17280 results for "the best way to get coins in fc 26 Navštivte Buyfc26coins.com Společnost známá transparentními transakcemi..CQ2q"

in 41.56 milliseconds.

• Combination of CDK4/6 with BET-bromodomain and PI3K/mTOR inhibitors in medulloblastoma in vitro and in vivo

  Despite improvement in the treatment of medulloblastoma (MB) over the last years, numerous patients with MYC- and MYCN-driven tumors still fail the current therapeutic regimen. The retinoblastoma (RB) pathway is often compromised in MB with RB remaining intact suggesting that CDK4/6 inhibition might represent a therapeutic strategy for which drug combination remains understudied. Using tumor lines grown in stem cell conditions referred as tumorspheres as well as tumor cells freshly dissociated from the brain of mice harboring intracranial patient-derived xenografts (PDX) of Group3 (G3) and Sonic Hedgehog (SHH) MB, we conducted high throughput drug combination screens using the CDK4/6 inhibitor (CDK4/6i) ribociclib as an anchor and 87 oncology drugs approved by FDA or currently in clinical trials. Bromodomain and extra terminal (BET) and PI3K/mTOR inhibitors potentiated ribociclib’s inhibition of proliferation in G3 and SHH MB. A reverse combination screen using BET inhibitor JQ1 as the anchor, revealed the three FDA approved CDK4/6i as the most potentiating drugs. Those synergistic combinations were tested in vivo in mice intracranially implanted with G3 and SHH MB tumor cells. Ribociclib showed single agent activity in several in vivo MB models. However, despite in vitro synergy, combinations of ribociclib with JQ1 and ribociclib with the PI3K/mTOR inhibitor paxalisib failed to improve the survival of MB bearing mice compared to ribociclib alone. Our data illustrates the difficulty in translating in vitro findings to in vivo for brain tumors partly due to insufficient free brain concentration and altered signaling pathways activation in vitro compared to in vivo.

  Study EGAS00001006286

• Intervention with Micronutrients and Long-Term Impact in Brazil-RECODISA

  Intervention with Micronutrients and Long-Term Impact in Brazil, a partnership between the Federal University of Ceará, Brazil and the University of Virginia, USA, enrolled infants in the age group of 2-36 months to investigate trends in gastrointestinal infections and their effects on growth and development and to identify genetic factors contributing to these diseases.A total of 1044 children from six urban communities in Brazil's semiarid region, were enrolled during active surveillance; those with diarrhea (three or more liquid stools in the last 24 hours at enrollment) were defined as a cases and matched with controls having no diarrhea during the past two weeks (at enrollment) to evaluate their growth and development. A subset of 664 children with their genetic and associated phenotypic data is included in this submission. More information on this project and its related projects can be found here: Studies of diarrheal susceptibility, growth, and development, in pediatric populations in Northeastern Brazil

  Study phs003174

• RNA Editing in breast cancer

  High-throughput sequencing screens suggest that RNA editing, which consists in the substitution of adenosine with inosine by the RNA-specific adenosine deaminase (ADAR) enzyme, occurs at several thousand positions across the human genome. Recent evidences have shown that RNA-editing could promote proliferation and carcinogenesis; however, the general principles of ADAR activity on the transcriptome and how ADAR is controlled in cancers remain to be established. The main aim of this project was to investigate the phenomenon of RNA editing in breast and other cancers. The frequency of A-to-I editing was evaluated in 58 breast cancers equally distributed among the different molecular subtypes and 10 normal breast tissues. The analysis was focused on defining: the relationship between the global amount of editing and ADAR expression; the ability to predict the level of editability of specific sites; the distribution of editing in normal and tumour samples and among different breast cancer subtypes; and the clinical, pathological and genomic factors affecting editing.

  Study EGAS00001000495

• Genetics and transcriptomes of pediatric B cell precursor leukemia with gain of chromosome 21

  Down syndrome (DS, constitutive trisomy 21) children have a 27-fold increased risk of developing B-ALL (DS-ALL), face a worse outcome due to treatment-related morbidities, and an increased rate of relapses compared to other children. This highlights the need to better understand the mechanisms of DS-associated leukemogenesis to develop more adapted treatment. In this study, we characterized the genetic and transcriptomic landscapes of DS-ALL and found a high incidence of somatic mutations leading to RAS/MAPK pathway activation in DS-ALL, as seen in other pediatric B-ALL presenting somatic gains of the chromosome 21 (B-ALL+21).

  Study EGAS00001003760

• Cystic Fibrosis Nasal Epithelium Gene Expression by RNAseq

  Cystic fibrosis (CF) is a monogenic disorder leading to multi-organ system dysfunction, with the primary cause of morbidity and mortality being lung disease. Mutations in CFTR result in defective ion channel transport leading to hyperviscous mucus, airway infection, inflammation and lung function decline. While the Phe508del mutation is the most common CFTR mutation in North American people with CF, it is well known that there is a broad range of lung disease severity even amongst Phe508del homozygotes, including twins/siblings. Heritability analyses showing the relative contribution of non-CFTR modifier genes in such differences in phenotype, have led to our genomic and transcriptomic studies of gene modifiers in CF. Complementary to two international CF GWAS studies, this study was performed to a) determine differential expression of genes relative to a quantitative lung disease severity phenotype score (KNoRMA; as used in CF GWAS studies) and b) to assess expression quantitative trait loci. To better understand genetic modification of CF lung disease severity, we analyzed gene expression (transcriptomic) profiles by mRNA sequencing from nasal mucosal biopsy specimens of 134 people with CF. Each study participants was characterized for CF lung disease severity phenotype by averaging three years of lung function data (forced expiratory volume in 1 second; FEV1), normalized to a CF-specific reference population matching for age, sex, and height. Participants completed nasal lavage and nasal curettage mucosal sampling, with directed sampling to the inferior nasal turbinate, a well validated surrogate for cellular characteristics and CFTR function of the lower CF airways. Participants were further invited to complete a second set of these sampling procedures for validation analysis. Specimen and concurrent clinical data collection occurred across four North American study sites and nasal mucosal specimens were subjected to RNASeq analysis. These data were to be made available in the dbGaP. Our association analyses of gene expression relative to quantitative CF lung disease phenotype, taken together with previously identified GWAS signals, identified biological pathways correlated with CF lung disease pathogenesis. Our further association analyses of gene expression relative to single nucleotide polymorphism variation at significant CF GWAS loci further identified potential mechanisms of genetic variants associated with CF lung disease. This resource is intended to aid researchers in characterizing airway mucosal gene expression from the CF airways for the purpose of gene expression profiling in CF and in muco-obstructive airways disease.

  Study phs002254

• Proteomic measurements in BioBank Japan

  The BioBank Japan (BBJ) is a biobank established in the Institute of Medical Science, the University of Tokyo to collect clinical information and biological materials (DNA and serum samples). It collected about 200 thousand participants of 47 diseases started in 2003 (BBJ 1st cohort), and 67 thousand participants of 38 diseases started in 2013 (BBJ 2nd cohort), both in collaboration with 12 medical centers through the MEXT and AMED's "The BioBank Japan Project." This project is aiming at further utilization of the materials, and clinical and genomic information managed by BBJ to contribute to precision medicine by storing, managing, and providing the materials and data, as well as identifying biomarkers associated with disease risk, prognosis, and drug sensitivity.

  Study JGAS000785

• Whole-Genome Sequencing in Multiplex Epilepsy Families

  Epilepsy is one of the most common neurologic disorders, affecting approximately 4% of individuals at some time in their lives. More than 30% of people with epilepsy continue to have seizures despite treatment, and improved approaches to treatment and prevention are sorely needed. In the search for new strategies to reduce the burden of disease, the discovery of specific genes that influence risk offers a novel opportunity to clarify pathogenic mechanisms, identify susceptible individuals prior to seizure onset, and treat and prevent seizures in people at risk. Despite clear evidence of the importance of genetics in susceptibility to epilepsy, only limited progress has been made in identifying the specific genes that influence risk. One of the greatest challenges for genetic research on this disorder is its extreme clinical and genetic heterogeneity. Although epilepsy is broadly defined by recurrent unprovoked seizures, it is so variable in its clinical manifestations, natural history, and treatment response that most epileptologists view it as a collection of different syndromes ("epilepsies") with distinct etiologies. The genetic effects on susceptibility are also likely to be extremely variable, ranging from rare variants with high penetrance (some of which produce Mendelian patterns of inheritance) to common variants with low penetrance. Recent findings strongly suggest that rare gene variants play a major role in the genetic architecture of the epilepsies. The purpose of this study was to discover new genetic risk factors for epilepsy. The primary approach was to use whole-genome sequencing to interrogate classes of genetic variants, including very rare variants, in multiplex families. Our main hypothesis was that, in at least some proportion of these families, a single variant would explain all instances of epilepsy. Variants identified within the families could then be tested for cosegregation within the family and also validated by seeing enrichment in sporadic epilepsy cases. Furthermore, understanding the impact of rare variation in epilepsy also has the potential to provide insight into the genetic architecture of other complex human diseases. Our analysis focused on families containing multiple individuals with non-acquired (idiopathic or unknown cause) epilepsy under the hypothesis that these would be enriched for genetic control. The families studied had been previously collected and phenotyped in detail, and contain an average of 3.8 individuals per family with a range of different types of epilepsy. We selected one or two affected individuals from each family for sequencing. This work has generated NGS data on 60 samples from 29 multiplex epilepsy families. We have established that, under a monogenic model of inheritance, sequencing pairs of distantly related relatives is an effective method for reducing the number of candidate variants. Critically, we have found that no single variant can explain a large proportion of these epilepsy families. This work emphasizes that identifying causal variants among the many genetic candidates found in this work will require very large sample sizes and gene-based analyses.

