistically rigorous way of quantifying uncertainty on an edge-by-edge basis. It also can inform the user of the positional uncertainty for query sequences by calculating expected distance between placement locations, which is crucial in the estimation of uncertainty with a well-sampled reference tree. The software provides visualizations using branch thickness and color to represent number of placements and their uncertainty. A simulation study using reads generated from 631 COG alignments shows a high level of accuracy for phylogenetic placement over a wide range of alignment diversity, and the power of edge uncertainty estimates to measure placement confidence. Pplacer enables efficient phylogenetic placement and subsequent visualization, making likelihood-based phylogenetics methodology practical for large collections of reads; it is available as source code, binaries, and a web service.

Journal ArticleDOI
TL;DR: The data indicate that constitutively active AR splice variants can contribute to the development of castration-resistant prostate cancers and may serve as biomarkers for patients who are likely to suffer from early recurrence and are candidates for therapies directly targeting the AR rather than ligand.
Abstract: Progression of prostate cancer following castration is associated with increased androgen receptor (AR) expression and signaling despite AR blockade. Recent studies suggest that these activities are due to the generation of constitutively active AR splice variants, but the mechanisms by which these splice variants could mediate such effects are not fully understood. Here we have identified what we believe to be a novel human AR splice variant in which exons 5, 6, and 7 are deleted (ARv567es) and demonstrated that this variant can contribute to cancer progression in human prostate cancer xenograft models in mice following castration. We determined that, in human prostate cancer cell lines, ARv567es functioned as a constitutively active receptor, increased expression of full-length AR (ARfl), and enhanced the transcriptional activity of AR. In human xenografts, human prostate cancer cells transfected with ARv567es cDNA formed tumors that were resistant to castration. Furthermore, the ratio of ARv567es to ARfl expression within the xenografts positively correlated with resistance to castration. Importantly, we also detected ARv567es frequently in human prostate cancer metastases. In summary, these data indicate that constitutively active AR splice variants can contribute to the development of castration-resistant prostate cancers and may serve as biomarkers for patients who are likely to suffer from early recurrence and are candidates for therapies directly targeting the AR rather than ligand.

Journal ArticleDOI
TL;DR: Using reported GWAS findings for height, Crohn's disease and breast, prostate and colorectal cancers, it is determined that each of these traits is likely to harbor additional loci within the spectrum of low-penetrance common variants.
Abstract: We report a set of tools to estimate the number of susceptibility loci and the distribution of their effect sizes for a trait on the basis of discoveries from existing genome-wide association studies (GWASs). We propose statistical power calculations for future GWASs using estimated distributions of effect sizes. Using reported GWAS findings for height, Crohn's disease and breast, prostate and colorectal (BPC) cancers, we determine that each of these traits is likely to harbor additional loci within the spectrum of low-penetrance common variants. These loci, which can be identified from sufficiently powerful GWASs, together could explain at least 15-20% of the known heritability of these traits. However, for BPC cancers, which have modest familial aggregation, our analysis suggests that risk models based on common variants alone will have modest discriminatory power (63.5% area under curve), even with new discoveries.

Journal ArticleDOI
24 Sep 2010-Science
TL;DR: It is shown that FSHD patients carry specific single-nucleotide polymorphisms in the chromosomal region distal to the last D4Z4 repeat that creates a canonical polyadenylation signal for transcripts derived from DUX4, a double homeobox gene of unknown function that straddles the last repeat unit and the adjacent sequence.
Abstract: Facioscapulohumeral muscular dystrophy (FSHD) is a common form of muscular dystrophy in adults that is foremost characterized by progressive wasting of muscles in the upper body. FSHD is associated with contraction of D4Z4 macrosatellite repeats on chromosome 4q35, but this contraction is pathogenic only in certain "permissive" chromosomal backgrounds. Here, we show that FSHD patients carry specific single-nucleotide polymorphisms in the chromosomal region distal to the last D4Z4 repeat. This FSHD-predisposing configuration creates a canonical polyadenylation signal for transcripts derived from DUX4, a double homeobox gene of unknown function that straddles the last repeat unit and the adjacent sequence. Transfection studies revealed that DUX4 transcripts are efficiently polyadenylated and are more stable when expressed from permissive chromosomes. These findings suggest that FSHD arises through a toxic gain of function attributable to the stabilized distal DUX4 transcript.

