14437 results for ""Pennsylvania+German"+ACS+study+'Socius'+open+access"

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• An isogenic human iPSC model unravels neurodevelopmental abnormalities in SMA

  Whether neurodevelopmental defects underlie the selective neuronal death that characterizes neurodegenerative diseases is becoming an intriguing question. To address it, we focused on the motor neuron (MN) disease Spinal Muscular Atrophy (SMA), caused by reduced levels of the ubiquitous protein SMN. Taking advantage of the first isogenic human induced pluripotent stem cell-derived SMA model that we have generated and a spinal cord organoid system, here we report that the relative and temporal expression of early neural progenitor and MN markers is altered in SMA. Furthermore, the corrected isogenic controls only partially reverse these abnormalities. These findings raise the relevant clinical implication that SMN-increasing treatments might not fully amend SMA pathological phenotypes. The approach we have taken demonstrates that the discovery of new disease mechanisms is greatly improved by using human isogenic models. Moreover, our study implies that SMA has a developmental component that might trigger the MN degeneration.

  Study EGAS00001007259

• Myeloid-specific KDM6B inhibition sensitizes Glioblastoma to PD1 blockade

  Glioblastoma (GBM) tumors are enriched in immune-suppressive myeloid cells and are refractory to immune checkpoint therapy (ICT). Targeting epigenetic pathways to reprogram the functional phenotype of immune-suppressive myeloid cells to overcome resistance to ICT remains unexplored. Single-cell and spatial transcriptomic analyses of human GBM tumors demonstrated high expression of an epigenetic enzyme - histone 3 lysine 27 demethylase (KDM6B) in intra-tumoral immune-suppressive myeloid cell subsets. Importantly, myeloid-cell specific Kdm6b deletion enhanced pro-inflammatory pathways and improved survival in GBM tumor-bearing mice. Mechanistic studies elucidated that the absence of Kdm6b enhances antigen-presentation, interferon response and phagocytosis in myeloid cells by inhibiting mediators of immune suppression including Mafb, Socs3 and Sirpa. Further, pharmacological inhibition of KDM6B mirrored the functional phenotype of Kdm6b deleted myeloid cells and enhanced anti-PD1 efficacy. Thus, this study identified KDM6B as an epigenetic regulator of the functional phenotype of myeloid cell subsets and a potential therapeutic target to improve response to ICT.

  Study EGAS00001007002

• Genetic Heterogeneity of the familial gastric neuroendocrine tumors (2018-06-06)

  Gastric neuroendocrine tumors (gNETs) occur with an estimated frequency of 2 per 100,000 in the general population. Type I gastric neuroendocrine tumors (NETs) represent the 75% of gNTEs and arise from gastric enterochromaffin-like (ECL) cells. They have late age of onset and usually benigh course. Classically, hypergastrinemia in patients who have autoimmune atrophic gastritis, causes hyperplasia of gastric ECL cells that progresses into type I gastric NETs and parietal cell (PC) destruction. The genetic bases in families with this disease are unknown. We performed an exome sequencing study of an atypical aggressive familial gNETs case (with early age onset, nodal infiltrations and gastric adenocarcinomas) that followed a recessive model. We identified a deleterious mutation in homozygosis in the ATP4A gene, which encodes the proton pump responsible for acid secretion by gastric parietal cells. This mutation lead to achlorhydria first, and hypergastrinemia and gNET developing as consequence (Calvete et al. 2014). Recently, two more families with gNETs, classical clinical traits and recessive model have been studies by WES but we didn't find any mutation in the ATP4a gene. However, putative mutations affecting genes that contribute to the development and the integrity of PC have been found suggesting that genetic alterations associated to this disorder target to a unique cell type (parietal cells). In order to cinfirm this hypothesis, it is necessary the search for new genes implicated in the gNETs, more familial cases are needed to be studied. We have identified four more new familial gNETs cases. Here, we propose their study by WES. The first family is formed by thress siblings with gNETs. The other families include two siblings with gNETs. 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 2018-06-06.

  Dataset EGAD00001004153

• Immune cell atlas of environmental and ancestral diversity in Indonesia [scRNAseq]

  Island Southeast Asia (ISEA) remains consistently underrepresented in large-scale human genomic resources despite its rich ancestral and lifestyle diversity. The region's complex population history and environmental/pathogen pressures could have shaped its populations' unique immune responses. Here, we generated single-cell PBMC profiles from 199 Indonesians sampled across four populations in the islands of Bali and New Guinea. The dataset consists of low-pass whole genome sequencing and pooled single-cell PBMC transcriptome sequencing. These groups capture diversity in regional genetic ancestries (West ISEA-like and Papuan-like) and lifestyle contrasts (urban versus rural communities in Bali; highland versus lowland communities in New Guinea), providing a window into how ancestry and environment jointly shape immune variation across ISEA. Together, this study provides the first large-scale single-cell immune atlas of ISEA, highlighting how ancestral and environmental diversity jointly shape human immunity in this globally important yet understudied region.