  Study phs000690

• The genomic complexity of sporadic and inherited retinoblastoma with a matched orthotopic xenograft

  Retinoblastoma is a pediatric cancer of the developing retina. All retinoblastomas are believed to initiate with biallelic inactivation of the RB1 gene. To identify subsequent genetic lesions in retinoblastoma, we performed whole genome sequencing of tumor and normal DNA of 4 children with retinoblastoma and one matched orthotopic xenograft. Both alleles of RB1 were inactivated in the tumor samples. 3 of the patients had sporadic retinoblastoma and one patient had inherited retinoblastoma. Overall, there were few single nucleotide changes in coding regions of the genome and some of the tumors had few chromosomal lesions. There were very few new genetic lesions in the xenograft compared to the primary tumor. These data suggest that the genome in retinoblastoma is more stable than previously believed and there are relatively few recurrent genetic lesions in known cancer pathways other than the RB1 pathway.

  Study phs000352

• The mutational landscape of primary central nervous system lymphoma (Hipo H050, A050, XD013)

  ]Primary lymphomas of the central nervous system (PCNSL) are diffuse large B-cell lymphomas (DLBCLs) which are confined to the central nervous system (CNS). Despite extensive research, the molecular alterations leading to PCNSL have not been fully elucidated. In order to provide a comprehensive description of the mutational landscape in PCNSL, we here performed integrative whole genome and transcriptome sequencing analysis of 51 lymphomas presenting in the CNS, including 42 EBV-negative PCNSL, 6 secondary CNS lymphomas (SCNSL) and 3 EBV+ CNSL.

  Study EGAS00001005339

• Clonal Evolution in Patients with Chronic Lymphocytic Leukemia

  We analyzed clonal evolution in serial samples from five CLL patients who became resistant to the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib, using whole-exome and deep targeted sequencing. We observe a BTK-C481S mutation in one of five patients, and multiple PLCG2 mutations in a second patient. The other patients had an expansion of clones harboring del(8p) carrying additional driver mutations (EP300, MLL2, EIF2A), with one patient developing trans-differentiation into CD19-negative histiocytic sarcoma. We calculated the growth kinetics of ibrutinib-resistant subclones and estimated the size of the resistant clones at treatment initiation, which we validated by droplet-microfluidic technology. Haplo-insufficiency of TRAIL-R, a consequence of del(8p), led to TRAIL insensitivity which may contribute to development of ibrutinib resistance. These findings demonstrate that ibrutinib therapy has the potential to lead to clonal selection and expansion of rare cell populations already present at the time of treatment initiation. They also provide insight into the heterogeneity of genetic changes associated with ibrutinib resistance, previously attributed solely to mutations in BTK and related pathway molecules.

  Study phs001091

• National Eye Institute (NEI) Ocular Hypertension Treatment Study (OHTS)

  The Ocular Hypertension Treatment Study (OHTS) is an National Eye Institute-sponsored multi-center, randomized, prospective treatment trial designed to determine whether lowering intraocular pressure (IOP) in individuals with ocular hypertension delays or prevents the development of primary open angle glaucoma (POAG). A total of 1,636 individuals with ocular hypertension between 40 and 80 years old were enrolled in the study. In addition to ocular hypertension, subjects in the OHTS were required to have normal optic nerve appearance as determined by the OHTS Optic Disc Reading Center and normal and reliable visual field tests at the time of enrollment by the OHTS Visual Field Reading Center. OHTS subjects were randomly assigned to either an observational group which received close observation or a topical medication group which received medication as needed to achieve a 20% reduction in IOP from their baseline levels. Subjects then were examined at regular intervals for optic disc cupping or visual field defects. Other clinical measures were also obtained from OHTS subjects including central corneal thickness (CCT) and intraocular pressure. The primary outcome monitored for the OHTS was the development of glaucoma in one or both eyes as defined by reproducible visual field abnormality or reproducible optic disc deterioration attributed to POAG by the masked OHTS Endpoint Committee. The OHTS study design has been reported in detail (Gordon, 1999; PMID: 10326953). The OHTS confirmed that ocular hypertension is a risk factor for developing POAG and showed that lowering IOP reduced the risk for developing POAG (Kass, 2002; PMID: 12049574). The OHTS also demonstrated that thin CCT is a significant risk factor for the development of POAG (Gordon, 2002; PMID: 12049575). Blood samples were also collected from 1,077 OHTS participants for an ancillary genetics study. DNA was prepared from these samples and used in a genome-wide association scan (GWAS) designed to identify genetic factors that control the magnitude of quantitative features of glaucoma (baseline IOP, baseline cup-to-disc ratio, and CCT). Genotypes from the GWAS and these clinical data (IOP, cup-to-disc ratio, and CCT) have been provided to dbGaP.

  Study phs000240

• DGCR8 and the six hit, three-step model of schwannomatosis

  In our manuscript, we report the second case of a patient with peripheral schwannomatosis and thyroid alterations cause by the germline pathogenic variant E518K in DGCR8 and analyzed a total of 13 schwannomas from patients in the two kindreds identified up to date. Our analyses revealed how path to tumorigenesis prompted by DGCR8 requires the loss of the wild type allele of Chrm22q and in more than two thirds of the tumors a complete inactivation of NF2.

  Study EGAS00001005665

• Center for Sub-Cellular Genomics

  A cell is a highly complex system with distributed molecular physiologies in structured sub-cellular compartments whose interplay with the nuclear genome determine the functional characteristics of the cell. A classic example of distributed genomic processes is found in neurons. Learning and memory require modulation of individual synapses through RNA localization, localized translation, and localized metabolites, such as those from dendritic mitochondria. Dendrites of neurons integrate distributed synaptic signals into both electrical and nuclear transcriptional response. Dysfunction of these distributed genomic functions in neurons can result in a broad spectrum of neuropsychiatric diseases such as bipolar and depressive disorders, autism, among others. The Center for Sub-Cellular Genomics' (CSG) mission is to develop new technologies to enable the dissection of complex genomic interactions within a single cell. New technologies include methods to target DNA and RNA sampling at sub-cellular resolution in live cells; high-throughput isolation and microfluidics chemistry for sub-cellular fractions; sub-cellular resolution mass-spectrometry; and computational tools for analysis of sub-cellular genomics data. The new technologies developed by CSG will enable the broader genomics community to associate sub-cellular processes to cell function and dysfunction. These technologies will be utilized in the center to generate a comprehensive atlas of genomic signatures of sub-cellular compartments in the mammalian neuron system. The technologies and neuron-focused data obtained here will be relevant to neurodegenerative and neuropsychiatric diseases including schizophrenia, depression, autism spectrum disorder, traumatic brain injury, and Alzheimer's.

  Study phs002120

• Identification_of_drug_resistance_genes_in_melanoma

  Our aim is to analyze the genome of human melanoma cell lines and short term culture from human melanoma samples in order to identify genes that confer drug resistance to clinically relevant targeted therapies. We will perform whole-exome sequencing, copy number variation analysis and methylome analysis in a collection of human melanoma cell lines and short term culture that will be then screened for drug sensitivity/resistance through a library of clinically relevant drugs and drug combinations. By the combined analysis of the genomic lesion and the drug sensitivity/resistance profile of different cell lines, we will look for genes whose mutation is associated to the sensitivity or resistance to a specific drug in different samples.

