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• Prognostic and therapeutic significance of leukemia subtypes and minimal residual disease measurements in pediatric acute lymphoblastic leukemia treated with contemporary risk-directed trial: a cohort study

  Background Genomic analyses to identify leukemia subtypes and refinement of minimal residual disease (MRD) determination are two recent advances that would have substantial impact on the management of children with acute lymphoblastic leukemia (ALL). However, the combined application of these two approaches to determine the prognostic and therapeutic significance of MRD measurement and full spectrum of leukemia subtypes in the context of contemporary risk-directed therapy has not been studied comprehensively.MethodsBetween October 29, 2007 and March 26, 2017, 598 consecutive children with newly diagnosed ALL were enrolled in a clinical trial at St. Jude Children’s Research Hospital. Patients were provisional classified according to the presenting clinical and laboratory features including immunophenotype and cytogenetics. Patients with ETV6-RUNX1 and high hyperdiploid B-progenitor ALL were provisionally included in the low-risk groups; those with TCF3-PBX1, hypodiploidy and T-cell ALL in the standard (intermediate)-risk group; and patients with BCR-ABL1, KMT2A and early T-cell precursor ALL in the high-risk group. Final risk assignment was based primarily on MRD levels measured by flow cytometry on Day 15 (≥1%) and Day 42 (<0.01% or ≥1%) of remission induction. Using genomic classification based on cytogenetics and genomic analysis (single nucleotide polymorphism array analysis and transcriptome, exome, and genome sequencing), patients were classified into 17 subtypes. The primary aim was to determine the event-free survival, overall survival and cumulative risk of relapse according to specific leukemia subtypes and MRD levels on Days 8, 15 and 42 of remission induction. This clinical trial was registered at ClinicalTrials.gov, number NCT00549848.FindingsPatients with ETV6-RUNX1, high hyperdiploidy and DUX4-rearranged B-ALL all received low- or standard-risk therapy, and had the highest 5-year event-free survival rates: 98.4% (95% CI, 95.9-100), 95.3% (91.2-99.4), and 95.0% (84.2-100), respectively. All 142 patients with Day 8 MRD<0.01%, except two with KMT2A-rearranged ALL and one with TCF3-PBX1, were in continuous complete remission. The TCF3-PBX1, PAX5alt, T-cell, early T-cell precursor, iAMP21 and hypodiploid ALL had intermediate outcome with 5-year event-free survival rates ranging from 80.0% (39.4-100) to 88.2% (71.7-100). Patients with KMT2A-rearranged, BCR-ABL1, BCR-ABL1-like and ETV6-RUNX1-like ALL had the worst outcomes, with 5-year event-free survival rates between 64.1% (43.9-84.3) and 76.2% (51.9-100), despite most patients receiving standard- or high-risk therapy. Treatment intensification based on MRD and genotype improved outcome. Relapse did not occur in any of the patients with ETV6-RUNX1, DUX4-rearranged, TCF3-PBX1, iAMP21, ZNF384-rearranged, hypodiploid, or BCR-ABL1-like B-ALL who had day 15 MRD≥1% and received standard-risk therapy. However, day 42 MRD<0.01% did not preclude relapse in patients with intermediate-risk or unfavorable subtypes including TCF3-PBX1, PAX5alt, T-cell, iAMP21, BCR-ABL1, BCR-ABL1-like, ETV6-RUNX1-like, KMT2A-rearranged, and MEF2D-rearranged ALL, despite intensified treatment in the standard- or high-risk arms. InterpretationContemporary risk-directed treatment based on genotypes and MRD can cure virtually all patients with ETV6-RUNX1, hyperdiploid>50 and DUX4-rearranged ALL. While intensified treatment improve outcome for patients with high MRD during induction, substantial proportions of patients with intermediate-risk or unfavorable subtypes would still relapse even achieving negative MRD status at the end of induction and require novel therapeutics to improve outcome.

  Study EGAS00001004739

• Luminal breast epithelial cells from wildtype and BRCA mutation carriers harbor copy number alterations commonly associated with breast cancer

  Cancer-associated mutations have been documented in normal tissues, but the prevalence and nature of somatic copy number alterations and their role in tumor initiation and evolution is not well understood. Here, using single cell DNA sequencing, we describe the landscape of CNA variants in >48,000 breast epithelial cells from women with normal or high risk of developing breast cancer. Individual cells with one or two of a specific subset of CNAs (e.g. 1q gain and 16q, 22q, 7q, and 10q loss) are detectable in almost all breast tissues and, in those from BRCA1 or BRCA2 mutations carriers, occurs prior to loss of heterozygosity (LOH) of the wildtype alleles. These CNAs, which are among the most common associated with ductal carcinoma in situ (DCIS) and malignant breast tumors, are enriched almost exclusively in luminal cells and are generally absent from basal myoepithelial cells. Allele-specific analysis of the enriched CNAs reveals that each allele was independently altered, demonstrating convergent evolution of these CNAs in an individual breast. Tissues from BRCA1 or BRCA2 mutation carriers contained a small percentage of cells with extreme aneuploidy, featuring loss of TP53, LOH of BRCA1 or BRCA2, and multiple breast cancer-associated CNAs in addition to one or more of the common CNAs in 1q, 10q or 16q. Notably, cells with intermediate levels of CNAs were not detected, arguing against a stepwise gradual accumulation of CNAs. Overall, our findings demonstrate that chromosomal alterations in normal breast epithelium including from high risk women, link early stage CNAs to clonally expanded tumor genomes .