  Study EGAS50000001656

• Immune cell atlas of environmental and ancestral diversity in Indonesia [WGS]

  Island Southeast Asia (ISEA) remains consistently underrepresented in large-scale human genomic resources despite its rich ancestral and lifestyle diversity. The region's complex population history and environmental/pathogen pressures could have shaped its populations' unique immune responses. Here, we generated single-cell PBMC profiles from 199 Indonesians sampled across four populations in the islands of Bali and New Guinea. The dataset consists of low-pass whole genome sequencing and pooled single-cell PBMC transcriptome sequencing, including T-cell receptor (TCR). These groups capture diversity in regional genetic ancestries (West ISEA-like and Papuan-like) and lifestyle contrasts (urban versus rural communities in Bali; highland versus lowland communities in New Guinea), providing a window into how ancestry and environment jointly shape immune variation across ISEA. Together, this study provides the first large-scale single-cell immune atlas of ISEA, highlighting how ancestral and environmental diversity jointly shape human immunity in this globally important yet understudied region.

  Study EGAS50000001655

• Single Cell RNA Transcriptomics of Mantle Cell Lymphoma Reveals the Presence of Treatment-Resistant Subclones at the Time of Diagnosis

  Mantle cell lymphoma is a chronically relapsing B cell neoplasm characterized by clonal heterogeneity. We implemented single cell RNA sequencing of paired tumor samples from four patients with an aggressive nodal MCL at diagnosis and after failure of standard immunochemotherapy. Clustering the cells based on the inferred CNVs showed small subclones present at diagnosis with a CNV profile similar to the major subclone at relapse. Comparison of these subclones to major subclones present at diagnosis revealed 119 upregulated pathways common for the four patient with an aggressive MCL, including NF-kappaB and PTEN signaling pathways. Additionally, we sequenced a patient with an indolent to blastoid MCL transformation with intestinal tissue involvement. In contrast to other compartments at relapse, the cells in the intestine showed strikingly different CNV profile and presence of new driver mutations including NOTCH1. In conclusion, our study demonstrates that scRNAseq can potentially detect therapy resistant subclones at diagnosis.

  Study EGAS50000000825

• scRNA-seq of LN and lymphoma stroma

  The activities of non-haematopoietic cells (NHCs), including mesenchymal stromal cells and endothelial cells, in lymphomas, reportedly underlie lymphomagenesis. However, understanding of lymphoma NHCs has been hampered by unexplained NHC heterogeneity, even in normal human lymph nodes (LNs). Here, we constructed a single-cell transcriptome atlas of >100,000 NHCs collected from 27 human samples, including LNs and various nodal lymphomas, revealing 30 distinct subclusters, including some that were previously unrecognized. Notably, this atlas was highly useful for comparative analysis with lymphoma NHCs, which revealed an unanticipated landscape of subcluster-specific changes in gene expression and interaction with malignant cells in follicular lymphoma NHCs, facilitating our understanding of stromal remodelling in lymphoma and potentially suggesting novel biomarkers. Our study largely updates NHC taxonomy in human LNs and pertains to analysis of disease status, providing a rich resource and deeper insights into LN and lymphoma biology and offering to advance lymphoma management and therapy.

  Study EGAS00001005732

• Pediatric Patient-Derived-Xenograft development in MAPPYACTS – international pediatric cancer precision medicine trial in relapsed and refractory tumors

  Pediatric patients with recurrent and refractory cancers are in most need for new treatments. This study developed patient-derived-xenograft (PDX) models within the European MAPPYACTS cancer precision medicine trial (NCT02613962). To date, 131 PDX models were established following heterotopical and/or orthotopical implantation in immunocompromised mice: 76 sarcomas, 25 other solid tumors, 12 central nervous system tumors, 15 acute leukemias, and 3 lymphomas. PDX establishment rate was 43%. Histology, whole exome and RNA sequencing revealed a high concordance with the primary patient’s tumor profile, human leukocyte-antigen characteristics and specific metabolic pathway signatures. A detailed patient molecular characterization, including specific mutations prioritized in the clinical molecular tumor boards are provided. Ninety models were shared with the IMI2 ITCC Paediatric Preclinical Proof-of-concept Platform (IMI2 ITCC-P4) for further exploitation. This new PDX biobank of unique recurrent childhood cancers provides an essential support for basic and translational research and new treatments development in advanced pediatric malignancies.