  Study EGAS00001000617

• A Comprehensive Platform for Analyzing Longitudinal Multi-Omics Data

  PALMO (Platform for Analyzing Longitudinal Multi-omics data) is a platform for analyzing longitudinal data from bulk as well as single cell. It allows to identify inter-, intra-donor variations in genes over longitudinal time points. The analysis can be done on bulk expression dataset without known cell type information or single cell with cell type or user defined groups. It allows to infer stable and variable features in a given donor and each cell type or a user defined group. The outlier analysis can be performed to identify technical/biological perturbed samples in a donor or a participant. Further, differential analysis can be performed to decipher time-wise changes in gene expression in a cell type. The data that is available in the dbGaP is the demo longitudinal samples used in the study, which includes hashed raw fastq files for single-cell RNA-sequencing (scRNA-seq) and non-hashed fastq files for single-cell ATAC-sequencing (scATAC) experiment.

  Study phs003203

• Whole exome sequencing of long-term, never relapse exceptional responders of trastuzumab-treated HER2+ metastatic breast cancer

  Trastuzumab has significantly improved the overall survival of patients with HER2+ metastatic breast cancer (MBC). However, outcomes can vary, with patients progressing within 1-year of treatment or exceptional cases of complete response to trastuzumab for ≥ 10 years. Identification of the underlying genomic aberrations of “exceptional responders (ExRs)” compared to “rapid non-responders (NR)” increases our understanding of the mechanisms involved in MBC progression and identification of biomarkers of trastuzumab response and resistance. Whole exome sequencing was performed on six ExRs compared to five NR. The overall fraction of genome copy number alteration (CNA) burden was higher in NR patients (P=0.07), while more significantly pronounced in copy number gains (P=0.03) in NR compared to ExRs. Delineation of the distribution of CNA burden across the genome identified a greater degree of CNA burden in NR within chr8 (P=0.02) and in chr17 (P=0.06) and conferred a statistically significant benefit in overall survival.

  Study EGAS00001004486

• Somatic Mutations and Their Etiological Determinants for Breast Cancer in African American Women (B-CAUSE Study)

  The breast cancer health disparity between women of African ancestry (AA) and European ancestry (EA) remains a major public health challenge in the United States. AA women are afflicted by higher rate of triple-negative breast cancer (TNBC) and bear the highest mortality rate of all populations from the disease. Even within TNBC, some data suggest that AA women have poorer outcomes than EA women. Mounting evidence points to population differences in cancer biology, a fundamental question that remains unsettled. The disparity also manifests in representativeness in tumor sequencing projects, due to the low inclusion of AAs in genomic studies. A recent analysis of The Cancer Genome Atlas (TCGA) data revealed that the number of AA cases sequenced was sufficient only for studying frequently mutated genes (≥10%), and the power was worse for TNBC as a separate disease entity. As a result, the breast tumor mutational landscape elucidated to date is derived mostly from EA cases, and may not necessarily represent AA cancer genomes. Moreover, as discovery potential for new driver genes has come close to a plateau, cancer in AAs derived from distinct genetic and environmental contexts may provide a powerful venue for discovering mutations that are rare in EA cases. This is showcased in recent studies in colon and prostate cancer. Thus, we carried out a collaborative project, B-CAUSE, to characterize the mutational landscape of AA breast cancer genomes by pooling resources from five established studies, including the Women's Circle of Health Study (WCHS), the Black Women's Health Study (BWHS), the Southern Community Cohort Study (SCCS), the Nashville Breast Health Study (NBHS), and the Southern Tri-State Breast Health Study (STSBHS). This effort has created the largest AA-specific breast tumor mutation dataset to date in an efficient manner. The data deposited here are from the whole-exome sequencing (WES) of matched tumor-normal pairs of 462 TNBC in AA women from the B-CAUSE Study.

