13415 results for ""pdc"+"heritage+language"+census+study"

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• Genomic Landscape of Multiple Myeloma and of its Precursor Conditions, and its Clinical Implications

  Reliable strategies to capture patients at risk of progression from precursor stages of multiple myeloma (MM) to overt disease are still missing. In this study, we generated whole-genome sequencing (WGS) data from matched tumor and normal samples from 98 individuals from the PCROWD study (Precursor Crowd, NCT02269592). These individuals have either a precursor condition for MM, which can be a monoclonal gammopathy of undetermined significance (MGUS) or smoldering multiple myeloma (SMM), or an active multiple myeloma (MM). To do so, we enriched tumor plasma cells from the bone marrow by magnetic bead selection (CD138+), sequenced the DNA of these samples to a target depth of 60X (tumor), and analyzed them against normal white blood cells (peripheral blood mononuclear cells) from the same individuals sequenced to a target depth of 30X (normal). In our first publication [Alberge, Dutta, Poletti, et al., 2025], we integrated and homogeneously analyzed these data together with data from mostly publicly available datasets (phs003084 and phs000748) to reach 1,030 total samples. We used these data to identify recurrent coding and non-coding candidate drivers, as well as significant hotspots of structural variation, and used those drivers to define and validate a simple “MM-like” score which we could use to place patients' tumors on a gradual axis of progression toward active disease. Our MM precursor genomic map provides new insights on the time of initiation and cell of origin of the disease, on the order of acquisition of genomic alterations, and on mutational processes found across stages of the transformation. Taken together, we highlight here the potential of genome sequencing to better inform risk assessment and monitoring of MM precursor conditions.

  Study phs003846

• Field Studies of Human Immunity to Amebiasis in Bangladesh

  Amebiasis is a common cause of diarrhea and is associated with malnutrition in grade-school aged children in an urban slum of Dhaka, Bangladesh. Field Studies of Human Immunity to Amebiasis in Bangladesh was designed to determine the contribution of amebiasis to illness in the first 2 years of life when most deaths due to diarrhea occur, and understand the immunologic and genetic factors that protect children from amebiasis. The hypothesis underlying the study is that susceptibility to amebiasis is determined by host innate and acquired immune responses that vary between individuals in part due to: human genetic polymorphisms; environmental influences including malnutrition and concurrent geohelminth infection; and virulence differences among Entamoeba histolytica genotypes. Specific aims proposed in the design of the study were to: a) Measure the incidence of amebiasis and correlate it with human and parasite genetic polymorphisms, immune responses, and environmental factors such as geohelminth infection and malnutrition; b) Test the hypothesis that protective immunity is mediated both by innate immune responses initiated via TLR stimulation as well as by mucosal IgA against the Gal/GalNAc lectin and systemic IFN-γ; c) Test for the association of common genetic polymorphisms in host innate and acquired immune genes with incidence of amebiasis. 629 newborn babies were enrolled and followed regularly through bi-weekly surveillance for diarrheal episodes, anthropometry at 3-month interval until 60 months of age. The infants that were consented for GWAS analysis were genotyped in 3 separate batches at different times, on 3 different arrays. Quality control was performed on the 3 separate data sets and then jointly after merging. Genetic data available on 447 infants together with their phenotype data is made available in this submission.

  Study phs001476

• Involvement of the FGF8/FGF Receptor Signaling Pathway in the Maintenance and Progression of Fusion-Positive Rhabdomyosarcoma