  Study EGAS00001007716

• Autism Post-Mortem Brain RNA-Sequencing: SRRM4 Splicing Study

  Purpose: The goal of this study was to assess the status of splicing changes in microexons in the cortex of individuals with autism. Methods: We performed RiboZero Gold (rRNA depleted) 50bp PE RNA-seq in a larger set of case and control samples to define 12 autism and 12 control samples showing the greatest global differential gene expression change. These samples, which show differential expression of the splicing regulator SRRM4, were used to evaluate global splicing changes. Results: Within these samples, 126 of 504 (30%) detected alternative microexons display, a mean ΔPSI > 10 between ASD and control subjects of which 113 (90%) also display neural-differential regulation. By contrast, only 825 of 15,405 (5.4%) longer (i.e. > 27 nt) exons show such misregulation, of which 285 (35%) correspond to neural-regulated exons. Notably, we also observe significantly higher correlations between microexon inclusion and nSR100 mRNA expression levels across the stratified ASD samples and controls, for those microexons regulated by nSR100 relative to those microexons that are not regulated by this factor (p=1.4x10-7, Wilcoxon Sum Rank test). Conclusions: These data suggest microexon regulation is a potentially important mechanism underlying ASD and likely other neurodevelopmental disorders.

  Study phs000872

• CAGEKID: Cancer Genomics of the Kidney

  The aim of CAGEKID is to carry out comprehensive detection of DNA markers for conventional (clear cell) renal carcinoma. The project includes complete analysis of somatic and constitutional DNA variation, methylation patterns and expression in a large number of constitutional/tumor pairs. CAGEKID is a part of the International Cancer Genome Consortium, ICGC.

  Study EGAS00001000083

• CAGEKID: Cancer Genomics of the Kidney - Targeted Sequencing

  The aim of CAGEKID is to carry out comprehensive detection of DNA markers for conventional (clear cell) renal carcinoma. The project includes complete analysis of somatic and constitutional DNA variation, methylation patterns and expression in a large number of constitutional/tumor pairs. CAGEKID is a part of the International Cancer Genome Consortium, ICGC.

  Study EGAS00001007004

• Longitudinal Assessment of Methylmercury and Gut Microbes During Pregnancy

  Methylmercury is a potent neurotoxin, and the fetal period is the most vulnerable exposure period. There is significant variability in methylmercury metabolism, which has been attributed to differences in the structure and function of the gut microbiome. Our main objective was to better understand the interplay between gut microorganisms and methylmercury metabolism during pregnancy. To address this aim, associations were investigated between maternal biomarkers (blood, hair, stool) for prenatal methylmercury exposure and maternal gut microbiota during early and late gestation.

  Study phs001768

• Pooled Genome-Wide Analysis of Kidney Cancer Risk (KIDRISK)

  Incidence rates of renal cell carcinoma (RCC) are rising and the latest estimates show that it accounts for over 300,000 cases and 120,000 deaths worldwide each year. Mechanisms underlying RCC occurrence are not fully understood and a large part of the disease heritability remains unexplained. The study aimed at augmenting the size of available RCC genome-wide association studies to increase the statistical power to detect genetic variants associated with the disease. The study includes genome-wide genotyping data from RCC cases (n=2,781) and controls (n=2,526) recruited in Western Europe, Central and Eastern Europe, and Australia.

  Study phs001271

• Post_Mortem_Tissue_COVID19_RNA

  Single cell analysis of post mortem tissue samples from SARS-CoV2-infected patients We aim to directly identify the human cell types infected by SARS-CoV-2 and measure the cellular response to COVID19 infection across 20 different tissues from infected patient autopsies. We have examined the expression pattern of viral entry receptors across healthy human tissues to predict several candidate target cell types across the airway and heart. In addition, high prevalence of cardiac failure and abnormal renal function in COVID19 patients implicates heart and kidney involvement, but the pathogenesis of organ specific damage - whether via a direct cytopathic mechanism or an indirect inflammatory response - remains unknown . Currently, we lack confirmation of target cell types and cellular processes in infected tissues as autopsies are discouraged in most countries due to health and safety risks. Our collaborators Drs Michael Osborn and Brian Hanley (Imperial College) have outlined guidelines to perform post-mortem in COVID19 patients (Hanley et al., 2020) and have established a programme of autopsies for research to be performed in a high-risk facility at Westminster Public Mortuary. Here, we propose to identify infected cell types and aberrant molecular pathologies in this precious tissue resource using single cell and spatial genomics. We will prioritise three organ systems: the human airway, heart and the kidney. We will directly examine the cellular identities of SARS-CoV-2 infected cell types and identify the cellular responses to infection across these organs. This fundamental knowledge will help guide future treatment choices for COVID19. This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/