  Study phs003962

• Women's Health Initiative Clinical Trial and Observational Study - Imaging

  Objectives: The clinical trial assessed the safety and efficacy of three interventions. Specifically, it evaluated (1) the major health benefits and risks of estrogen plus progestin and estrogen alone, (2) the effects of a low-fat eating pattern on risk of colorectal cancer, and (3) the efficacy of calcium with vitamin D supplementation for preventing hip and other fractures. The objective of the memory study was to determine whether estrogen plus progestin therapy protects global cognitive function, and evaluate the therapy's effect on the incidence of dementia and mild cognitive impairment.The observational study is examining the relationship between lifestyle, socioeconomic, health, and other risk factors with cardiovascular, breast cancer, colorectal cancer and osteoporotic fracture outcomes. Secondary objectives include providing more reliable estimates of the extent to which known risk factors predict disease, more precise estimates of new occurrences of disease, and to provide a future resource for the identification of new or novel risk factors especially factors found in blood. Background: The Women's Health Initiative (WHI) is a long-term national health study that has focused on strategies for preventing the major causes of death, disability, and frailty in postmenopausal women, specifically heart disease, cancer, and osteoporotic fractures. The WHI is primarily composed of an observational study (OS), as well a clinical trial (CT) with three components: Hormone Replacement Therapy (HT), Dietary Modification, (DM) and Calcium/Vitamin D supplementation (CaD).Prior to the WHI, observational studies suggested that postmenopausal hormone therapy was associated with a decreased risk of coronary heart disease (CHD). Potential cardioprotection was based on generally supportive data on lipid levels in intermediate outcome clinical trials, trials in nonhuman primates, and a large body of observational studies suggesting a 40% to 50% reduction in risk among users of either estrogen alone or, less frequently, combined estrogen and progestin. Observational studies primarily examining unopposed estrogen preparations have suggested a 30% to 50% reduction in coronary events, and an 8% to 30% increase in breast cancer with extended use. Other research findings indicated that hormone therapy was also associated with a decreased risk of osteoporosis and increased bone density. The WHI HT trials were designed to test the effects of postmenopausal hormone therapy on risk for coronary heart disease and assess overall risks and benefits in predominantly healthy women. The Women's Health Initiative Memory Program (WHIMS) consists of a suite of studies which include cohorts of women who participated in the WHI HT trials. Postmenopausal women have a greater risk than men of developing Alzheimer's disease, but studies of the effects of estrogen therapy on Alzheimer's disease have been inconsistent. Additionally, observational studies have suggested that postmenopausal hormone treatment may improve cognitive function, but data from randomized clinical trials have been sparse and inconclusive. International comparisons and migration studies have suggested that countries with 50% lower fat intake than the US population had approximately one third the risk of colorectal cancer. Additionally, fairly consistent evidence existed for an effect of dietary fat, vegetables and fruits, and grains on colorectal cancer risk from within-country observational studies, although the protective effect of lower fat intake was no longer clear after adjusting for energy intake. The WHI DM trial was the first randomized trial to directly address the health effects of a low-fat eating pattern in predominantly healthy postmenopausal women from diverse racial/ethnic, geographic, and socioeconomic backgrounds. Osteoporosis is a major cause of injury, loss of independence, and death, and contributes to hip fractures. Observational evidence and data from previous randomized clinical trials suggest that calcium and/or vitamin D supplements may slow bone loss and reduce the risk of falls in postmenopausal and elderly women. However, evidence from trials, observational studies, and meta-analyses of calcium and vitamin D supplementation with respect to hip and other fractures was limited at the time the WHI was initiated. In two prior randomized trials, calcium plus vitamin D supplements did not reduce the risk of nonvertebral fractures among older women. When the WHI CaD trial was designed, guidelines recommended daily intakes of 800 to 1200 mg of calcium with 400 IU of vitamin D for the prevention of osteoporosis, which was not met by many American women. Therefore, the WHI CaD trial was designed to test the primary hypothesis that postmenopausal women randomly assigned to calcium plus vitamin D supplementation would have a lower risk of hip fracture and, secondarily, of all fractures than women assigned to placebo. Subjects: Postmenopausal women ages 50 to 79 were eligible to participate. A woman was considered postmenopausal if she had experienced no vaginal bleeding for 6 months (12 months for women under 55 years of age), had had a hysterectomy, or had ever used postmenopausal hormones. Recruitment was carried out in 40 US clinical centers in 1993-1998. The clinical trial components had additional specific inclusion or exclusion criteria.A total of 68,132 women were randomized into at least one component of the clinical trial. 27,347 women were enrolled in the hormone therapy component with 16,608 in the estrogen plus progestin trial and 10,739 in the unopposed estrogen trial, 48,835 women were enrolled in the diet modification component, and 36,282 women were enrolled in the calcium/vitamin D component. 7,479 women 65 years of age and older at baseline and that participated in the HT trial component were enrolled in the ancillary memory study. Women who were either ineligible or unwilling to participate in the clinical trial component were enrolled in the observational study. For example, many potential participants to the clinical trial component of the study were already undertaking a low fat diet or were using hormone replacement therapy. The effect of the selection process was that women enrolled in the observational study tended to have healthier lifestyles compared to those enrolled in the clinical trial. In total, 93,676 subjects were enrolled in WHI OS, with over 16% being members of a racial/ethnic minority group. The first WHI Extension Study enrolled 115,407 consenting participants from all components of the original WHI study for an additional five years of follow-up, from 2005 to 2010. In 2010, 93,567 women consented to continued follow-up. Design: The clinical trial component of the WHI included three randomized comparisons: hormone therapy, dietary modification, and calcium/vitamin D supplementation. Women could have been randomized into one, two or all three trials.The hormone therapy trial enrolled women to one of two double-blinded trials: estrogen (0.625 mg of conjugated equine estrogens daily) plus progestin (2.5 mg of medroxyprogesterone acetate daily) or estrogen alone. Women with a prior hysterectomy were eligible for the trial of unopposed estrogen. Women with an intact uterus at screening were initially also eligible for unopposed estrogen, but were reassigned to the trial of combined postmenopausal hormones beginning in 1995. Both trials randomized participants 1:1 to either hormone therapy or placebo. A 3-month washout period was required before baseline evaluation of women using postmenopausal hormones at initial screening. Study participants were contacted by telephone 6 weeks after randomization to assess symptoms and reinforce adherence. Follow-up contacts by telephone or clinic visit occurred every 6 months, with clinic visits required annually. The estrogen plus progestin trial was halted in July 2002 after a mean 5.2 years of follow-up because health risks, including increased risk of breast cancer and cardiovascular disease, exceeded benefits. The estrogen alone trial was stopped early in March 2004, because an increased risk of stroke was found with no benefit for coronary heart disease. The primary outcome was coronary heart disease (CHD) (nonfatal myocardial infarction and CHD death), with invasive breast cancer as the primary adverse outcome. The dietary modification trial evaluated the effect of a low-fat, high fruit, vegetable, and grain diet on preventing cardiovascular disease and cancer. Participants were randomly assigned to an intervention or a comparison group in the ratio of 2:3 for cost-efficiency. The intervention was an intensive behavioral modification program, using 18 group sessions in the first year and quarterly sessions thereafter, led by specially trained and certified nutritionists. The program was designed to promote dietary change with the goals of reducing total fat to 20% of energy intake, increasing vegetables and fruits to at least 5 servings daily and grains to at least 6 servings daily. The intervention did not include total energy reduction or weight loss goals. Comparison group participants received a copy of the US Department of Health and Human Services' Dietary Guidelines for Americans and other health-related materials but were not asked to make dietary changes. Dietary intake was monitored using the WHI food frequency questionnaire at 1 year and in a rotating one-third subsample every year thereafter. Women completed a medical update questionnaire every 6 months, and medical records were sought for all women reporting colorectal cancer. The primary outcome was invasive colorectal cancer incidence. Participants in the calcium/vitamin D trial were randomized 1:1 to either supplements or placebo. Active tablets contained 500 mg of elemental calcium (as calcium carbonate) and 200 IU of vitamin D3, to be taken twice daily with meals. The presence and severity of symptoms, safety concerns, and outcomes were ascertained at annual clinic visits and telephone or clinic visits at intervening six-month intervals. Risk factors for fracture were assessed by questionnaire, interview, and clinical examination. The primary outcome was incidence of hip fracture. Participants in the observational study attended a baseline examination and were re-examined three years later. Participants completed annual updates of exposures and clinical outcomes by mail. Final data were collected by mail during the close-out period in April 2004 to March 2005. The major clinical outcomes of interest were coronary heart disease, stroke, breast cancer, colorectal cancer, endometrial cancer, ovarian cancer, osteoporotic fractures, diabetes, and total mortality. Most outcomes were initially ascertained by self-report on an annual questionnaire and documented by hospital and related records. Charts with potential cardiovascular, cancer, and fracture outcomes were sent to the local physician adjudicator for evaluation and classification. Staff at the Clinical Coordinating Center coded and adjudicated all cancers of major interest in the study using standardized SEER guidelines. In 2005, WHI participants were invited to join the Extension Study for an additional five years of follow-up in order to collect long-term outcomes. Participants completed annual data collection forms primarily by mail, similar to the OS follow-up. Women reporting study outcomes were contacted by WHI field center staff to obtain additional details and medical records, which were evaluated by physician adjudicators. In 2010, the woman remaining were invited to join the next Extension Study. In the second extension, women were divided into two groups, one of which would have outcomes documented with medical records (the Medical Records Cohort, MRC), and the other would just be followed by self-report (the Self-Report Cohort, SRC). The MRC consists of women who were in the hormone therapy trials, and all African-American and Hispanic women. In 2012-2013, a subset of the MRC was identified for a potential in-home visit to collect blood and several objective measures of physical functioning. Conclusions: Overall health risks exceeded benefits from use of combined estrogen plus progestin after an average 5.2 year follow-up among healthy postmenopausal US women (Rossouw et al., 2002, PMID:12117397). Among postmenopausal women aged 65 years or older, estrogen plus progestin did not improve cognitive function when compared with placebo (Rapp et al., 2003, PMID: 12771113), increased the risk for probable dementia, and did not prevent mild cognitive impairment (Shumaker, et al., 2003, PMID: 12771112). The use of conjugated equine estrogen increased the risk of stroke, decreased the risk of hip fracture, and did not affect CHD incidence in postmenopausal women with prior hysterectomy after an average of 6.8 years of follow-up (Anderson et al., 2004, PMID: 15082697). Over approximately 8 years of follow-up, a low-fat dietary pattern did not reduce the risk of colorectal cancer (Beresford, et al., PMID: 16467233). Calcium with vitamin D supplementation resulted in a small but significant improvement in hip bone density; however, no significant difference was observed in hip fractures (Jackson, et al., 2006, PMID: 16481635). A recent review summarizes the conclusions from the WHI clinical trials with a focus on clinical practice (Manson, et al., 2024, PMID: 38691368).Description of ECG Imaging Data: Electric cardiograms (ECGs) were given to all clinical trial participants at baseline and in years 3, 6, and 9 of the original WHI study.EKG data consist of 12 lead 10 seconds ECGS sampled at 500Hz via GE ECG machines and process via GE MUSE system. The ECG waveform were directly exported from GE MUSE using MUSE export function in XML format, which include EKG waveform data as well as other ECG characteristics. Waveform data is in base64 encoded format, when it is decoded, it is a binary data that can be used to draw waveform graph. Many programming languages and data tools have built in functions to decode base64 strings. All the other necessary information is included in the LeadData section, total byte size, total sample size etc. (usually 1 sample is 2 bytes). See example below: encoded-data (base64 encoded string) JwAoAC0AKAAiACIAJAAkACQAIwAiACIAHgAcABwAGwAZABgAGAAYABcAEwAQABAAEAAL^/AAsADAAM... decoded-binary-data (1 sample is 2 bytes) 270028002D002800220022002400240024002300220022001E001C001C001B00 1900180018001800170013001000100010000B000B000C000C000D000D000D00 0A000A000A0009000600040004000700070005000500020... These binary values are integers (Y axis data of the graph), hence it is a straightforward process to draw the waveform graph. Acquisition dates have been redacted from this ECG data to comply with WHI policy. All acquisition dates within files and in file names have been set to January 1, 1900 (19000101) to comply with this policy.

  Study phs003824

• STAMPEED: Cardiovascular Health Study (CHS) GWAS to identify genetic variants associated with aging and CVD risk factors and events

  The primary aim of the study is to conduct a genome-wide association study to identify genetic variants associated with the incidence of myocardial infarction (MI), stroke, and heart failure (HF) among participants enrolled in the Cardiovascular Health Study (CHS) who were free of clinical cardiovascular disease at baseline. The secondary aim is to conduct genome-wide association study of other phenotypes in CHS. The study is an ancillary study to CHS. CHS is a population-based cohort study of risk factors for heart disease and stroke among older adults recruited at 4 US sites in 1989-1990. Subjects underwent an extensive baseline examination, and annual follow-up examinations through 1988-1999.

  Study phs000226

• 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.