  In our previous work, we used a myoblast model of fusion-positive rhabdomyosarcoma (FP-RMS) to demonstrate that FGF8, a target of the PAX3-FOXO1 (P3F) transcription factor, is essential for tumorigenicity driven by P3F. When aberrantly expressed, FGF8 can also sustain tumorigenicity in recurrent tumors that are independent of P3F. In this study, we report that FGF8, along with its receptors FGFR1 and FGFR4, is often highly expressed in FP-RMS tumors. We found that high levels of FGF8 expression in FP-RMS cells correlate with increased sensitivity to an FGFR4 inhibitor and a pan-FGFR inhibitor. Conversely, downregulating FGF8 led to a loss of sensitivity to these inhibitors. Interestingly, when FGF8 was upregulated in myoblasts, it resulted in decreased FGFR4 expression and sensitized the cells to an FGFR1 inhibitor and a pan-FGFR inhibitor. The downregulation of FGFR4 expression mediated by FGF8 could be reversed by inhibiting FGFR1, MEK, or ERK, thereby defining a signaling pathway through which FGF8 exerts its regulatory effects. Additionally, we discovered that high FGF8 expression in P3F-independent recurrent tumors is due to a rearrangement of viral long terminal repeat (LTR) sequences into the 3' untranslated region (UTR) of FGF8, leading to increased stability of FGF8 mRNA. These findings indicate that FGF8 plays an oncogenic role in FP-RMS through FGFR4 and may also exert oncogenic effects in P3F-independent relapses via FGFR1. Our study highlights the functional significance of FGF8 in FP-RMS and supports the rationale for preclinical investigations of FGFR inhibitors in treating this type of cancer.

  Study phs004009

• Mortality and risk of progression to adult T-cell leukemia/lymphoma in patients with HTLV-1-associated myelopathy/tropical spastic paraparesis

  Human T-cell leukemia virus (HTLV)-1 causes the functionally debilitating disease HTLV-1-associated myelopathy/ tropical spastic paraparesis (HAM/TSP) as well as adult T-cell leukemia lymphoma (ATLL). Although there were concerns that the mortality of HAM/TSP could be affected by the development of ATLL, prospective evidence was lacking in this area. In this 5-year prospective cohort study, we determined the mortality, prevalence, and incidence of ATLL in 527 HAM/TSP patients. The standard mortality ratio of HAM/TSP patients was 2.25, and ATLL was one of the major causes of death (5/33 deaths). ATLL prevalence and incidence in these patients were 3.0% and 3.81 per 1,000 person-years, respectively. To identify patients at a high risk of developing ATLL, flow cytometry, Southern blotting, and targeted sequencing data were analyzed in a separate cohort of 218 HAM/TSP patients. In 17% of the HAM/TSP patients, we identified an increase in T-cells positive for cell adhesion molecule 1 (CADM1), a marker for ATLL and HTLV-1 infected cells. Genomic analysis of these patients revealed that somatic mutations of HTLV-1 infected cells were seen in 90% of the cases and 11% of them had dominant clone and developed ATLL in the longitudinal observation. In this study, we were able to demonstrate for the first time that the increased mortality in patients with HAM/TSP and a significant effect of ATLL on their prognosis. Having dominant clonal expansion of HTLV-1- infected cells with ATLL-associated somatic mutations may be important characteristics of patients with HAM/TSP who are at an increased risk of developing ATLL.

  Study JGAS000226

• Cholesterol homeostasis and lipid raft dynamics at the basis of tumor-induced immune dysfunction in chronic lymphocytic leukemia

  Autologous T-cell therapies show limited efficacy in chronic lymphocytic leukemia (CLL), where acquired immune dysfunction prevails. In CLL, disturbed mitochondrial metabolism has been linked to defective T-cell activation and proliferation. Recent research suggests that lipid metabolism regulates mitochondrial function and differentiation in T cells, yet its role in CLL remains unexplored. This comprehensive study compares T-cell lipid metabolism in CLL patients and healthy donors, revealing critical dependence on exogenous cholesterol for human T-cell expansion following TCR-mediated activation. Using multi-omics and functional assays, we found that T cells present in viably frozen samples of patients with CLL (CLL T cells) showed impaired adaptation to cholesterol deprivation and inadequate upregulation of key lipid metabolism transcription factors. CLL T cells exhibited altered lipid storage, with increased triacylglycerols and decreased cholesterol, and inefficient fatty acid oxidation (FAO). Functional consequences of reduced FAO in T cells were studied using samples from patients with inherent FAO disorders. Reduced FAO was associated with lower T-cell activation but did not affect proliferation. This implicates low cholesterol levels as a primary factor limiting T-cell proliferation in CLL. Consequently, CLL T cells displayed fewer and less clustered lipid rafts, potentially explaining the impaired immune synapse formation observed in these patients. Our findings highlight significant disruptions in lipid metabolism as drivers of functional deficiencies in CLL T cells, underscoring the pivotal role of cholesterol in T-cell proliferation. This study suggests that modulating cholesterol metabolism could enhance T-cell function in CLL, presenting novel immunotherapeutic approaches to improve outcome in this challenging disease.