  Study EGAS00001004442

• Post_Mortem_Tissue_COVID19_spatial

  Single cell analysis of post mortem tissue samples from SARS-CoV2-infected patients We aim to directly identify the human cell types infected by SARS-CoV-2 and measure the cellular response to COVID19 infection across 20 different tissues from infected patient autopsies. We have examined the expression pattern of viral entry receptors across healthy human tissues to predict several candidate target cell types across the airway and heart. In addition, high prevalence of cardiac failure and abnormal renal function in COVID19 patients implicates heart and kidney involvement, but the pathogenesis of organ specific damage - whether via a direct cytopathic mechanism or an indirect inflammatory response - remains unknown . Currently, we lack confirmation of target cell types and cellular processes in infected tissues as autopsies are discouraged in most countries due to health and safety risks. Our collaborators Drs Michael Osborn and Brian Hanley (Imperial College) have outlined guidelines to perform post-mortem in COVID19 patients (Hanley et al., 2020) and have established a programme of autopsies for research to be performed in a high-risk facility at Westminster Public Mortuary. Here, we propose to identify infected cell types and aberrant molecular pathologies in this precious tissue resource using single cell and spatial genomics. We will prioritise three organ systems: the human airway, heart and the kidney. We will directly examine the cellular identities of SARS-CoV-2 infected cell types and identify the cellular responses to infection across these organs. This fundamental knowledge will help guide future treatment choices for COVID19. This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/

  Study EGAS00001004441

• Integrated copy number and expression analysis identifies profiles of whole-arm chromosomal alterations and subgroups with favorable outcome in ovarian clear cell carcinomas

  Ovarian clear cell carcinoma (CCC) is generally associated with chemoresistance and poor clinical outcome, even with early diagnosis; whereas high-grade serous carcinomas (SCs) and endometrioid carcinomas (ECs) are commonly chemosensitive at advanced stages. Although an integrated genomic analysis of SC has been performed, conclusive views on copy number and expression profiles for CCC are still limited. In this study, we performed single nucleotide polymorphism arrays in 57 (31 CCCs, 14 SCs, and 12 ECs) and expression microarrays in 55 epithelial ovarian cancers (25 CCCs, 16 SCs, and 14 ECs), and then evaluated PIK3CA mutations and ARID1A expression in CCCs. SNP array analysis classified 13% of CCCs into a cluster with high frequency and focal range of copy number alterations (CNAs), significantly lower than for SCs (93%, P < 0.01) and ECs (50%, P = 0.017). The ratio of whole-arm to all CNAs was higher in CCCs (46.9%) than SCs (21.7%) (P < 0.0001). SCs with loss of heterozygosity (LOH) of BRCA1 (85%) also had LOH of NF1 and TP53, and LOH of BRCA2 (62%) coexisted with LOH of RB1 and TP53. Microarray analysis classified CCCs into three clusters. One cluster (CCC-2, n = 10) showed more favorable prognosis than the others (CCC-1and CCC-3) (P = 0.041). Coexistent alterations of PIK3CA and ARID1A were more common in CCC-1 and CCC-3 (7/11, 64%) than in CCC-2 (0/10, 0%) (P < 0.01). Being in cluster CCC-2 was an independent favorable prognostic factor in CCC. In conclusion, CCC was characterized by a high ratio of whole-arm CNAs; whereas CNAs in SC were mainly focal, but preferentially caused LOH of well-known tumor suppressor genes. As such, expression profiles might be useful for sub-classification of CCC, and might provide useful information on prognosis.

  Study JGAS000022

• Gene Expression Study of Individuals with Sex Chromosome Aneuploidies

  Males and females show dramatic differences in their vulnerability to the same diseases. For example, compared to men, lupus is six times more prevalent, thyroid cancer is three times more prevalent, and unipolar depression is twice as prevalent in women. Diseases with a strong male bias include autism (5:1), dilated cardiomyopathy (3:1), and ankylosing spondylitis (5:1). Historically, such differences have been attributed solely to extrinsic factors such as circulating sex hormones or environmental influences. We hypothesized that intrinsic factors - genetic differences between XX and XY cells - have unappreciated biological consequences throughout the body and contribute to sex differences in disease incidence and severity. This hypothesis stems from our long-term effort to sequence the sex chromosomes of diverse mammalian species, which has identified a set of homologous genes on the X and Y chromosomes that are dosage-sensitive, expressed throughout the body, and encode regulators of chromatin modification, transcription, translation, and protein stability. These X- and Y-encoded genes differ in sequence and expression pattern, which likely manifests in genome-wide differences in gene regulation between XX and XY cells and influences all aspects of human biology, including sex differences in disease susceptibility. These hard-wired molecular sex differences have been largely overlooked and understudied, representing a significant gap in our knowledge of human biology.The gene expression study of individuals with sex chromosome aneuploidies takes advantage of natural human variation in sex chromosome number, i.e. sex chromosome aneuploidy, to investigate alterations in genome-wide gene expression that correlate with changes in X- and Y-chromosome dosage. We analyzed samples from 114 individuals with a variety of sex chromosome aneuploidies, including 45,X; 47,XXY; 47,XYY; 47,XXX; 48,XXYY; and 49,XXXXY. We generated lymphoblastoid cell lines (LCLs) from blood samples and, in some cases, fibroblast cultures from skin biopsies. We supplemented our collection with previously-derived cell lines. To evaluate gene expression, we performed deep profiling of the transcriptome (RNA-seq) from these LCLs and fibroblasts. We performed parallel analyses on samples collected from 62 control 46,XX and 46,XY individuals, 6 individuals with trisomy 21, and 14 individuals with structural variations of the X and Y chromosomes. In addition, we performed CRISPRi knockdowns on 3 of the 46,XX and 3 of the 46,XY fibroblast samples for the homologous transcription factors ZFX and ZFY, encoded on the X and Y chromosomes, respectively.In the April 2024 update, we added RNA-seq datasets derived from isolated CD4+ T cells and monocytes from 76 and 72 adults, respectively, with the following sex chromosome constitutions: 45,X; 46,XX; 46,XY; 47,XXX; 47,XXY; 47,XYY. These individuals are largely a subset of the same cohort described above. In addition, we performed RNA-seq on in-vitro stimulated CD4+ T cells with the following sex chromosome constitutions: 45,X; 46,XX; 46,XY; 47,XXY.In the August 2024 update, we added RNA-seq datasets generated from the following: 1) LCLs derived from individuals with AZFa deletions of the Y chromosome, 2) DDX3X and DDX3Y knockdown (via CRISPRi) in XY fibroblasts, and 3) 5-ethyl uridine (5-EU) treatment in XY and XYYYY LCLs.

