12389 results for ""statistically+reactive"+taxa+in+microbial+community"

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• pancreatic ductal adenocarcinoma exomes in study: Pro-immunogenic Impact of MEK inhibition combined with an anti-CD40 immunostimulatory antibody

  Cancer types with lower mutational load and a non-permissive tumor microenvironment are intrinsically resistant to immune checkpoint blockade. While the combination of cytostatic drugs and immunostimulatory antibodies constitutes an attractive concept for overcoming this refractoriness, suppression of immune cell function by cytostatic drugs may limit therapeutic efficacy. Here we show that targeted inhibition of mitogen-activated protein kinase (MAPK) kinase (MEK) does not impair dendritic cell-mediated T-cell priming and activation. Accordingly, combining MEK inhibitors (MEKi) with agonist antibodies (Abs) targeting the immunostimulatory CD40 receptor resulted in potent synergistic anti-tumor efficacy. Detailed analysis of the mechanism of action of MEKi GDC-0623 by means of flow cytometric analysis of the tumor immune infiltrate and whole tumor transcriptomics showed that, in addition to its cytostatic impact on tumor cells, this drug exerts multiple pro-immunogenic effects, including the suppression of M2-type macrophages, myeloid derived suppressor cells and CD4+ T-regulatory cells. In addition, MEKi was found to induce tumor-cell intrinsic interferon signaling, which contributed to antigen presentation by tumor cells. Finally, the tumoridical impact of MEKi involves the activation of multiple pro-inflammatory pathways involved in immune cell effector function in the tumor microenvironment. Our data therefore indicate that the combination of MEK inhibition with agonist anti-CD40 Ab is a promising therapeutic concept, especially for the treatment of mutant Kras-driven tumors such as pancreatic ductal adenocarcinoma. The pancreatic ductal adenocarcinoma exomes were generated in the context of the Heidelberg Center for Personalized Oncology project HIPO-K28E.

  Study EGAS00001004196

• A unidirectional histone code in bidirectional promoters across cell types

  Recent studies indicate that thousands of genes are expressed from bidirectional promoters (BDPs). Gene regulation at BDPs is poorly understood, in particular how the cell is able to regulate them differently. Here we investigate the effect of histone Modifications in BDP regulation. In this study, we model the gene activity using different gene expression assays, such as RNA-Seq, GRO-cap, and CAGE around the BDP transcription start sites (TSSs) using different histone modifications in various cell types. We develop a new statistical approach that links histone modifications to gene expression at BDPs. It improves over previous methods, because it is able to capture spatial dependencies of histone modifications along a promoter and leads to more interpretable results. We predict a general histone code that is independent of transcript orientation, cell type, and promoter configuration. The histone code at BDPs reveals that promoters are regulated unidirectionally, such that the majority of histone marks associated with gene expression occur downstream of the gene's TSS. By contrasting associations of histone marks with steady-state levels of capped RNAs in CAGE and nascent capped RNAs in GRO-cap, we show which histone marks have a preference for initiating polymerases and actively elongating polymerases. Using single-cell data we show that the bidirectional histone signal of activating marks is often due averaging of a heterogeneous cell population. Our results have implications for other experiments where the relationship between histone modification and gene initiation or gene elongation is investigated on a genome-wide scale.

  Study EGAS00001001656

• Transcriptome of Chronic Pain and Disease

  The Functional Genomics Section (FGS) is a part of the National Institute of Dental and Craniofacial Research (NIDCR) within the National Institutes of Health (NIH). Research at the FGS focuses on understanding the mechanics involved in nociception through both clinical samples from patients with chronic pain and mouse models of pain. Pain is relayed from the periphery to the central nervous system through specialized sensory neurons known as nociceptors. The cell body of nociceptors resides in neuronal structures that branch off of the spinal cord known as dorsal root ganglia (DRG). The DRG is a heterogenous tissue containing not only sensory neurons like nociceptors, but also glial cells, capillaries, fibroblasts, and resident macrophages. The interaction between the nociceptors and these DRG cell types can have a significant role in affecting neuronal hyperexcitability and downstream pain sensitivity. To better understand the cellular factors involved in producing conditions of chronic pain, DRGs from consenting organ donors were collected from individuals experiencing pain disorders such as painful diabetic neuropathy and rheumatoid arthritis. A multi-omics approach is being used to identify molecular mechanisms that lead to pain hypersensitivity in patients with chronic pain.  