  Study EGAS50000000933

• Altered oligodendrocyte heterogeneity in Multiple sclerosis revealed by single nuclei RNA sequencing

  This study is currently hosted by the European Nucleotide Archive. To access the data contained within the Study please follow the link below: https://www.ebi.ac.uk/ena/browser/view/PRJEB39323 Oligodendrocyte (OL) pathology is increasingly implicated in neurodegenerative diseases, as they are involved in metabolic support of axons and functional cross-talk with other brain cells. Rodent OLs are heterogeneous, with developmental and biological differences, but the extent of heterogeneity in the normal human brain and its contribution to any changes to disease remains unknown. Here we performed single nuclei RNA-sequencing (snRNA-seq) from white matter (WM) areas of post mortem human brain both in control (Ctr) and multiple sclerosis (MS) patients. We identified several sub-clusters of oligodendroglia in the Ctr human WM, some similar to those in mouse, and defined new markers for these cell states. Strikingly, some of these sub-clusters were under-represented in MS tissue, while others were more prevalent than in controls. We found a lack of OL precursor cells (OPCs) and an OL subcluster in an intermediate stage of differentiation in MS lesions and in normal appearing white matter (NAWM), suggesting either depletion by the disease or by a regenerative response. The differences in mature OL sub-clusters indicate different functional states of OLs in MS tissue and, as this is similar in NAWM to lesions, that MS is a more diffuse brain disease than the focal demyelinating lesions suggest. We were also able to identify new putative markers of different MS lesion subtypes. Our findings of an altered heterogeneity of oligodendroglia in MS may have an important contribution to our understanding of disease progression and may alter therapeutic approaches to MS.

  Study EGAS00001003412

• Induced Pluripotent Cells Derived from Differentiated Rod Photoreceptors Undergo Efficient Retinogenesis in Three-Dimensional Cultures

  "Embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) are used to study lineage-specific differentiation in culture. We developed a standardized quantitative protocol called STEM-RET to compare eye field specification, optic cup formation, and retinal differentiation across stem cell populations. We reprogrammed individual rod photoreceptors into iPSCs by inducible expression of Oct3/4, Klf4, Sox2, and Myc. We also developed ESC lines from rods by somatic cell nuclear transfer. Using the STEM-RET protocol, we compared the abilities of ESCs, fibroblast-derived iPSCs (f-iPSCs), rod photoreceptor-derived iPSCs (r-iPSCs), and rod photoreceptorderived ESCs to form retinae using STEM-RET. r-iPSCs were the most efficient at producing differentiated retina. Retinae derived from f-iPSCs lacked an inner nuclear layer (INL) and had a concomitant reduction in amacrine cells and other INL cell populations. The INL-specific LIM homeobox gene, Lhx9, was hypermethylated in fiPSCs and concomitantly downregulated in retinae derived from those stem cells. ChIP-seq analysis for H3K36me3, H3K4me1, H3K4me3, H3K9/14Ac, H3K27me3, H3K9me3, CTCF and 5 hydroxymethyl cytosine showed that the major difference between the r-iPSCs and the f-iPSCs were in the genes marked by the CTCF insulator protein. Importantly, CTCF binding enrichment at rod photoreceptor specific genes was at least 10-fold higher in r-iPSCs relative to f-iPSCs. Taken together, our data suggest that both inhibitory and permissive epigenetic marks important for retinal development can be retained in iPSCs and such marks can be exploited to select the most favorable stem cell population to study retinal development or produce photoreceptor precursors for cell transplantation."