  Study phs002481

• Genome Diversity in Africa Project: Benin (2021-02-16)

  Globally, human populations show structured genetic diversity as a result of geographical dispersion, selection and drift. Understanding this genetic variation can provide insights into the evolutionary processes that shape both human adaptation and variation in disease. Populations from SSA have the highest levels of genetic diversity. This characteristic, in addition to historical genetic admixture, can lead to complexities in the design of studies assessing the genetic determinants of disease and human variation. However, such studies of African populations are also likely to provide new opportunities to discover novel disease susceptibility loci and variants and refine gene-disease association signals. A systematic assessment of genetic diversity within SSA would facilitate genomic epidemiological studies in the region. The Genome Diversity in Africa Project (GDAP) aims to produce a comprehensive catalogue of human genetic variation in SSA, including single nucleotide polymorphisms (SNPs), structural variants, and haplotypes. This resource will make a substantial contribution to understanding patterns of genetic diversity within and among populations in SSA, as well as providing a global resource to help design, implement and interpret genomic studies in SSA populations and studies comprising globally diverse populations, complementing existing genomic resources. Specifically, we plan to carry out high depth whole genome sequencing of up to 2000 individuals across Africa (25 individuals from each ethnolinguistic group). Our scientific objectives are to: 1) develop a resource that provides a comprehensive catalogue of genetic variation in populations from SSA accessible to the global scientific community; 2) characterise population genetic diversity, structure, gene flow and admixture across SSA; 3) develop a cost-efficient, next-generation genotype array for diverse populations across SSA; and 4) facilitate whole genome-sequencing association studies of complex traits and diseases by developing a reference panel for imputation and resource for enhancing fine-mapping disease susceptibility loci. These scientific objectives will be supported by cross-cutting operational activities, including network and management of the consortium, research ethics, and research capacity building in statistical genetics and bioinformatics This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/ . This dataset contains all the data available for this study on 2021-02-16.

  Dataset EGAD00001006970

• Developmental Mechanisms of Human Congenital Heart Disease in Subjects with 22q11.2 Deletion Syndrome (DiGeorge Syndrome/Velocardiofacial Syndrome)

  The study is designed to identify genetic modifiers of cardiovascular defects in subjects with 22q11.2 deletion syndrome (22q11.2DS), also known as DiGeorge syndrome or velo-cardio-facial syndrome. Affymetrix 6.0 arrays were processed on 1,480 subjects with known cardiovascular anomalies or with normal structures, all with 22q11.2DS. One sample is a duplicate so it was removed. There are 1,472 samples total of unrelated, de-identified, probands. Over 90% have the same sized 3 million base pair deletion flanked by low copy repeats (LCR22) A and D, while approximately 6% have nested A to B deletions. The rest have other nested deletions, that include a deletion in the vicinity of TBX1 (between LCR22 A and B). A subset of the data was used to identify copy number variations serving as modifiers. Some data were previously published by Dr. Emanuel&#39;s team at Children&#39;s Hospital of Philadelphia in PA, USA (PMID:26742502; PMID:4896312; PMID:25892112; PMID:4570279). The de-identified DNA data from unrelated subjects come from multiple research sites in the US and Europe as part of the International 22q11.2 Consortium and the International 22q11.2 Brain and Behavior Consortium.

