1567 results for "Sweden+NDA+enforceability+one+party+signed"

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• Heart Failure Network - Effectiveness of Ultrafiltration in Treating People with Acute Decompensated Heart Failure and Cardiorenal Syndrome (HFN CARRESS - BioLINCC)

  ObjectiveThe CARRESS trial examined the effectiveness of ultrafiltration compared with a strategy of diuretic-based stepped pharmacologic therapy on renal function and weight loss in patients with heart failure who have worsening renal function and persistent congestion.BackgroundAcute cardiorenal syndrome is defined as worsening renal function in patients with acute decompensated heart failure. It occurs in 25 to 33% of patients and is associated with poor outcomes. Current heart failure treatments focus on removing excess fluid buildup, however administration of intravenous diuretics may contribute to worsening renal function. Venovenous ultrafiltration is one alternative therapy that may be effective in patients with acute decompensated heart failure complicated by acute cardiorenal syndrome and persistent congestionSubjectsA total of 188 patients were randomized.DesignHospitalized subjects were randomly assigned to receive either ultrafiltration therapy or pharmacologic therapy. Ultrafiltration was performed at a fluid-removal rate of 200 ml per hour and loop diuretics were discontinued for the duration of the intervention. The addition of intravenous vasodilators or positive inotropic agents was prohibited, unless they were deemed to be necessary as rescue therapy. Patients assigned to stepped pharmacologic therapy received intravenous diuretics to manage congestion and maintain a urine output of 3 to 5 liters per day. In both groups, the assigned treatment strategy was to be continued until the signs and symptoms of congestion in the patient were reduced as much as possible. The primary end points were baseline changes in serum creatinine and weight as assessed at 96 hours after treatment assignment.ConclusionsThe use of a stepped pharmacologic-therapy algorithm was superior to a strategy of ultrafiltration for the preservation of renal function, and there was a similar amount of weight loss between the two groups. Ultrafiltration was associated with a higher rate of adverse events (Bart, et al., 2012, PMID: 23131078).

  Study phs003510

• Structure and Diversity of Urinary Cell-Free DNA Informative of Host-Pathogen Interactions in Human Urinary Tract Infection

  The risk of acquiring urinary tract infection (UTI) is very high for patients who have received kidney transplants; nearly half will develop bacteriuria and an eighth viruria via BK polyomavirus in the first three years following transplantation. Current methodology for diagnosing viral and bacterial infections, while well practiced, is often limited in scope. The advent of next generation sequencing of cell-free DNA has shown promise in its ability to capture multiple perspectives of human health from discovering the origin of cell-free DNA in plasma; such a diagnostic has not been readily applied to urinary cell-free DNA. In this study, we selected 141 urine samples from a cohort of kidney transplant patients, which were collected and stored at Weill Cornell Medical College - New York Presbyterian Hospital. Of these samples, 43 samples were determined to be culture positive (> 10,000 CFU) for one or more bacterial species, including E. coli, Enterococcus, Klebsiella, Haemophilus, and Raoultella. A separate 23 samples were confirmed for BK virus nephropathy, with presence of BK polyomavirus confirmed via qPCR. We also included 29 samples from 14 patients who did not develop UTIs in the first three months following transplantation, and 11 samples that were negative for BK virus nephropathy. For a full description of samples, please see the Supplementary Data 1 in https://pubmed.ncbi.nlm.nih.gov/29925834/. From these urine samples, we aimed to capture and sequence urinary cell-free DNA using a single-stranded library preparation. In addition, we performed whole-genome bisulfite sequencing to 170 plasma samples collected from 27 hematopoietic cell transplant patients who developed graft-versus host disease and BK polyomavirus infection. We also performed Sample-Intrinsic microbial DNA Found by Tagging and sequencing (SIFT-seq) on 196 cell-free DNA (cfDNA) samples (154 plasma and 42 urine) collected from five groups of subjects. For a full description of samples, please see publications in PMID: 35864089 and PMID: 35058359.