  Study phs002548

• Method to Assess Lung Water Accumulation During Exercise

  The goal of this non-significant risk medical device study is to test the initial technical feasibility of a 0.55T MRI in healthy volunteers by technical optimization of scanner protocols, and to test accuracy of standard MR measurements in adult patients with known stable disease. Exercise-induced lung water is a key feature in heart failure. Dynamic quantitative lung water imaging during exercise stress is therefore of interest to unmask latent heart failure. We developed a novel magnetic resonance imaging (MRI) method using a proton density weighted ultrashort echo time MRI sequence along with a time-resolved and respiratory motion compensated image reconstruction for exercise lung water imaging. We validated our method in a porcine model of dynamic lung water accumulation (n=5), and tested its feasibility for use in humans using 12 healthy subjects, 1 patient with heart failure with preserved ejection fraction, and 1 patient with heart failure with reduced ejection fraction. Data suggest the novel imaging method is capable of dynamically imaging lung water accumulation during exercise stress. Reference 1 (PMID: 37288601) contains the main results for this study.

  Study phs003346

• Nicotine dependence GWAS meta-analysis across European and African American ancestries

  Cigarette smoking is the leading cause of preventable morbidity and mortality. Knowledge is evolving on genetics underlying initiation, regular smoking, nicotine dependence (ND), and cessation. We performed a genome-wide association study using the Fagerström Test for ND (FTND) in 58,000 smokers of European or African ancestry. Five genome-wide significant loci, including two novel loci MAGI2/GNAI1 (rs2714700) and TENM2 (rs1862416) were identified, and loci reported for other smoking traits were extended to ND. Using the heaviness of smoking index (HSI) in the UK Biobank (N=33,791), rs2714700 was consistently associated, but rs1862416 was not associated, likely reflecting ND features not captured by the HSI. Both variants were cis-eQTLs (rs2714700 for MAGI2-AS3 in hippocampus, rs1862416 for TENM2 in lung), and expression of genes spanning ND-associated variants was enriched in cerebellum. SNP-based heritability of ND was 8.6%, and ND was genetically correlated with 13 other smoking traits (rg=0.40-0.95) and co-morbid diseases. Our results emphasize the FTND as a composite phenotype that expands genetic knowledge of smoking, including loci specific to ND.

  Study phs001532

• NIH Roadmap Epigenomics Program - Broad Institute

  For the NIH Roadmap Epigenomics project, we applied ChlP-Seq, HTBS and WGBS pipelines to generate comprehensive high-resolution maps of chromatin state and DNA methylation for 100 diverse cell types. Cell types were selected for their biological and medical importance, and for their potential to maximize the comprehensiveness of acquired epigenomic data. They include human ES cells, ES-derived cells, mesenchymal stem cells, reprogrammed stem cells and primary tissues. Comprehensive characterization of epigenetic marks ("the epigenome") is a critical step towards a global understanding of the human genome in health and disease. In this study we provide unprecedented views of the human epigenetic landscape and its variation across cell states, which offer fundamental insight into the functions and interrelationships of epigenetic marks, and provide a framework for future studies of normal and diseased epigenomes. The Roadmap Epigenomics Broad cohort is utilized in the following dbGaP sub-study. To view molecular data and derived variables collected in this sub-study, please click on the following sub-study below or in the "Sub-studies" box located on the right hand side of this top-level study page phs000700 the Roadmap Epigenomics Broad cohort. phs000610 RM_Epigenomics_Broad_Alz