  Study phs001339

• ILyAD (Indolent Lymphoma And vitamin D)

  Indolent non-Hodgkin lymphomas are incurable diseases, and require intermittent and often morbid and expensive therapy during their prolonged natural history. Lower intensity and better-tolerated, cost-effective treatment strategies are needed for these patients. Low vitamin D levels at diagnosis of indolent lymphomas are strongly associated with inferior outcomes to treatment. Standard therapy for low tumor burden, indolent lymphoma includes a single agent monoclonal antibody (rituximab). In our double-blind, placebo-controlled, randomized trial we evaluated if vitamin D supplementation with 2000IU oral cholecalciferol daily for three years improved the progression-free survival of patients with indolent lymphoma treated with single agent rituximab. Stratification factors for randomization included histology and Follicular Lymphoma International Prognostic Index (FL-IPI) prognostic score. The primary endpoint of the trial was progression-free survival over three years; secondary endpoints included response at 13 weeks, and overall survival. Eligible participants were adults with biopsy proven follicular lymphoma (grades 1-3a), small lymphocytic lymphoma, marginal zone lymphoma and mucosal-associated lymphoid tissue with no prior anti-lymphoma systemic therapy. Participants had Ann Arbor stage II or greater, measurable disease defined by Lugano criteria. Participants with osteoporosis requiring prescription treatment, symptomatic primary hyperthyroidism, hypercalcemia, creatinine greater than 1.5 times the upper limit of normal or a history of calcium-related kidney stones were excluded. Germline DNA was isolated from saliva samples obtained from participants at baseline. Whole exome sequencing was performed and SNPs were analyzed using the Agilent SureSelectXT Human All Exon V6 +UTR array. SNP data from 185 participants are available through dbGaP.

  Study phs003503

• Exome_sequencing_of_Congenital_Heart_Disease_families_Royal_Brompton

  This project aims to study at least 90 exomes from families with congenital heart disease. The samples have been selected at the Royal, Brompton Hospital in collaboration with Stuart Cook and Piers Daubeney. Ethic approval has been sought for in the UK and a HDMMC agreement for submitting these samples is in place at the WTSI. The phenotype we wil primarily focus our analysis is severe Left Ventricular Outflow Tract Obstructions (LVOTO) and Atrioventricular Septal Defect (AVSD). The indexed Agilent whole exome pulldown libraries will be sequenced on 75bp PE HiSeq (Illumina).

  Study EGAS00001000187

• Sequencing data from MethylScan assay on plasma

  Machine learning models in biomedical research are often hindered by demographic imbalances in clinical datasets, leading to biased predictions that disadvantage minority populations. Existing bias correction methods face limitations in handling the heterogeneity of biomedical data and the complexity of demographic influences. Here, we present DeBias, a computational framework for mitigating demographic biases in high-dimensional biomedical datasets. DeBias eliminates bias-associated subspaces within the entire feature space using control samples and enables global bias correction across all features, effectively preserving disease-specific signals while minimizing demographic distortions. To demonstrate its effectiveness, we applied DeBias to cfDNA methylation data for cancer detection. It achieved a &gt;6-fold reduction in the number of features containing biases and outperformed existing methods in improving the cancer detection performance for minority populations. Our method represented a promising step toward developing machine learning models that are more accurate, reliable, and equitable for minority populations.

  Study EGAS00001008127

• Women's Health Study Accelerometry Dataset

  Background The Women&#39;s Health Study (WHS) was a randomized trial testing low-dose aspirin and vitamin E for preventing cancer and CVD among 39,876 women aged &#8805;45 years throughout the US from 1992-2004. When the trial ended as planned, women who were willing to participate continued in an observational follow-up study. Participants in Accelerometer Study From 2011-2015, an ancillary study collected data on physical activity and sedentary behavior using accelerometers. Women were mailed a triaxial accelerometer (ActiGraph GT3X+, ActiGraph Corp) with a wear log, and asked to wear this on their hip for seven consecutive days, removing it only during sleep and water-based activities. Further details have previously been published (PMID: 30666321). A total of 17,708 women wore and returned their devices, and data were downloaded from the devices of 17,466 women; no data were available from the other 242 (device failure). By convention, a "valid day" of wear has data on at least 10 hours (PMID: 22698174). Among these 17,466 women, 17,062 had at least one valid day of wear. The data are provided for all 17,062 women. Additionally, "compliant wear" is conventionally defined for participants wearing the device for at least 10 hours, on at least 4 days (PMID: 22698174). Of the 17,062 women, 16,741 had compliant wear (PMID: 29109088). Self-reported Physical Activity and Sedentary Behavior After we received the accelerometer from a WHS participant, she was sent a questionnaire asking her to report the time she spent in different physical activities during the week that the accelerometer was worn (see questionnaire below). A total of 15,514 women (91% of participants in the Accelerometer Study) returned their physical activity questionnaires. In addition, beginning in October 2012, we included questions on sedentary behavior; a total of 9,430 women returned questionnaires that included questions on both physical activity and sedentary behavior.