  Study phs001564

• Integrating molecular imaging and transcriptomic profiling in advanced HER2-positive breast cancer receiving trastuzumab emtansine (T-DM1): an analysis of the ZEPHIR clinical trial

  Purpose: The ZEPHIR clinical trial evaluated the role of [89Zr]trastuzumab-PET/CT (HER2-PET/CT) and 2-[18F]fluoro-2-deoxy-D-glucose PET/CT ([18F]FDG-PET/CT) in predicting outcomes in patients with advanced HER2-positive breast cancer treated with trastuzumab emtansine (T-DM1). Here, we combined molecular/metabolic imaging and transcriptomic data to investigate the biological processes associated with [89Zr]trastuzumab and [18F]FDG uptake, and to dissect the mechanisms involved in T-DM1 resistance. Experimental design: RNA was extracted from metastasis biopsies obtained at study inclusion in the ZEPHIR trial. HER2-PET/CT and [18F]FDG-PET/CT imaging data of biopsied lesions were integrated with RNA sequencing data. Lesions were compared based on the level of [89Zr]trastuzumab uptake (dichotomized into high/low classes) as well as on the presence/absence of metabolic response, defined comparing baseline and on-treatment [18F]FDG-PET/CT. Results: We analyzed matched transcriptomic and molecular/metabolic imaging data for 24 metastases (one lesion/patient). Pathways involved in extracellular matrix (ECM) organization, glycosylphosphatidylinositol synthesis, and collagen formation were enriched in lesions presenting low [89Zr]trastuzumab uptake. [18F]FDG uptake at baseline correlated with proliferation and immune-related processes. Hypoxia and ECM-related processes were enriched in lesions that showed no metabolic response to T-DM1. Interestingly, immune-related processes (e.g., Fc gamma receptor activation, complement cascade) were associated with high [89Zr]trastuzumab uptake and metabolic response. Conclusions: To our knowledge, this study represents the first correlative analysis between [89Zr]trastuzumab tumor uptake and gene expression profiling in humans. Our findings point toward a role of ECM in impairing [89Zr]trastuzumab tumor uptake and T-DM1 metabolic response in advanced HER2-positive breast cancer, and highlight the potential of molecular imaging to depict tumor microenvironment features.

  Study EGAS50000000470

• Genomic Profiling of Pediatric Tumors by Cell Free DNA Sequencing

  BACKGROUND Analysis of cell-free DNA (cfDNA) from peripheral blood has been studied extensively for detection and monitoring therapy response in adult cancers, but utility in pediatric tumors is unclear. METHODS We studied 233 children with hematologic, solid and brain tumors. cfDNA was extracted from 1 mL of plasma collected at diagnosis. Circulating tumor DNA (ctDNA) in cfDNA was quantified and diverse classes of somatic genomic variants were detected using PeCan-Seq. PeCan-Seq findings were compared with matched tumor whole-genome and whole-exome sequencing data. Minimal residual disease (MRD) status was evaluated by cfDNA PeCan-Seq in 14 patients with B-cell acute lymphoblastic leukemia. RESULTS Plasma cfDNA yields at diagnosis were higher for hematologic malignancies than for solid and brain tumors. Patients with hematologic malignancy were 100% ctDNA-positive, the median ctDNA fraction in cfDNA was 0.77. We detected 97% variants that were present in tumors and covered by the capture panel, and 50 subclonal variants that were present in cfDNA only. Our approach enabled detection of sequence and structural variants in B-ALL ctDNA at varying levels of MRD. Nineteen of 38 patients with solid tumors were ctDNA-positive, with high prevalence in Ewing Sarcoma, liver tumors and osteosarcoma. One of 19 brain tumor patients was ct-DNA positive, indicating lack of utility for plasma-derived cfDNA in this disease. Notably, cfDNA analysis of a single plasma sample identified genomic features in ctDNA derived from B-ALL, concurrent primary neuroblastoma, and a later neuroblastoma relapse, indicating that genomic variations from multiple tumors could be detected simultaneously. CONCLUSIONS Pediatric patients with hematologic malignancy had an abundance of plasma ctDNA at diagnosis. Plasma ctDNA levels varied between different solid tumor types, more studies are needed to determine utility. Panel-based cfDNA sequencing could serve as a non-invasive approach for pediatric cancer diagnosis and disease monitoring.