  Study EGAS00001000251

• Mutations in the RAS/MAPK pathway drive replication repair deficient hypermutated tumors and confer sensitivity to MEK inhibition

  The RAS/MAPK pathway is an emerging targeted pathway across a spectrum of both adult and pediatric cancers. Typically, this is associated with a single, well-characterized point mutation in an oncogene. Hypermutant tumors which harbor many somatic mutations may obscure the interpretation of such targetable genomic events. We find that replication repair deficient (RRD) cancers which are universally hypermutant and affect children born with RRD cancer predisposition, are enriched for RAS/MAPK mutations (p=10-8). These mutations are not random, exist in subclones, and increase in allelic frequency over time. The RAS/MAPK pathway is activated both transcriptionally and at the protein level in patient derived RRD tumors and these tumors responded to MEK inhibition in vitro and in vivo. Treatment of patients with RAS/MAPK hypermutant gliomas reveal durable responses to MEK inhibition. Our observations suggest that hypermutant tumors may be addicted to oncogenic pathways resulting in favorable response to targeted therapies.

  Study EGAS00001005008

• Center for Oral Health Research in Appalachia (COHRA) Genomic Studies of Oral Health and Disease

  The purpose of this project is to identify the genetic factors contributing to dental caries in children and adults. The datasets come from the Center for Oral Health Research in Appalachia (COHRA), which has the long-term goal of determining the sources of oral health disparities in a high risk, Northern Appalachian population so that effective preventive interventions can be designed and targeted. The Specific Aims of this project are to perform genome-wide association scans of dental caries of the (1) primary dentition in children, and (2) permanent dentition in adults, to identify novel risk variants and to replicate previously nominated risk variants. This project brings together samples from three cohorts: COHRA1 is a cross-sectional cohort comprising members of 862 northern Appalachian families; approximately 80% of the cohort has been previously genotyped by the Center for Inherited Disease Research with support from NIDCR using the Illumina Quad W array (see dbGaP Study Accession: phs000095.v3.p1). Dental SCORE is a cross-sectional cohort comprising approximately 550 unrelated individuals who underwent the same data collection protocol as COHRA1. COHRA2 is an ongoing longitudinal cohort that recruited approximately 1100 northern Appalachian women during pregnancy, and followed them and their children through their children's early childhood; the current project period will continue data collect though age 6 of the child. Phenotypes for this project were derived from intra-oral examinations performed by trained and calibrated research hygienists. In brief, each tooth was recorded as present or absent, and each surface of each present tooth was scored for evidence of decay. From these data, dental caries indices were generated. This project contains two phases of genotyping: (1) collection of exome SNP Chip data for the previously genotyped COHRA1 samples, and (2) collection of whole-genome SNP Chip data for the remaining COHRA1 samples and all Dental SCORE and COHRA2 samples. These data will support efforts to test hypotheses regarding the causal relationships of risk factors contributing to the unusually high rates of caries formation in the Appalachian population. Ultimately, these data may inform the development of an integrated model of caries risk, in which the effects of genetics, oral ecology, diet, and other environmental/psychosocial factors and behaviors are modeled in concert to explain the disparities, including the high rate of caries onset before age 6. The gene-mapping Aims of this project, which seek to identify the genetic factors that contribute to caries risk, are a requisite step in realizing this integrated model.

  Study phs001591

• Malignant pheochromocytomas/paragangliomas harbor mutations in transport and cell adhesion genes

  One out of ten patients with pheochromocytoma (PCC) and paraganglioma (PGL) develop malignant disease. Today there are no reliable pathological methods to predict malignancy at the time of diagnosis. Tumors harboring mutations in the succinate dehydrogenase subunit B (SDHB) gene often metastasize but the sequential genetic events resulting in malignant progression are not fully understood. The aim of this study was to identify somatic mutations that contribute to the malignant transformation of PCC/PGL. We performed pair-wise (tumor-normal) whole-exome sequencing to analyze the somatic mutational landscape in five malignant and four benign primary PCC/sympathetic PGL (sPGL), including two biological replicates from each specimen. In total, 225 unique somatic mutations were identified in 215 genes, with an average mutation rate of 0.54 mutations/megabase. Malignant tumors had a significantly higher number of mutations compared to benign tumors (p<0.001). Three novel genes were identified as recurrently mutated; MYCN, MYO5B and VCL, and mutations in these genes were exclusively found in malignant sPGL tumors. Mutations in the MYO5B gene could be verified in two publicly available data sets. A gene ontology analysis of mutated genes showed enrichment of cellular functions related to cytoskeletal protein binding, myosin complex, and motor activity, many of which had functions in Rab and Rac/Rho GTPase pathways. Conclusively, we have identified recurrent mutations in genes related to intracellular transport and cell adhesion, and we have confirmed recurrent mutations of MYO5B in PCC/PGL cases with malignant potential. Our study suggests that deregulated Rab and Rac/Rho pathways may be important in PCC/PGL tumorigenesis.

  Study EGAS00001001601

• Rare coding variants in lupus risk genes

  Systemic lupus erythematosus (SLE) is the prototypic systemic autoimmune disease. It is thought that many common variant gene loci of weak effect act additively to predispose to common autoimmune diseases, while the contribution of rare variants remains unclear. Here we describe that rare coding variants in lupus-risk genes are present in most SLE patients and healthy controls. We demonstrate the functional consequences of rare and low frequency missense variants in the interacting proteins BLK and BANK1, which are present alone, or in combination, in a substantial proportion of lupus patients. The rare variants found in patients, but not those found exclusively in controls, impair suppression of IRF5 and type-I IFN in human B cell lines and increase pathogenic lymphocytes in lupus-prone mice. Thus, rare gene variants are common in SLE and likely contribute to genetic risk.

  Study EGAS00001003548

• Cooperative Study of Sickle Cell Disease (CSSCD)

  The Cooperative Study of Sickle Cell Disease was initiated in 1977 to determine the natural history of sickle cell disease (SCD) from birth to death in order to identify those factors contributing to the morbidity and mortality of the disease. Specific objectives included: 1) to study the effect of sickle cell disease on growth and development from birth through adolescence 2) to study the conditions or events that may be related to the onset of painful crises 3) to obtain data on the nature, duration, and outcome of major complications of SCD 4) determine the nature, prevalence, and age- related incidence of organ damage due to SCD, and 5) study the role of SCD and its interaction with selected health events.Phases 2 and 3 of the study involved followup of the infant cohort. A total of 709 infants (age less than 6 months) were enrolled during Phase 1 of the Cooperative Study of Sickle Cell Disease (CSSCD), and Phases 2 and 3 of the CSSCD was designed to follow these children for an additional 10 years. The study objectives included: 1) define prospectively the natural history of sickle cell disease; 2) determine the relationships between cognitive and academic functioning and brain status as determined by MRI; 3) determine the cognitive or behavioral markers of silent infarct; 4) determine the relationship of family functioning on the Family Environment Scale (FES) to brain status, cognitive functioning, and social and demographic factors; 5) continue studies that will enhance the state of knowledge on the influence of sickle cell disease on the psychosocial adjustment of children and adolescents. Phase 2A of the study sought to examine the progression of organ damage in the heart, lung, kidney, and liver in adult cohort patients (born before 1/1/56) enrolled in phase 1 of the study between 3/79 and 5/81. A total of 620 patients from 11 centers were eligible for phase 2A.Instructions for requesting individual-level data are available on BioData Catalyst at https://biodatacatalyst.nhlbi.nih.gov/resources/data/. Apply for data access in dbGaP. Upon approval, users may begin accessing requested data in BioData Catalyst. For questions about availability, you may contact the BioData Catalyst team at https://biodatacatalyst.nhlbi.nih.gov/contact.

  Study phs002362

• Enhancing Open Data Sharing for Functional Genomics Experiments: Measures to Quantify Genomic Information Leakage and File Formats for Privacy Preservation

  This study was designed to develop methods that address the privacy risk associated with genetic variants obtained from genomic sequencing experiments. The preponderance of readily available genetic sequencing experiments has enabled the generation of datasets whose target purposes range from the genotyping of individuals for medical and forensic analyses, to the acquisition of molecular information for biological model development. However, by virtue of the experimental procedure, the raw sequences are tagged with small bits of patients' private variant information. In addition, depending on the protocol, these experiments may identify sequences from exogenous species. Raw human and microbial sequences can be analyzed as a whole to learn both general facts about biology, but can also be used to determine sensitive information about an individual. This presents a privacy conundrum for data sharing.To address privacy concerns, we have developed several mathematical and computational approaches to quantify the risk of disclosure of sensitive information from genetic sequence data, and to sanitize the associated reads in a manner that optimally maintains the utility of the data. In addition, we have generated environmental samples containing genetic information from consented individuals to evaluate the risk posed by such data. These samples were then used to assess the efficacy of the computational methods. Human-derived and -associated samples that are damaged or obscured by environmental factors represent the scope of samples used for experimentation in this study. Samples include, but were not limited to, swabs of contacted objects and glass slides coated in saliva from consented individuals. Blood samples were also acquired from the same consented individuals to create gold-standard comparison datasets.