  Study phs001964

• The Melbourne Urological Research Alliance (MURAL) Collection of Patient-Derived Models of Prostate Cancer

  1. Low-Dose Carboplatin Modifies the Tumor Microenvironment to Augment CAR T Cell Efficacy in Human Prostate Cancer Models.Single-cell RNA sequencing (scRNA-seq) was performed to analyze the transcriptional modifications in the tumor microenvironment of prostate cancer patient-derived xenografts (PDX). The analyzed PDX tumor was PDX-287R from the MURAL collection of PDXs (PMID: 34413304). Mice harboring PDX tumors were treated with the carboplatin chemotherapy, and tumors were harvested 3 weeks later. RNA sequencing (RNA-Seq) was used to define immune and non-immune cell populations and anti-tumor innate immune signaling within the tumor microenvironment.To investigate the response of tumor cells to carboplatin treatment in more detail, RNA-Seq was performed on FACs-isolated tumor cells from PDX-287R at one week post-treatment. Gene set enrichment analysis showed an enrichment for apoptotic pathways, with significantly increased expression of the pro-apoptotic genes FAS, BAX, BBC3, IFI6, and JUN. Previously, carboplatin has been shown to activate the cGAS/STING pathway, and here we also found an increase in STING signaling, with an enrichment for the cytosolic DNA sensing pathway and increased expression of STING1, STAT1 and STAT2. There was also a significant increase in the expression of genes involved in T cell chemotaxis, including CXCL10, CXCL11, and CCL20. Collectively, carboplatin-induced cell death in tumor cells likely initiated a pro-inflammatory phenotype in prostate cancer PDXs.2. Co-Targeting BET, CREBBP, and EP300 Inhibits Neuroendocrine Signaling in Androgen Receptor-Null Prostate Cancer.The landscape of castration-resistant prostate cancer (CRPC) is characterized by a multitude of phenotypes, among which neuroendocrine disease holds a prominent position, each displaying unique responses to therapeutic interventions. The efficacy of inhibitors targeting BET and CREBBP/EP300 in prostate cancer treatment is widely acknowledged, primarily due to their ability to attenuate androgen receptor (AR) signaling. However, the effectiveness of these inhibitors in prostate cancers devoid of AR remains uncertain.This investigation sought to elucidate the role of BRD4, CREBBP, and EP300, which are co-expressed in both AR-positive and AR-null prostate cancer. Our study revealed that a compound targeting all three proteins, NEO2734, exhibited efficacy in suppressing the growth of organoids from both AR-positive and AR-null tumors, as evidenced by alterations in viability, size, and cellular composition. Furthermore, NEO2734 treatment consistently led to transcriptional downregulation of cell cycle pathways across various models. In the context of neuroendocrine prostate cancer (NEPC), NEO2734 demonstrated notable efficacy. Treatment with NEO2734 resulted in decreased expression of ASCL1 and other neuroendocrine markers (including SYP) , accompanied by a reduction in tumor growth in vivo. These findings collectively underscore the potential of epigenome-targeted inhibitors in impeding the growth of neuroendocrine prostate cancer, by disrupting lineage regulators in a phenotype-dependent manner. Consistent with the NEPC organoids and explants, NKX3-1 was upregulated in NEO2734-treated PDXs.In this study, we examined the impact of NEO2734 treatment on 6 organoids (treated for 24 hrs), 3 explants treated with JQ1 (for 48 hrs) and 2 PDXs (at two time points) using bulk RNA sequencing (RNA-Seq). These results are available through this dbGaP submission. The implications of these results warrant further exploration and development of compounds possessing similar activities for clinical applications. The ability of NEO2734 to mitigate the growth of both AR-positive and AR-null prostate cancer underscores its potential as a versatile therapeutic agent. Moreover, its efficacy in targeting neuroendocrine phenotypes offers promising avenues for addressing a subtype of CRPC that poses significant clinical challenges. In conclusion, this study sheds light on the intricate interplay between epigenetic regulators and prostate cancer phenotypes. The observed effects of NEO2734 on growth inhibition and phenotype-specific disruption highlight the importance of continued research into compounds with similar epigenome-targeting mechanisms for advancing precision medicine approaches in the treatment of prostate cancer.3. Defining Focal Neuroendocrine Differentiation as a Transcriptionally Distinct Form of Prostate Cancer Pathology Characterized by the Expression of Androgen ReceptorsThe study aimed to understand the transcriptional differences among different neuroendocrine pathologies of prostate cancer. The study hypothesized that the diverse neuroendocrine pathology observed in prostate might be attributable to differences in transcriptional level that remain hidden in bulk RNA-Seq data. To investigate, we employed scRNA-seq to generate gene expression profiles of 18,632 individual tumor cells from 9 PDX models representing five distinct neuroendocrine pathologies of prostate cancer. Our analysis identified 3-8 transcriptionally distinct sub-populations per PDX. The expression of key oncogenic signaling pathways and master regulator activity varied across in neuroendocrine pathologies, with each type of pathology displaying a unique set of transcriptional sub-populations. We discovered that, like the amphicrine pathology, focal neuroendocrine differentiation (focal NED) cells maintain androgen receptor (AR) signaling. However, the expression profiles of focal NED cells differed from the other pathologies, indicating it should be considered as a distinct type of neuroendocrine pathology in prostate cancer. Analysis of copy number alterations suggested little clonal divergence between focal NED cells and neighboring adenocarcinoma cells, emphasizing the transcriptional distinctiveness of focal NED.Overall, the findings suggest potential differences in treatment approaches for tumors from prostate cancer patients showing neuroendocrine pathology, especially focal NED.4. Reprogramming of Androgen Receptor Activity in Castration-Resistant Prostate Cancer is Shaped by Truncated Variants.Under the influence of treatments that target the androgen receptor (AR) axis, prostate cancer cells undergo various changes to the AR gene. This includes the production of truncated AR variants that lack the ligand binding domain and are constitutively active. However, the exact role of these truncated variants in shaping the AR signaling axis and their importance in therapy resistance is not yet fully understood. By examining the AR cistrome in a group of patient-derived prostate cancer models with different mechanisms of castration resistance, we observed diverse changes in AR activity in metastatic prostate cancer, including castration-resistant models. Specifically, we identified a unique subset of tumors characterized by the expression of ARv567es, a variant resulting from structural rearrangements of the AR gene. Tumors positive for ARv567es showed a distinct AR binding profile and epigenome compared to those without ARv567es, which was linked to an altered transcriptional profile. The presence of ARv567es is associated with poor responses to treatments, such as castration and bipolar androgen therapy (BAT), regardless of the presence of full-length AR. This involves disruption of the autoregulatory loop that controls AR gene transcription and reduced transcriptional responses to treatment. Overall, this study demonstrates that ARv567es can lead to transcriptional reprogramming in advanced prostate cancer and drive therapy resistance. 5. The MURAL Collection of Prostate Cancer Patient-Derived Xenografts Enables Discovery Through Preclinical Models of Uro-Oncology.We created a comprehensive PDX resource for prostate cancer to facilitate the rapid and systematic evaluation of new therapies. This collection includes 59 tumors from 30 patients, gathered between 2012 and 2020, aligning with the availability of abiraterone and enzalutamide in the clinic. The PDXs cover the clinical, pathological, and genomic spectrum of prostate cancer, ranging from treatment-na&#239;ve primary tumors to castration-resistant metastases. We characterized heterogeneity in adenocarcinoma and neuroendocrine phenotypes using bulk and single-cell RNA sequencing. Additionally, organoids were cultured from PDXs, enhancing our preclinical study capabilities. Employing a 1x1x1 design, we quickly identified tumors with responses to combination therapies. To manage the distribution of PDXs, we established the Melbourne Urological Research Alliance (MURAL). This PDX collection significantly enhances our ability to test and prioritize effective treatments for future clinical trials in prostate cancer.6. Prostate Cancer Associated Fibroblasts Have Distinct Morpho-Mechanical Features That Are Associated With Patient Outcome.The tumor stroma, including cancer-associated fibroblasts (CAFs), has a crucial role in tumor progression. This study focused on the morphological and mechanical properties of CAFs and normal prostatic fibroblasts. The findings revealed that CAFs had distinct morphological and mechanical characteristics compared to normal fibroblasts, such as differences in nuclear size, shape, F-actin arrangement, cellular volumes, and elasticity. Additionally, the study correlated these biophysical properties with transcriptomic data, identifying pathways and cellular components linked to the observed changes. Overall, high-throughput assessments of biophysical properties in prostate cancer cells and stromal components may serve as predictive tools for patient outcomes and help identify new therapeutic approaches targeting the tumor stroma.