  Study EGAS00001001288

• Survival Benefit and Genetic Profile of Pemetrexed as Initial Chemotherapy in Selected Chinese Patients with Advanced Lung Adenocarcinoma

  We retrospectively collected patients (n=1047) enrolled in the Chinese Patient Assistance Program from multiple centers who received pemetrexed alone or combined with platinum as initial chemotherapy and continued pemetrexed maintenance therapy for advanced lung adenocarcinoma from November 2014 to June 2017. The outcomes were duration of treatment (DOT) and overall survival (OS). Clinical features were analyzed for their influence on the treatment effect and prognosis. Next-generation sequencing (NGS) was performed to identify genetic biomarkers associated with the efficacy of pemetrexed. The median DOT was 9.1 months (95% CI: 8.5-9.8), and the median OS was 26.2 months (95% CI: 24.2-28.1). OS was positively correlated with DOT (r=0.403, P<0.001). Multivariable analysis showed that smoking status and Eastern Cooperative Oncology Group (ECOG) performance status (PS) were independently associated with DOT; smoking status, ECOG PS, targeted therapy, and EGFR/ALK/ROS1 status were independently associated with OS. NGS in 22 patients with available samples showed genes with high mutation rates were: TP53 (54.5%), EGFR (50.0%), MYC (18.2%), PIK3CA (13.6%). When grouped based on progression-free survival (PFS) reported in the PARAMOUNT study, the DOT >6.9 months set was associated with PIK3CA, ALK, BRINP3, CDKN2A, CSMD3, EPHA3, KRAS, and RB1 mutations, while ERBB2 mutation was observed only in the DOT ≤6.9 months set. This study shows that initial chemotherapy with pemetrexed is an effective regimen for advanced lung adenocarcinoma in selected Chinese patients. There is no specific genetic profile predicting the benefit of pemetrexed found by NGS. Biomarkers predicting the efficacy of pemetrexed need further exploration.

  Study EGAS00001004546

• 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

• Genetic diversity and continuity of the population of the UAE

  With high consanguinity rates on the Arabian Peninsula, it would not have been unexpected if the population of the UAE was shown to be relatively homogenous. However, this study of 1,000 UAE nationals, provided a contrasting perspective, one of a relatively heterogeneous population. Located at the apex of Europe, Asia and Africa, the observed diversity could be explained by a plethora of migration patterns since the first Out-of-Africa movement. A strategy to explore the extent of genetic variation of the population of the UAE is presented. The first step involved a comprehensive population stratification study that was instructive for subsequent Whole Genome Sequencing (WGS) of suitable representatives (which is described elsewhere). When this UAE data was compared to previous smaller studies from the region, the findings were consistent with a population that is a diverse and admixed group of people. However, rather than sharp and distinctive clusters, a continuous genotype distribution was observed. The analysis showed a continuous gradient of ancestral populations, suggesting that admixture on the south eastern tip of Arabian Peninsula occurred gradually. When visualized using a unique technique that combined admixture ratios and Principal Component Analysis (PCA), unappreciated diversity was revealed while mitigating projection bias of conventional PCA. The analytical strategy used here highlights the complementary nature of data from genotype array and WGS for anthropological studies. Specifically, genotype array data was instructive to select representative subjects for WGS. Furthermore, from the 2.3 million allele frequencies obtained from genotype arrays, we identified 46,481 loci with allele frequencies that were significantly different with respect to other world populations. This comparison of allele frequencies facilitates variant prioritization in common diseases. In addition, these loci bear great potential as biomarkers in anthropological and forensic studies.

  Study EGAS00001004362