  Study phs003166

• Health Effects of Arsenic Longitudinal Study

  The Health Effects of Arsenic Longitudinal Study (HEALS), a multidisciplinary and large prospective cohort study in Araihazar, Bangladesh, was established to evaluate the effects of full-dose range arsenic (As) exposure on various health outcomes. We applied array-based genotyping technologies to baseline DNA samples from a subset of the HEALS study and linked those genotypes to data on arsenic species measured in urine. We used these data to identify regions influencing arsenic metabolism (AS3MT and FTCD). We also applied array-based DNA methylation technologies to baseline DNA samples from a subset of individuals from HEALS. These data were linked to data on arsenic concentration (in both urine and drinking water) to identify regions of the genome where DNA methylation is impacted by arsenic exposure.

  Study phs003839

• ESGI_Exome_sequencing_in_Circulating_Tumor_Cells_to_determine_therapy_related_markers_____

  The objectives of this project are the identification of markers related to cancer therapy resistance in the blood of breast cancer patients and to study the genetic changes in cancer cells during this development of resistance. Whole genome amplified DNA from Circulating Tumor Cells (CTCs), selected during the course of systemic treatment from blood of metastatic breast cancer patients, will be exome sequenced . The patients selected for this study did not respond to therapy.

  Study EGAS00001000747

• ANGIOPREDICT - an FP7-funded project enabling personalised medicine for patients with metastatic colorectal cancer.

  In ANGIOPREDICT, academic cancer biologists and industry-based biotechnology researchers will work together with clinicians to identify biomarkers to predict whether individual metastatic colorectal cancer patients will respond positively to Avastin® combination therapy. Diagnostic tests using these biomarkers will also be developed to provide clinicians with the means to predict patient treatment responses in the future.

  Study EGAS00001005423

• The Incidence of Thromboembolic Events in Patients with Antibodies to Heparin-PF4 after Cardiac Bypass

  The purpose of this study is to determine how often heart surgery patients who receive heparin develop an immune response (heparin-induced thrombocytopenia) that leads to clots forming in different parts of the body. These clots usually occur in the legs (deep venous thrombosis or DVT) or lungs (pulmonary embolism or PE) or cause heart attacks (myocardial infarction or MI) and strokes.

  Study phs000606

• Reconstruction of the personal information from human genome reads in gut metagenome sequencing data

  Human DNA present in fecal samples can result in a small number of human reads in gut shotgun metagenomic sequencing data. However, it is currently unclear how much personal information can be reconstructed from such reads and this has not been quantitatively evaluated. Such a quantitative evaluation is necessary to clarify the ethical concerns related to data sharing and to enable the efficient use of human genetic information in stool samples, such as for research and forensics. Here, we used genomic approaches to reconstruct personal information from fecal metagenomes of 343 Japanese individuals with associated human genotype data.

  Study JGAS000600

• The Library of Integrated Network-Based Cellular Signatures (LINCS) - NeuroLINCS

  The NeuroLINCS Center is part of the NIH Common Fund's Library of Integrated Network-based Cellular Signatures (LINCS) program, which aims to characterize how a variety of human cells, tissues and the entire organism respond to perturbations by drugs and other molecular factors. As Part of the LINCS program, the NeuroLINCS study concentrates on human brain cells, which are far less understood than other cells in the body. Our initial focus is to produce diseased motor neurons from patients by utilizing high-quality induced pluripotent stem cell (iPSC) lines from Amyotrophic Lateral Sclerosis (ALS) and Spinal Muscular Atrophy (SMA) patients in addition to unaffected normal healthy controls. Using state-of-the-art OMICS methods (genomics, epigenomics, transcriptomics, and proteomics), we intend to create a wealth of cellular data that is patient-specific in the context of their baseline genetic perturbations and in the presence of other genetic and environmental perturbagens (e.g. endoplasmic reticulum stress). The primary data will be used to build cell signatures that convey the key features that distinguish the state of a cell and determine its behavior. Ultimately, the analysis of these datasets will lead to the identification of a network of unique signatures relevant to each of these motor neuron diseases. The datasets represented in this study are generated from assays interrogating RNA expression (RNA-seq), chromatin accessibility (ATAC-seq) and whole genome sequencing.

  Study phs001231

• Women's Ischemia Syndrome Evaluation (WISE-BioLINCC)

  Data Access NOTE: Please refer to the "Authorized Access" section below for information about how access to the data from this accession differs from many other dbGaP accessions. Objectives: This is a National Heart, Lung and Blood Institute sponsored, four-center study designed to: 1) optimize symptom evaluation and diagnostic testing for ischemic heart disease; 2) explore mechanisms for symptoms and myocardial ischemia in the absence of epicardial coronary artery stenoses, and 3) evaluate the influence of reproductive hormones on symptoms and diagnostic test response.Background: Women tend to have a higher prevalence of chest pain than men, yet a lower prevalence of epicardial coronary stenoses, and diagnostic tests such as exercise-induced ECG changes tend to have a higher false-positive rate in women than in men. Thus, accurate diagnosis of ischemic heart disease in women is a major challenge to physicians. In addition, prognosis in women with abnormal diagnostic tests is largely unknown and the role reproductive hormones play in this diagnostic uncertainty is unexplored. Moreover, the significance and pathophysiology of ischemia in the absence of significant epicardial coronary stenoses is unknown.Participants: In Phase I (1996-1997), a pilot phase, 256 women were studied. During Phase II (1997-1999) angiographic and baseline data were collected on an additional 680 women to bring total enrollment to 936. Baseline data was also collected on a reference population of 70 women.Conclusions: Among women without CAD, abnormal Magnetic Resonance Spectroscopy (MRS) consistent with myocardial ischemia predicted cardiovascular outcome, notably higher rates of anginal hospitalization, repeat catherization, and greater treatment costs.

  Study phs004310

• Tissue-specificity and co-expression analyses identify human long non-coding RNAs related to inherited retinal disease genes

  The role of long non-coding RNAs (lncRNAs) in biological and pathological processes is still poorly understood. In this study, we aimed to identify lncRNAs that potentially contribute to retinal biology and Inherited Retinal Disease (IRD) by using two complementary strategies, tissue-specificity and location in topologically associating domains (TADs) containing IRD genes on one hand, and co-expression analyses on the other, applied to human retinal omics datasets. This combined approach resulted in the selection of 11 Retina Enriched IRD-gene Related (REIR) lncRNAs, one of which is novel. In-depth in silico and experimental characterization of REIRs identified novel REIR isoforms and confirmed retina-predominant (often photoreceptor-specific) expression as well as predicted functional association with visual function. Long-read direct cDNA sequencing (ONT) of three post-mortem human retina samples was used to delineate the novel REIR isoforms.

  Study EGAS50000000963

• HCA_Female_Reporductive_Adult_WSSS_RNA

  Cell atlas of the human placenta The Human Cell Atlas initiative is an ambitious global research effort which aims to describe every cell in the human body across all developmental stages to generate a reference map to accelerate progress in science and medicine particularly relating to human development and disease. The initiative is led by investigators based at the Wellcome Sanger Institute and the Broad Institute of MIT and Harvard and funding support from the Wellcome and NIH. This specific project will assess human development. We aim to interrogate the cellular composition and molecular regulators underpinning development and maturation through single cell RNA-sequencing/spatial transcriptomics and computational algorithms to predict cellular developmental trajectories and cell-cell interactions. We will subsequent validate these findings in situ using allied imaging technologies e.g. immunohistochemistry and RNAscope and in vitro culture of human intestinal organoids (HIOs). 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 EGAS00001004210

• RNA Sequencing of Pulmonary Arterial Endothelial Cells in Pulmonary Hypertensive Patients and Controls

  The transcriptome of pulmonary arterial endothelial cells from healthy lungs and from lungs of patients with idiopathic pulmonary arterial hypertension have been analyzed and specific differences in disease-relevant pathways were identified. The genes identified as altered in these patients have direct effects on pulmonary arterial endothelial cell function. This finding may underlie the inability of the pulmonary vasculature to respond to and repair the damage observed in pulmonary hypertension.