Journal ArticleDOI
TL;DR: These data provide the first systematic assessment of the overall neutralization sensitivities of a genetically and geographically diverse panel of circulating HIV-1 strains and can facilitate the systematic characterization of NAb responses elicited by candidate vaccine immunogens.
Abstract: The restricted neutralization breadth of vaccine-elicited antibodies is a major limitation of current human immunodeficiency virus-1 (HIV-1) candidate vaccines. In order to permit the efficient identification of vaccines with enhanced capacity for eliciting cross-reactive neutralizing antibodies (NAbs) and to assess the overall breadth and potency of vaccine-elicited NAb reactivity, we assembled a panel of 109 molecularly cloned HIV-1 Env pseudoviruses representing a broad range of genetic and geographic diversity. Viral isolates from all major circulating genetic subtypes were included, as were viruses derived shortly after transmission and during the early and chronic stages of infection. We assembled a panel of genetically diverse HIV-1-positive (HIV-1(+)) plasma pools to assess the neutralization sensitivities of the entire virus panel. When the viruses were rank ordered according to the average sensitivity to neutralization by the HIV-1(+) plasmas, a continuum of average sensitivity was observed. Clustering analysis of the patterns of sensitivity defined four subgroups of viruses: those having very high (tier 1A), above-average (tier 1B), moderate (tier 2), or low (tier 3) sensitivity to antibody-mediated neutralization. We also investigated potential associations between characteristics of the viral isolates (clade, stage of infection, and source of virus) and sensitivity to NAb. In particular, higher levels of NAb activity were observed when the virus and plasma pool were matched in clade. These data provide the first systematic assessment of the overall neutralization sensitivities of a genetically and geographically diverse panel of circulating HIV-1 strains. These reference viruses can facilitate the systematic characterization of NAb responses elicited by candidate vaccine immunogens.

Journal ArticleDOI
TL;DR: Angiogenic models are developed to demonstrate that EC-derived angiocrine growth factors support in vitro self-renewal and in vivo repopulation of authentic LT-HSCs, and establish an instructive vascular niche for clinical-scale expansion of LT- HSCs and a cellular platform to identify stem cell-active trophogens.

Journal ArticleDOI
TL;DR: In 2010, approximately 222,520 new cases of lung or bronchial cancer will be diagnosed in the USA, and 157,300 patients are expected to die of this disease as discussed by the authors.
Abstract: In 2010, approximately 222,520 new cases of lung or bronchial cancer will be diagnosed in the USA, and 157,300 patients are expected to die of this disease [1]. Lung cancer is the leading cause of cancer-related death in both men and women, and non-small cell lung cancer (NSCLC) accounts for about 80 % of these cases. Lung cancer is most often asymptomatic in its early stages; consequently, the disease is usually diagnosed at an advanced stage, when it is much more difficult to treat. One or more genes are believed to be responsible for an inherited increase in risk of developing lung cancer in the general population. Smoking remains one of the main environmental factors associated with the development of lung cancer [2]. Although the development of lung cancer seems to be the result of several sequential molecular abnormalities in individuals at high risk of developing the disease, the genetic mechanisms by which an individual develops lung cancer remain largely unknown. These steps involve abnormalities in the expression of angiogenic factors (e.g., vascular endothelial growth factor, or VEGF and epithelial growth factor receptors, or EGFRs) [3]. The heterogeneity of lung cancer and the diversity of its morphologic appearance and molecular properties make the application of molecular targeted therapies used in other cancers more complex, but such therapies are certainly a goal for the future.