  Study phs003369

• EstMB cohort participants sequenced with MGISEQ-2000 platform

  Participants collected a fresh stool sample immediately after defecation using a sterile Pasteur pipette and placed it in a 15 mL conical polypropylene tube. They were instructed to collect the sample as close as possible to their study center visit. Samples were transported and stored at −80 °C until DNA extraction. Microbial DNA was extracted from 200 mg of stool using a QIAamp DNA Stool Mini Kit (Qiagen), following manufacturer's instructions, after all samples were collected. DNA was quantified using a Qubit 2.0 Fluorometer with a dsDNA Assay Kit (Thermo Fisher Scientific). Library preparation and circularization of equimolarly pooled libraries were done with MGIEasy FS DNA Library Prep Set (MGI Tech Co, Ltd, Shenzhen, China) according to the standard protocol. The sequencing was performed with MGISEQ-2000 High-throughput Sequencing Set (FCL PE150) according to the manufacturer’s instructions (MGI Tech, Shenzhen, China)

  Dataset EGAD50000002213

• A Phase II Neoadjuvant Study of Palbociclib in Combination with Letrozole and Trastuzumab as Neoadjuvant Treatment of Stage II-III ER+ HER2+ Breast Cancer (PALTAN)

  Women with early stage ER+/HER2+ breast cancer (BC) are less likely to achieve pathological complete response (pCR) after chemotherapy with standard of care dual HER2 blockade than patients with ER-/HER2+ BC. Additionally, the toxicity burden of standard systemic therapy is high. Thus, this single arm phase 2 clinical trial investigated a novel de-escalation regimen with trastuzumab, letrozole, and palbociclib in those with early stage ER+/HER2+ BC. The aim was to determine if this treatment regimen will achieve similar pCR rates as conventional treatment and spare women the toxicity burden of regular treatments. The primary endpoint was pCR after 16 weeks of treatment with trastuzumab, letrozole, and palbociclib. Patients with newly diagnosed ER+ HER2+ invasive BC with clinical stages II and III were eligible for this protocol. Research biopsies were performed during the treatment course for whole exome and RNA sequencing, PAM50 molecular subtyping, and Ki67 assessment using immunohistochemistry for complete cell cycle arrest (CCCA: Ki67 &#8804;2.7%). Results showed a pCR of 7.7% and a rate of residual cancer burden at 0 or I of 38.5%. CCCA was observed in 85% at Cycle 1 day 15 post palbociclib, trastuzumab, and letrozole treatment (C1D15), compared to 27% at surgery after palbociclib was discontinued. PAM50 subtyping identified 31.2% HER2-E, 43.8% Luminal B, 25% Luminal A. 161 genes were differentially expressed comparing C1D15 to baseline. Whole exome and RNA sequencing data will be available through dbGaP.