  Study phs000998

• Center for Common Disease Genomics (CCDG)-Neuropsychiatric: A Study of the Genetic Causes of Complex Pediatric Disorders (CAG)

  In this study, we address the enormous challenges common complex diseases pose for genomic analysis and the enormous opportunities surmounting them offers for advancing healthcare. The common genetic disorders proposed for study here are believed to have extreme locus heterogeneity, requiring the analysis of large numbers of samples to comprehensively identify the genomic variants underlying them. We propose that a combination of deep population studies and joint analysis of SNPs, indels, and structural variants both in coding and noncoding regions will provide the next level of understanding of common genetic disorders. Whole genome sequencing (WGS) will be critical to this next-generation approach to the genomics of complex disease. WGS will need to be accompanied by the technical ability to generate and handle very large data sets, a particular focus and strength of NYGC. WGS will also need to be accompanied by new statistical tools and algorithms, which will be developed by the strong core group committed to this proposal. An overarching goal of this proposal, one that capitalizes on the power of WGS, is to identify disease-associated variants at the individual nucleotide level. In many cases pathogenic mutations fall in noncoding regions of the genome, which can only be fruitfully explored with WGS. A major effort was put into building new computational strategies to functionally annotate noncoding transcribed sequences, and to build new datasets to enable such strategies, opening new frontiers of understanding of disease-related regulatory variants.

  Study phs002004

• Center for Common Disease Genomics (CCDG) Neuropsychiatric: The Autism Simplex Collection (TASC)

  In this study, we address the enormous challenges common complex diseases pose for genomic analysis and the enormous opportunities surmounting them offers for advancing healthcare. The common genetic disorders proposed for study here are believed to have extreme locus heterogeneity, requiring the analysis of large numbers of samples to comprehensively identify the genomic variants underlying them. We propose that a combination of deep population studies and joint analysis of SNPs, indels, and structural variants both in coding and noncoding regions will provide the next level of understanding of common genetic disorders. Whole genome sequencing (WGS) will be critical to this next-generation approach to the genomics of complex disease. WGS will need to be accompanied by the technical ability to generate and handle very large data sets, a particular focus and strength of NYGC. WGS will also need to be accompanied by new statistical tools and algorithms, which will be developed by the strong core group committed to this proposal. An overarching goal of this proposal, one that capitalizes on the power of WGS, is to identify disease-associated variants at the individual nucleotide level. In many cases pathogenic mutations fall in noncoding regions of the genome, which can only be fruitfully explored with WGS. A major effort was put into building new computational strategies to functionally annotate noncoding transcribed sequences, and to build new datasets to enable such strategies, opening new frontiers of understanding of disease-related regulatory variants.

  Study phs001741

• Whole genome sequencing of ASD quartet families

  Autism spectrum disorder (ASD) is genetically heterogeneous with >100 susceptibility genes known. We used whole-genome sequencing (WGS) of 85 quartet families (two parents and two ASD-affected siblings) to comprehensively examine mutation characteristics. Our results emphasize using WGS to maximize the detection of all classes of mutations potentially involved in autism, and to enable the interpretation of that data in confirmatory and predictive diagnosis in different individuals in a family.

  Study EGAS00001001023

• Complement C1s deficiency in a male Caucasian patient with systemic lupus erythematosus: A case report

  This study involves whole genome sequencing of a 34-year-old male with a rare deficiency in complement component C1s, linked to systemic lupus erythematosus (SLE). Genomic analysis revealed two novel mutations in the C1S gene, resulting in absent C1s protein and impaired classical complement pathway function. The goal was to confirm the C1s deficiency and identify the specific mutations causing this condition.

  Study EGAS50000000707

• First datasets available in the Federated EGA Network

  In February 2024, a great milestone was reached for the human omics data community: the first datasets are now available in the Federated European Genome-phenome Archive (FEGA). These datasets - hosted by national nodes in Poland, Norway, and Sweden - are discoverable in the EGA portal and accessible according to national laws. These datasets include: From FEGA Poland - The Genomic Map Of Poland From FEGA Norway - CRCbiome: Gut metagenome of Norwegian screening participants using FIT sampling Also from FEGA Norway - Single cell transcriptomics in expanded Tregs of APS-1 patients From FEGA Sweden - A Combined Omics and Tissue Biobank for Paediatric Cancers The establishment of these datasets represents a significant step towards achieving the broader objectives of the FEGA; to facilitate the sharing of high-quality human genomic and phenotypic data across borders. “The value for users is twofold: it becomes easier to make data available securely compared to storing data locally, and data becomes easier to find for other researchers. The possibility of reuse improves the chances of both verifying scientific discoveries and reaching groundbreaking conclusions, of benefit to the research community and later also patients,” said Anna Hagwall, project manager and head of human data at FEGA Sweden, NBIS. About Federated EGA FEGA was launched in 2022 as a network to store and lawfully share sensitive human omics data safely. It relies on the technology originally developed by the EGA and support from ongoing collaborations with ELIXIR - a European life sciences infrastructure. FEGA has contributed to and benefitted from the implementation of community standards for sensitive data management including those developed by the Global Alliance for Genomics and Health (GA4GH). “The FEGA concept and the development of the Nordic FEGA nodes have been made possible thanks to several projects coordinated by NeIC,” said Kjell Petersen, FEGA Norway technical lead. Managing human omics data is challenging due to its sheer size and privacy concerns, often resulting in restrictions on how and where sensitive data can be shared. The FEGA network follows a federated data access model whereby sensitive data is stored securely within a local or national jurisdiction, while discovery across the network for data of interest is enabled via a central portal. As of February 2024, the FEGA network comprises seven European national nodes with tens of additional national partners working towards establishing a FEGA node. As the FEGA network continues to onboard nodes from around the world, populated with more and more data, we move closer to a vision of a truly global resource for discovery of and access to sensitive human omics data to accelerate disease research and improve human health. "The Federated EGA network is entering a key phase where the first research datasets are now available across the network. In coming years, we look forward to expanding these datasets to cover key areas such as cancer and rare diseases for the benefit of patients" said Thomas Keane, Group Leader at EMBL-EBI.

  Blog first-datasets-available-in-Federated-EGA

• Phase II Study of Cryoablation and Post-Progression Immune Checkpoint Inhibition in Metastatic Melanoma

  Percutaneous cryoablation guided by imaging is a well-established, minimally invasive treatment for oncological conditions. We posited that cryoablation could alter the immune microenvironment by directly influencing the tumor, potentially eliciting an anti-tumor response in cases resistant to immune checkpoint inhibition (ICI). In this non-randomized phase II single-center study (NCT03290677), individuals with unresectable melanoma experiencing progression on ICI underwent cryoablation in a single progressing metastasis, while ICI was continued for at least two additional cycles. The main objectives were to assess safety and feasibility and to evaluate tumor response in non-ablated lesions. Between May 2018 and July 2020, 17 patients participated in the study. The treatment regimen proved safe, revealing an objective response rate of 23.5% and a disease control rate of 41% (comprising 4 partial responses and 3 stable diseases). In our investigation into the factors influencing response to cryoablation therapy in ICI-resistant melanoma, we conducted single-cell RNA sequencing (scRNA-seq) using both 10x Genomics and Smart-seq2 technologies on biopsies from metastatic sites of 15 patients. We collected pre-treatment samples from all patients and post-treatment samples from 5 patients, totaling 20 samples. After quality control, excluding cells specific to anatomical sites or rare cell types (e.g., alveolar type II, neurons), and batch correction, we analyzed 49,071 single cells spanning melanocyte, endothelial, stromal, T, myeloid, and B/plasma cell lineages. Differential gene expression (DGE) analysis between myeloid cells identified the genes MARCKS and IL10, two genes involved in anti-inflammatory responses that can inhibit macrophages activation to be associated with failed response. Moreover, DGE analysis of T cells identified the gene TXK, which acts as a Th1 transcription factor, and the gene CMKLR1 (chemerin-like-receptor-1), which triggers migration of CD8 T-cells to be upregulated in patients who benefited from cryoablation treatment. In contrast, MTHFD2 and GGH, two genes involved in one-carbon metabolism and the folate cycle, were upregulated in T cells from patients who did not respond to therapy. Our analysis revealed a significant increase in B/plasma cells in patients who responded positively to the therapy combination, along with an enrichment of oxidative phosphorylation in T cells among non-responsive patients with progressive disease. These findings advocate for further investigation into this innovative and synergistic therapeutic approach.