Journal ArticleDOI
TL;DR: As childhood cancer survivors progress through adulthood, risk of subsequent neoplasms increases and patients surviving Hodgkin lymphoma are at greatest risk.
Abstract: Background The occurrence of subsequent neoplasms has direct impact on the quantity and quality of life in cancer survivors. We have expanded our analysis of these events in the Childhood Cancer Survivor Study (CCSS) to better understand the occurrence of these events as the survivor population ages. Methods The incidence of and risk for subsequent neoplasms occurring 5 years or more after the childhood cancer diagnosis were determined among 14 359 5-year survivors in the CCSS who were treated from 1970 through 1986 and who were at a median age of 30 years (range = 5–56 years) for this analysis. At 30 years after childhood cancer diagnosis, we calculated cumulative incidence at 30 years of subsequent neoplasms and calculated standardized incidence ratios (SIRs), excess absolute risks (EARs) for invasive second malignant neoplasms, and relative risks for subsequent neoplasms by use of multivariable Poisson regression. Results Among 14 359 5-year survivors, 1402 subsequently developed 2703 neoplasms. Cumulative incidence at 30 years after the childhood cancer diagnosis was 20.5% (95% confidence interval [CI] = 19.1% to 21.8%) for all subsequent neoplasms, 7.9% (95% CI = 7.2% to 8.5%) for second malignant neoplasms (excluding nonmelanoma skin cancer), 9.1% (95% CI = 8.1% to 10.1%) for nonmelanoma skin cancer, and 3.1% (95% CI = 2.5% to 3.8%) for meningioma. Excess risk was evident for all primary diagnoses (EAR = 2.6 per 1000 person-years, 95% CI = 2.4 to 2.9 per 1000 person-years; SIR = 6.0, 95% CI = 5.5 to 6.4), with the highest being for Hodgkin lymphoma (SIR = 8.7, 95% CI = 7.7 to 9.8) and Ewing sarcoma (SIR = 8.5, 95% CI = 6.2 to 11.7). In the Poisson multivariable analysis, female sex, older age at diagnosis, earlier treatment era, diagnosis of Hodgkin lymphoma, and treatment with radiation therapy were associated with increased risk of subsequent neoplasm. Conclusions As childhood cancer survivors progress through adulthood, risk of subsequent neoplasms increases. Patients surviving Hodgkin lymphoma are at greatest risk. There is no evidence of risk reduction with increasing duration of follow-up.

Book ChapterDOI
TL;DR: A simple procedure for quantifying mutations that result from DNA double-strand break repair via non-homologous end joining based on the ability of the Surveyor nuclease to selectively cleave distorted duplex DNA formed via cross-annealing of mutated and wild-type sequence is described.
Abstract: The development of zinc finger nucleases for targeted gene modification can benefit from rapid functional assays that directly quantify activity at the endogenous target. Here we describe a simple procedure for quantifying mutations that result from DNA double-strand break repair via non-homologous end joining. The assay is based on the ability of the Surveyor nuclease to selectively cleave distorted duplex DNA formed via cross-annealing of mutated and wild-type sequence.