  Study EGAS00001007327

• NHLBI GO-ESP: Heart Cohorts Exome Sequencing Project (Siblings with Ischemic Stroke Study, SWISS)

  The NHLBI "Grand Opportunity" Exome Sequencing Project (GO-ESP), a signature project of the NHLBI Recovery Act investment, was designed to identify genetic variants in coding regions (exons) of the human genome (the "exome") that are associated with heart, lung and blood diseases. These and related diseases that are of high impact to public health and individuals from diverse racial and ethnic groups will be studied. These data may help researchers understand the causes of disease, contributing to better ways to prevent, diagnose, and treat diseases, as well as determine whether to tailor prevention and treatments to specific populations. This could lead to more effective treatments and reduce the likelihood of side effects. GO-ESP is comprised of five collaborative components: 3 cohort consortia - HeartGO, LungGO, and WHISP - and 2 sequencing centers - BroadGO and SeattleGO. The Siblings with Ischemic Stroke Study (SWISS) is an affected sibpair (ASP) study of patients and their brothers/sisters who have had similar strokes. The study was conducted to determine the genes that contribute to an individual's risk of developing an ischemic stroke (a stroke due to sudden interruption of blood flow to a part of the brain). Over 600 people have participated in SWISS, with the coordination of the recruitment and flow of the samples occurring at the Mayo Clinic, Jacksonville, FL, under the direction of James F. Meschia, MD. The University of Virginia (Stephen S. Rich, PhD) served as the analytic site for the genetic data. Participants were excluded from SWISS if they had stroke following an invasive cerebrovascular or cardiovascular procedure, if their stroke occurred shortly following an aneurismal subarachnoid hemorrhage, if the stroke occurred in the setting of a mechanical aortic or mitral valve, if the patient had definite CNS vasculitis or if the patient had a Mendelian mitochondrial stroke disorder, including CADASIL, MELAS, Fabry disease, sickle cell anemia or homocysteinemia. For the NHLBI ESP, the youngest 51 ASPs (102 individuals) from SWISS were selected to undergo exome sequencing. These ASPs were selected from among all SWISS participants, excluding those pedigrees with individuals who had TOAST subtypes of stroke of other etiology or of stroke with undetermined etiology. In addition, the affected siblings were required to have the same TOAST subtype (both small vessel (lacunar) or both large vessel (atherosclerotic)). Of those selected, 98 samples passed initial quality control metrics, and 94 completed exome sequencing and were deposited in dbGaP. An additional set of 590 samples from the SWISS collection has been genotyped on the ExomeChip that contained a subset of rare/infrequent variants identified by exome sequencing. These samples include 495 affected individuals (from multiple affected family members) as well as 95 unaffected family members. These genetic and phenotypic data also will reside in dbGaP.

  Study phs000327

• The National Institute of Neurological Disorders and Stroke (NINDS) Human Genetics Resource Center: DNA and Cell Line Repository (the NINDS Repository): Motor Neuron/Amyotrophic Lateral Sclerosis (ALS) Study

  The National Institute of Neurological Disorders and Stroke (NINDS) Human Genetics Resource Center: DNA and Cell Line Repository (the NINDS Repository), banks phenotypic data and biological samples, including from individuals with motor neuron disease, in order to facilitate gene discovery in neurological disorders. Those samples are used in a number of studies, and genotyping data from studies using this resource are encouraged to be shared via dbGaP. Many studies have already shared data in this fashion, which in turn, can be linked back to the biologicals banked at the NINDS Repository. Motor Neuron Disease is characterized by selective degeneration of the motor neurons of the spinal cord, brainstem, or motor cortex. Clinical subtypes are distinguished by the major site of degeneration. In Amyotrophic Lateral Sclerosis (ALS), there is involvement of upper, lower, and brainstem motor neurons. In progressive muscular atrophy and related syndromes, the motor neurons in the spinal cord are primarily affected. With progressive bulbar palsy, the initial degeneration occurs in the brainstem. In primary lateral sclerosis, the cortical neurons are affected in isolation (Adams et al, Principles of Neurology, 6th ed, p 1089). The Motor Neuron Disease Collection of DNA and cell lines in the NINDS Repository is largely Amyotrophic Lateral Sclerosis cases (others include progressive muscular atrophy, primary lateral sclerosis, progressive bulbar palsy, Kennedy's disease). Amyotrophic lateral sclerosis (ALS) is the most common form of motor neuron disease (MND). Although ALS is the most common MND, it is still a relatively rare disease with an incidence of around 1.6 per 100,000 in the United States. It is currently incurable and treatment is largely limited to supportive care. Family history is associated with an increased risk of ALS, and many Mendelian causes have been discovered (including SOD1). However, most forms of the disease are not obviously familial. It is suspected that the sporadic forms of neurodegenerative disorders are caused by multiple genetic variants that individually make relatively weak contributions to risk. There is also an associated Control collection (see dbGaP and Coriell). Studies in motor Neuron Disease may use cases from the NINDS repository, controls from the NINDS repository, as well as cases, and controls, from other sources. A subset of subjects from The National Institute of Neurological Disorders and Stroke (NINDS) Human Genetics Resource Center: DNA and Cell Line Repository (the NINDS Repository): Motor Neuron/Amyotrophic Lateral Sclerosis (ALS) Study was utilized in the Genome-wide genotyping in amyotrophic lateral sclerosis and neurologically normal controls: first stage analysis and public release of data study. Note: The publication Chio et al., 2009 states that "Raw sample-level genotype data from the initial GWAS study ... are available for download through the dbGAP portal (phs000006.v1.p1)". Instead, please follow this link: phs000101.v1.p1.

  Study phs000006