  Study phs003579

• The last addition to the list of clonal evolution studies in the EGA

  Tumours of different types may arise from a single cell with at least one malignant mutation. Accumulation of subsequent hits generates lineages of cells with different cancer transformation power; thus, every clone follows an autonomous evolution, and several clones may co-exist into the same solid or liquid tumour. Clonal evolution studies are not new: the conceptual power of this approach has been recognized since the early ’80, especially in leukaemia patients. Nonetheless, these studies greatly benefit from recent technological improvements -machineries and protocols-, which enable ever-increasing sequencing depth, allowing the detection of low frequency variants and consequently more tumour clones. Note: the figure belongs to the original paper and is owned by the authors. Researchers at the University of Kyoto in Japan, have indeed used state of the art knowledge to investigate the clonal evolution of chronic myeloid leukemia (CML) in a large panel of patients. CML progresses from a majoritarian benign chronic phase into an often fatal blast crisis phase. It is nowadays known that blast crisis are triggered by genetic instability and disrupted DNA repair, which lead to accumulation of DNA mutations. The use of thyrosine kinase inhibitors targeting the Philadelphia chromosome have enormously improved the treatment of blast crisis, nonetheless resistant patients are still a medical challenge. Yotaro Ochi and collegues used Whole Exome Sequencing of paired chronic phase and blast crisis samples to depict the genetic landscape of progression from the first to the second stage of the disease (as illustrated in their figure). Their results were published in Nature Communication on this May 2021. They used a dataset previously deposited at the EGA (EGAS00001003071) and their new generated data have been made available under accession number EGAS00001005075. Their analysis of the occurring mutations contribute to understanding the mechanisms of CML evolution and therefore develop a protocol for early management of patients with a TKI resistance signature. Up to date, the EGA hosts 99 clonal evolution studies, developed in several cancer types, including myeloma, renal carcinomas and ovarian cancer, in addition to various leukaemia subtypes, where this approach has been more widely applied and produced important results and seminal papers. From a pan-cancer point of view, the definition of tumour architecture through clonal evolution studies is instrumental to unravel the mechanisms of disease progression and treatment-resistance insource. At the EGA, we are honoured to contribute to exciting and important science advances with our service!

  Blog the-last-addition-to-the-list-of-clonal-evolution-studies-in-the-ega

• Whole Transcriptome Sequencing of NXF1 or CRM1 depleted Cell

  mRNA exporters, NXF1 and CRM1 are known to function in mRNA export. However, since each target mRNA has not been identified genome-widely, it is not clear whether they export exclusive mRNA subsets. To reveal this point, we prepared the nuclear and the cytoplasmic RNAs under either exporter inhibited condition and carried out RNA-seq. In these experiments, we also focused in the export machinery of aberrant transcripts that usually retained and decayed in the nucleus.

  Study JGAS000294

• ATAC-seq iPSC cells or smNPC cells for allelic imbalance

  In order to confirm the predicted impact of the PD-associated allele of rs144814361 on BAG3 promoter, we proceeded with genome editing of the TH-REP1 cell line by using prime editing to insert the “T” allele at the position chr10:119651405 in the BAG3 promoter. 3 replicates for each condition: 1) iPSC Wild Type 2) SNP-BAG3 variant in iPSC 3) SNP-BAG3 variant in smNPC. Allelic imbalance is further assessed using read counting at this specific position.

  Study EGAS50000001579

• GATA2 Deficiency

  The aim of this study is to identify somatic mutations that contribute to the progression of GATA2 Deficiency patients from bone marrow failure to myelodysplastic syndrome (MDS) to acute myeloid leukemia (AML) or chronic myelomonocytic leukemia (CMML). We investigated somatic mutations in >100 patients by whole exome and myeloid malignancy targeted array sequencing to identify acquired mutations associated with myeloid malignancies. MDS was the most common diagnosis (~45%), followed by GATA2 Bone Marrow Immunodeficiency Disorder (G2BMID) (~35%). Approximately ten percent of our cohort were unaffected "carrier" family members with no disease manifestations. In contrast, about ten percent had progressed to a proliferative leukemia. There were no correlations with GATA2 mutation, patient age or gender and disease progression or survival. Somatic Recurrent somatic mutations were uncommon in cancer associated genes, and virtually absent in asymptomatic patients. However, mutations in the cohesin gene STAG2 and chromatin remodeling gene ASXL1 were detected in ~20% of patients. Patients with ASXL1 mutations had a lower survival. ASXL1 mutations were ~10-times more prevalent in female patients than males. Other recurrent mutations were in the DNMT3A, BCOR, and SETBP1 genes. There was a conspicuous absence of the most commonly mutated genes associated with myeloid malignancies, including TET2, RUNX, IDH1/2 and splicing factor genes. 

  Study phs002311

• H3Africa - An integrated approach to the identification of genetic determinants of susceptibility to trypanosomiasis

  The over-arching aim of this network is to improve the health of people living in some of the poorest countries in the world that carry a disproportionate burden of infectious diseases. Despite their importance, the study of many tropical diseases has lagged behind that of diseases of developed countries. This network will redress the balance by performing high quality research into two neglected tropical diseases, human African Trypanosomiasis (HAT) and schistosomiasis. Our aim is to investigate the genetic determinants of the human reservoirs of HAT and schistosomiasis, filling an important knowledge gap, while extending and strengthening the underpinning infrastructure to deliver these scientific objectives in particular by developing the next generation of African geneticists.

  Study EGAS00001007173

• Whole exome sequencing to discover genetic variation associated with aortopathy in Turner Syndrome

  Turner syndrome is a disorder affecting only girls and women, which is caused by a complete or partial loss of the second sex chromosome. Girls and women with Turner syndrome have a variety of phenotypes. Of interest to this study is aortopathy, including bicuspid aortic valve (BAV) and thoracic aortic dilation (TAD) in which we know that 25 - 50% of girls with Turner syndrome are born with. The aorta is the main artery that conducts the blood out of the heart. The aortic valve guards the entrance to the aorta. When the aortic valve has two leaflets instead of the usual three it is called a BAV. BAV is more common than all other congenital heart defects combined. BAV commonly causes obstructions to blood flow out of the heart or become leaky over time. BAV often occurs in combination with TAD. In Turner syndrome, TADs are increased 50-100 fold compared to the general population. Currently, there are no effective approaches or pre-surgical treatments for aortic disease. Therefore, progression of aortic disease in individuals with BAV/TAD can result in catastrophic aortic dissection, rupture, and death. Our goal is to leverage DNA sequencing and carefully curated patient samples to gain a better understanding of the molecular mechanisms that cause these inter-related aortic diseases.

  Study phs001531

• Pancreatic cancer organoids recapitulate disease and allow personalized drug screening

  We report derivation of 30 Patient-Derived Organoid lines (PDOs) from tumors arising in the pancreas and distal bile duct. PDOs recapitulate tumor histology and contain genetic alterations typical for pancreatic cancer. In vitro testing of a panel of 76 therapeutic agents revealed sensitivities currently not exploited in the clinic. The PRMT5 inhibitor EZP015556, shown to target MTAP negative tumors, was validated as such, but also appeared to constitute an effective therapy for a subset of MTAP+ tumors. Taken together, the work presented here provides a platform to identify novel therapeutics to target pancreatic tumor cells using PDOs.

  Study EGAS00001003369

• Ultra-fast deep-learned pediatric CNS tumor classification.

  The primary treatment of CNS tumors starts with a neurosurgical resection in order to obtain tumor tissue for diagnosis and to reduce tumor load and mass effect. The neurosurgeon has to decide between radical resection versus a more conservative strategy to prevent surgical morbidity. The prognostic impact of a radical resection varies between tumor types. However due to a lack of pre-operative tissue-based diagnostics, limited knowledge of the precise tumor type is available at the time of surgery. Current standard practice includes preoperative imaging and intraoperative histological analysis, but these are not always conclusive. After surgery, histopathological and molecular tests are performed to diagnose the precise tumor type. The results may indicate that an additional surgery is needed or that the initial surgery could have been less radical. Using rapid Nanopore sequencing, a sparse methylation profile can be directly obtained during surgery, making it ideally suited to enable intraoperative diagnostics. We developed a state-of-the-art neural-network approach called Sturgeon, to deliver trained models that are lightweight and universally applicable across patients and sequencing depths. We demonstrate our method to be accurate and fast enough to provide a correct diagnosis with as little as 20 to 40 minutes of sequencing data in 45 out of 49 pediatric samples, and inconclusive results in the other four. In four intraoperative cases we achieved a turnaround time of 60-90 minutes from sample biopsy to result; well in time to impact surgical decision making. We conclude that machine-learned diagnosis based on intraoperative sequencing can assist neurosurgical decision making, allowing neurological comorbidity to be avoided or preventing additional surgeries.

  Study EGAS00001007475