Journal ArticleDOI
20 Oct 2010-JAMA
TL;DR: Estrogen plus progestin was associated with greater breast cancer incidence, and the cancers are more commonly node-positive, and breast cancer mortality also appears to be increased with combined use of estrogen plus proggestin.
Abstract: Context In the Women's Health Initiative randomized, placebo-controlled trial of estrogen plus progestin, after a mean intervention time of 5.6 (SD, 1.3) years (range, 3.7-8.6 years) and a mean follow-up of 7.9 (SD, 1.4) years, breast cancer incidence was increased among women who received combined hormone therapy. Breast cancer mortality among participants in the trial has not been previously reported. Objective To determine the effects of therapy with estrogen plus progestin on cumulative breast cancer incidence and mortality after a total mean follow-up of 11.0 (SD, 2.7) years, through August 14, 2009. Design, Setting, and Participants A total of 16 608 postmenopausal women aged 50 to 79 years with no prior hysterectomy from 40 US clinical centers were randomly assigned to receive combined conjugated equine estrogens, 0.625 mg/d, plus medroxyprogesterone acetate, 2.5 mg/d, or placebo pill. After the original trial completion date (March 31, 2005), reconsent was required for continued follow-up for breast cancer incidence and was obtained from 12 788 (83%) of the surviving participants. Main Outcome Measures Invasive breast cancer incidence and breast cancer mortality. Results In intention-to-treat analyses including all randomized participants and censoring those not consenting to additional follow-up on March 31, 2005, estrogen plus progestin was associated with more invasive breast cancers compared with placebo (385 cases [0.42% per year] vs 293 cases [0.34% per year]; hazard ratio [HR], 1.25; 95% confidence interval [CI], 1.07-1.46; P = .004). Breast cancers in the estrogen-plus-progestin group were similar in histology and grade to breast cancers in the placebo group but were more likely to be node-positive (81 [23.7%] vs 43 [16.2%], respectively; HR, 1.78; 95% CI, 1.23-2.58; P = .03). There were more deaths directly attributed to breast cancer (25 deaths [0.03% per year] vs 12 deaths [0.01% per year]; HR, 1.96; 95% CI, 1.00-4.04; P = .049) as well as more deaths from all causes occurring after a breast cancer diagnosis (51 deaths [0.05% per year] vs 31 deaths [0.03% per year]; HR, 1.57; 95% CI, 1.01-2.48; P = .045) among women who received estrogen plus progestin compared with women in the placebo group. Conclusions Estrogen plus progestin was associated with greater breast cancer incidence, and the cancers are more commonly node-positive. Breast cancer mortality also appears to be increased with combined use of estrogen plus progestin. Trial Registration clinicaltrials.gov Identifier: NCT00000611

Journal ArticleDOI
Gloria M. Petersen1, Laufey T. Amundadottir2, Charles S. Fuchs3, Peter Kraft3, Rachael Z. Stolzenberg-Solomon2, Kevin B. Jacobs4, Kevin B. Jacobs2, Alan A. Arslan5, H. Bas Bueno-de-Mesquita6, Steven Gallinger7, Myron D. Gross8, Kathy J. Helzlsouer9, Elizabeth A. Holly10, Eric J. Jacobs11, Alison P. Klein12, Andrea Z. LaCroix13, Donghui Li14, Margaret T. Mandelson13, Sara H. Olson14, Harvey A. Risch15, Wei Zheng16, Demetrius Albanes2, William R. Bamlet1, Christine D. Berg2, Marie-Christine Boutron-Ruault17, Julie E. Buring3, Paige M. Bracci10, Federico Canzian18, Sandra Clipp12, Michelle Cotterchio7, Mariza de Andrade1, Eric J. Duell, J. Michael Gaziano19, J. Michael Gaziano3, Edward Giovannucci3, Michael Goggins12, Göran Hallmans20, Susan E. Hankinson3, Manal Hassan14, Barbara V. Howard21, David J. Hunter3, Amy K. Hutchinson2, Amy K. Hutchinson4, Mazda Jenab, Rudolf Kaaks18, Charles Kooperberg13, Vittorio Krogh, Robert C. Kurtz22, Shannon M. Lynch2, Robert R. McWilliams1, Julie B. Mendelsohn2, Dominique S. Michaud22, Dominique S. Michaud3, Hemang Parikh2, Alpa V. Patel11, Petra H.M. Peeters6, Petra H.M. Peeters22, Aleksandar Rajkovic23, Elio Riboli24, Laudina Rodríguez, Daniela Seminara2, Xiao-Ou Shu16, Gilles Thomas2, Gilles Thomas25, Anne Tjønneland, Geoffrey S. Tobias2, Dimitrios Trichopoulos3, Dimitrios Trichopoulos26, Stephen K. Van Den Eeden27, Jarmo Virtamo28, Jean Wactawski-Wende29, Zhaoming Wang2, Zhaoming Wang4, Brian M. Wolpin3, Herbert Yu15, Kai Yu2, Anne Zeleniuch-Jacquotte5, Joseph F. Fraumeni2, Robert N. Hoover2, Patricia Hartge2, Stephen J. Chanock2, Stephen J. Chanock30, Stephen J. Chanock22 
TL;DR: This paper conducted a genome-wide association study of pancreatic cancer in 3,851 affected individuals (cases) and 3,934 unaffected controls drawn from 12 prospective cohort studies and 8 case-control studies and identified eight SNPs that map to three loci on chromosomes 13q22.1, 1q32.1 and 5p15.33.
Abstract: We conducted a genome-wide association study of pancreatic cancer in 3,851 affected individuals (cases) and 3,934 unaffected controls drawn from 12 prospective cohort studies and 8 case-control studies. Based on a logistic regression model for genotype trend effect that was adjusted for study, age, sex, self-described ancestry and five principal components, we identified eight SNPs that map to three loci on chromosomes 13q22.1, 1q32.1 and 5p15.33. Two correlated SNPs, rs9543325 (P = 3.27 x 10(-11), per-allele odds ratio (OR) 1.26, 95% CI 1.18-1.35) and rs9564966 (P = 5.86 x 10(-8), per-allele OR 1.21, 95% CI 1.13-1.30), map to a nongenic region on chromosome 13q22.1. Five SNPs on 1q32.1 map to NR5A2, and the strongest signal was at rs3790844 (P = 2.45 x 10(-10), per-allele OR 0.77, 95% CI 0.71-0.84). A single SNP, rs401681 (P = 3.66 x 10(-7), per-allele OR 1.19, 95% CI 1.11-1.27), maps to the CLPTM1L-TERT locus on 5p15.33, which is associated with multiple cancers. Our study has identified common susceptibility loci for pancreatic cancer that warrant follow-up studies.