  Study phs000700

• Genetics of Cutaneous T-Cell Lymphoma

  Mycosis fungoides (MF) is a common extranodal T-cell lymphoma primarily arising in the skin. In early disease stages, MF presents as skin patches and plaques that in some cases may progress to tumor and disperse to lymph nodes and other internal organs. The 10-year overall survival is 50% in advanced stages. Early diagnosis is difficult as the histology overlaps with features of inflammatory skin diseases. Even when the diagnosis is established, there are no prognostic markers that predict whether the disease will be aggressive or indolent. Lastly, there are no curative treatments and MF will invariably relapse, even after aggressive chemotherapy. The disease is a diagnostic, prognostic and therapeutic challenge. The main objective of this study is to address the question of tumor heterogeneity in MF. To date, MF is considered to be monoclonal, derived from a transformed, mature memory T-cell. However, clinical observations and preliminary data suggest that MF comprises multiple subclones, which may be of importance for understanding disease evolution and resistance to therapy. We plan to address this objective using Whole Exome Sequencing (WES) of MF tissue prepared by laser microdissection (LMD).

  Study phs001877

• Human Pilocytic Astrocytoma Single Cell RNA Sequencing

  Pilocytic astrocytoma (PA), the most common childhood brain tumor, is a low-grade glioma with a single driver BRAF rearrangement. Here, we perform scRNAseq in six PAs using methods that enabled detection of the rearrangement. When compared to higher-grade gliomas, a strikingly higher proportion of the PA cancer cells exhibit a differentiated, astrocyte-like phenotype. A smaller proportion of cells exhibit a progenitor-like phenotype with evidence of proliferation. These express a mitogen-activated protein kinase (MAPK) program that was absent from higher-grade gliomas. Immune cells, especially microglia, comprise 40% of all cells in the PAs and account for differences in bulk expression profiles between tumor locations and subtypes. These data indicate that MAPK signaling is restricted to relatively undifferentiated cancer cells in PA, with implications for investigational therapies directed at this pathway. Note that 931 out of 1234 samples in the Sequence Read Archive (SRA) passed QC and have transcript count data available from the Broad Institute Single Cell Portal. The transcript count data can be found at https://singlecell.broadinstitute.org/single_cell/study/SCP271/pilocytic-astrocytoma-single-cell-rna-seq#study-download

  Study phs001854

• Development of CMT Peds Scale for Children with CMT

  Information about how different forms of CMT affect children is not readily available because there are not good methods to measure impairment of children with CMT. The purpose of this project is to develop and test such a method and to then test this scale to ensure that it is an effective measurement of impairment of CMT in children, that the children tolerate it well, that different investigators using this method obtain similar results and that changes over time with the scale allow measurement of progression of CMT in the children. Primary Objective: To develop and test the CMT Peds scale (CMTPedS) in children with CMT in order to refine the scoring for future natural history and therapeutic trials. Secondary Objective: We propose to test the sensitivity of the CMT Peds Scale in a longitudinal study and compare the CMT Peds Scale with the Children's Quality of Life scale CHQ-PF50. 2000 patients <21 years of age with various forms of CMT will be evaluated at baseline and at subsequent annual follow up visits when possible. This first study release makes available data of n=208 study participants.

  Study phs001553

• Multicenter Study of Hydroxyurea (MSH)

  This study aimed to determine whether or not treatment with hydroxyurea titrated to maximum tolerated doses would reduce the frequency of vaso-occlusive (painful) crises by at least 50% in 299 men and women between 18 and 50 years old with a diagnosis of sickle cell anemia by gel electrophoresis conducted by a Core Laboratory. A secondary objective investigated correlations of fetal hemoglobin (HbF) levels and other patient or treatment characteristics with the occurrence of vaso-occlusive (painful) crises, and the effect of treatment on the quality of life.This controlled trial made hydroxyurea the first drug of proven benefit in preventing vaso-occlusive pain crisis and acute chest syndrome caused by sickle cell disease, with additional findings including reduced mortality in adult patients taking hydroxyurea for frequent painful sickle cell episodes after 9 of years follow-up. No significant side-effects of hydroxyurea therapy were noted.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 phs002348