  Study phs003147

• Identification of point mutations, expression perturbations, and gene fusions in T-cell acute lymphoblastic leukemia by RNA-seq

  RNA-seq is a promising technology to re-sequence protein-coding genes for the identification of single nucleotide variants, while simultaneously obtaining information on structural variations and gene expression perturbations. T-cell acute lymphoblastic leukemia (T-ALL) is caused by a combination of gene fusions leading to the over-expression of transcription factors reinforced by point mutations in oncogenes and tumor suppressor genes. We asked whether RNA-seq is suitable for the detection of driver mutations in these leukemias. We analyzed 31 T-ALL patient samples and 18 T-ALL cell lines by high-coverage paired-end RNA-seq.

  Study EGAS00001000536

• Partner independent fusion gene detection by multiplexed CRISPR Cas9 enrichment and long read Nanopore sequencing (FUDGE)

  Targeted long-read nanopore sequencing. Abstract: Fusion genes are hallmarks of various cancer types and important determinants for diagnosis, prognosis and treatment. Fusion gene partner choice and breakpoint-position promiscuity restricts diagnostic detection, even for known and recurrent configurations. To accurately and impartially identify fusions, we developed FUDGE: FUsion Detection from Gene Enrichment. FUDGE couples target-selected and strand-specific CRISPR/Cas9 activity for fusion gene driver enrichment - without prior knowledge of fusion partner or breakpoint-location – to long-read Nanopore sequencing with the bioinformatics pipeline NanoFG. FUDGE has flexible target-loci choices and enables multiplexed enrichment for simultaneous analysis of several genes in multiple samples in one sequencing run. We observe on-average 665 fold breakpoint-site enrichment and identify nucleotide resolution fusion breakpoints - within two days. The assay identifies cancer cell line and tumor sample fusions irrespective of partner gene or breakpoint-position. FUDGE is a rapid and versatile fusion detection assay, providing unparalleled opportunity for diagnostic pan-cancer fusion detection.

  Dataset EGAD00001006111

• Melanoma-Til Study RNAseq

  In this study, mutations present in a series of human melanomas (stage IV disease) will be determined, using autologous blood cells to obtain a reference genome. From each of the samples that are analyzed, tumour-infiltrating T lymphocytes have also been isolated. This offers a unique opportunity to determine which (fraction of) mutations in human cancer leads to epitopes that are recognized by T cells. The resulting information is likely to be of value to understand how T cell activating drugs exert their action.

  Dataset EGAD00001000325

• Whole Genome Sequencing of Harvard University Embryonic Stem Cell Lines 63 and 64

  In this study we used next generation deep sequencing technologies to analyze the genomes of Harvard University Stem Cell lines 63 and 64. We performed 101-bp paired-end whole genome sequencing of the two cell lines using Illumina HiSeq platforms. The sequence reads obtained were analyzed for copy number and used for replication timing analysis. Our data suggests that read depth profiles can be used to map replication timing in Embryonic Stem Cells (ESCs). Further we observe that replication profiles are highly correlated across ESCs but distinct from those of other cell types such as Lymphoblastoid Cell Lines (LCLs). These results demonstrated that read depth data from whole genome sequencing can be used to study variation in replication timing within the human population and across different cell types. Whole genome sequences from HUES63 and HUES64 used for this study are being submitted.

  Study phs000825

• Dataset for the Pearl study

  Biomarkers to identify patients without benefit from adding everolimus to endocrine treatment in metastatic breast cancer (MBC) are needed. We report the results of the Pearl trial conducted in five Belgian centers assessing 18F-FDG-PET/CT non-response (n=45) and ctDNA detection (n=46) after 14 days of exemestane-everolimus (EXE-EVE) to identify MBC patients who will not benefit. Metabolic non-response rate was 66.6%. Median PFS in non-responding patients (using as cut-off 25% for SUVmax decrease) was 3.1 months compared to 6.0 months in those showing response (HR: 0.77, 95% CI: 0.40-1.50, p=0.44). Difference was significant when using a “post-hoc” cut-off of 15% (PFS 2.2 months vs 6.4 months). ctDNA detection at D14 was associated with PFS: 2.1 months vs 5.0 months (HR-2.5, 95% CI: 1.3-5.0, p=0.012). Detection of ctDNA and/or the absence of 18F-FDG-PET/CT response after 14 days of EXE-EVE identifies patients with a low probability of benefiting from treatment. Independent validation is needed.

  Dataset EGAD00001007979