Journal ArticleDOI
07 Oct 2010-Blood
TL;DR: KIR genotyping of several best HLA-matched potential unrelated donors should substantially increase the frequency of transplants by using grafts with favorable KIR gene content, which could result in superior disease-free survival for patients with AML.

Journal ArticleDOI
TL;DR: The most repeatable peptides were those corresponding to conventional tryptic cleavage sites, those that produced intense MS signals, and those that resulted from proteins generating many distinct peptides.
Abstract: The complexity of proteomic instrumentation for LC-MS/MS introduces many possible sources of variability. Data-dependent sampling of peptides constitutes a stochastic element at the heart of discovery proteomics. Although this variation impacts the identification of peptides, proteomic identifications are far from completely random. In this study, we analyzed interlaboratory data sets from the NCI Clinical Proteomic Technology Assessment for Cancer to examine repeatability and reproducibility in peptide and protein identifications. Included data spanned 144 LC-MS/MS experiments on four Thermo LTQ and four Orbitrap instruments. Samples included yeast lysate, the NCI-20 defined dynamic range protein mix, and the Sigma UPS 1 defined equimolar protein mix. Some of our findings reinforced conventional wisdom, such as repeatability and reproducibility being higher for proteins than for peptides. Most lessons from the data, however, were more subtle. Orbitraps proved capable of higher repeatability and reproduci...

Gloria M. Petersen1, Laufey T. Amundadottir2, Charles S. Fuchs3, Peter Kraft3, Rachael Z. Stolzenberg-Solomon2, Kevin B. Jacobs2, Kevin B. Jacobs4, Alan A. Arslan5, H. Bas Bueno-de-Mesquita6, Steven Gallinger7, Myron D. Gross8, Kathy J. Helzlsouer9, Elizabeth A. Holly10, Eric J. Jacobs11, Alison P. Klein12, Andrea Z. LaCroix13, Donghui Li14, Margaret T. Mandelson13, Sara H. Olson14, Harvey A. Risch15, Wei Zheng16, Demetrius Albanes2, William R. Bamlet1, Christine D. Berg2, Marie-Christine Boutron-Ruault17, Julie E. Buring3, Paige M. Bracci10, Federico Canzian18, Sandra Clipp12, Michelle Cotterchio7, Mariza de Andrade1, Eric J. Duell, J. Michael Gaziano19, J. Michael Gaziano3, Edward Giovannucci3, Michael Goggins12, Göran Hallmans20, Susan E. Hankinson3, Manal Hassan14, Barbara V. Howard21, David J. Hunter3, Amy K. Hutchinson2, Amy K. Hutchinson4, Mazda Jenab, Rudolf Kaaks18, Charles Kooperberg13, Vittorio Krogh, Robert C. Kurtz22, Shannon M. Lynch2, Robert R. McWilliams1, Julie B. Mendelsohn2, Dominique S. Michaud3, Dominique S. Michaud22, Hemang Parikh2, Alpa V. Patel11, Petra H.M. Peeters6, Petra H.M. Peeters22, Aleksandar Rajkovic23, Elio Riboli24, Laudina Rodríguez, Daniela Seminara2, Xiao-Ou Shu16, Gilles Thomas2, Gilles Thomas25, Anne Tjønneland, Geoffrey S. Tobias2, Dimitrios Trichopoulos26, Dimitrios Trichopoulos3, Stephen K. Van Den Eeden27, Jarmo Virtamo28, Jean Wactawski-Wende29, Zhaoming Wang4, Zhaoming Wang2, Brian M. Wolpin3, Herbert Yu15, Kai Yu2, Anne Zeleniuch-Jacquotte5, Joseph F. Fraumeni2, Robert N. Hoover2, Patricia Hartge2, Stephen J. Chanock30, Stephen J. Chanock22, Stephen J. Chanock2 
01 Jan 2010
TL;DR: This study has identified common susceptibility loci for pancreatic cancer that warrant follow-up studies and identified eight SNPs that map to three loci on chromosomes 13q22.1, 1q32.1 and 5p15.1 that are associated with multiple cancers.
Abstract: We conducted a genome-wide association study of pancreatic cancer in 3,851 affected individuals (cases) and 3,934 unaffected controls drawn from 12 prospective cohort studies and 8 case-control studies. Based on a logistic regression model for genotype trend effect that was adjusted for study, age, sex, self-described ancestry and five principal components, we identified eight SNPs that map to three loci on chromosomes 13q22.1, 1q32.1 and 5p15.33. Two correlated SNPs, rs9543325 (P = 3.27 x 10(-11), per-allele odds ratio (OR) 1.26, 95% CI 1.18-1.35) and rs9564966 (P = 5.86 x 10(-8), per-allele OR 1.21, 95% CI 1.13-1.30), map to a nongenic region on chromosome 13q22.1. Five SNPs on 1q32.1 map to NR5A2, and the strongest signal was at rs3790844 (P = 2.45 x 10(-10), per-allele OR 0.77, 95% CI 0.71-0.84). A single SNP, rs401681 (P = 3.66 x 10(-7), per-allele OR 1.19, 95% CI 1.11-1.27), maps to the CLPTM1L-TERT locus on 5p15.33, which is associated with multiple cancers. Our study has identified common susceptibility loci for pancreatic cancer that warrant follow-up studies.

Journal ArticleDOI
TL;DR: Daily acyclovir therapy did not reduce the risk of transmission of HIV-1, despite a reduction in plasma HIV- 1 RNA of 0.25 log(10) copies per milliliter and a 73% reduction in the occurrence of genital ulcers due to HSV-2.
Abstract: per milliliter (95% CI, 0.22 to 0.29; P<0.001) and the occurrence of HSV-2–positive genital ulcers by 73% (risk ratio, 0.27; 95% CI, 0.20 to 0.36; P<0.001). A total of 92% of the partners infected with HIV-1 and 84% of the partners not infected with HIV-1 remained in the study for 24 months. The level of adherence to the dispensed study drug was 96%. No serious adverse events related to acyclovir were observed. Conclusions Daily acyclovir therapy did not reduce the risk of transmission of HIV-1, despite a reduction in plasma HIV-1 RNA of 0.25 log 10 copies per milliliter and a 73% reduction in the occurrence of genital ulcers due to HSV-2. (ClinicalTrials.gov number, NCT00194519.)