  Study EGAS50000000072

• Precision High Intensity Training Through Epigenetics (PHITE)

  Exercising regularly promotes health, but these benefits are complicated by acute inflammation induced by exercise. A potential source of exercise-induced inflammation is cell-free DNA (cfDNA), yet the cellular origins, molecular causes, and immune system interactions of exercise-induced cfDNA are unclear. To study these, 10 healthy individuals were randomized to a 12-week exercise program of either high-intensity tactical training (HITT) or traditional moderate-intensity training (TRAD). Blood plasma was collected pre- and post exercise at weeks 0 and 12 and after 4 week of detraining upon program completion. Whole-genome enzymatic methylation sequencing (EM-seq) with cell-type proportion deconvolution was applied to cfDNA obtained from the 50 plasma samples and paired to concentration measurements for 90 circulating cytokines. Acute exercise increased the release of cfDNA from neutrophils, dendritic cells (DCs), and macrophages proportional to exercise intensity (HITT > TRAD). Exercise training reduced cfDNA released in HITT participants but not TRAD and from DCs and macrophages but not neutrophils. For most participants, training lowered mitochondrial cfDNA at rest, even after detraining. Using a sequencing analysis approach we developed, we concluded that rapid extracellular traps (ETosis) was the likely source of cfDNA, demonstrated by enrichment of nuclear DNA. Further, several cytokines were induced by acute exercise, such as IL-6, IL-10, and IL-16, and training attenuated the induction of only IL-6 and IL-17F. Cytokine levels were not associated with cfDNA induction, suggesting that these cytokines are not the main cause of exercise-induced cfDNA. Overall, exercise intensity and training modulated cfDNA release and cytokine responses, contributing to the anti-inflammatory effects of regular exercise. One additional subject was also used in the methyl-seq data as a control for comparing bisulfite-sequencing to enzymatic methyl sequencing. DNA methylation for MPO gene was found to be significantly different as well, in line with interpretation that neutrophils are primarily undergoing ETosis.

  Study phs003873

• Emirati Genome Project subset of 43,608 WGS samples for population-scale variant discovery and allele frequency mapping.

  Here, we present a comprehensive genomic characterization of a cohort of 43,608 Emirati genomes sequenced as part of the Emirati Genome Program (EGP). This study identified more than 421 million single nucleotide variants and indels and more than 600 million copy number- and structural variants. Small variants had 756 million molecular effects annotated. Of the identified variants, 69.04% were observed with more than one allele. Of 7.7 million polymorphic variants having an allele frequency (AF) of more than 5% in EGP, 1,348 have a predicted deleterious effect on a protein. Characterization of global variation reveals that EGP represents a genetic continuum encompassing the range of African, Asian, and European populations. It is best described by two Arabian, an Eurasian, and an African component, with the predominant Arabian component linked to mitochondrial haplogroups J and T, which are commonly attributed to the Middle East. Various aneuploidies of sex chromosomes were detected in 93 individuals overall and of chromosome 21 in 41 individuals. The median inbreeding coefficient and cumulative runs of homozygosity (ROHs) lengths were increased due to extensive consanguinity, being largest in the groups with Arabian main ancestry components and higher than reported for Qatar. Families were identified based on genetic relatedness and classified into 264 families with unrelated parents and 247 families with third- and fourth-degree consanguineous parents. Representative consanguineous pedigrees of families in EGP were outlined. Cumulative ROHs were affected by the main ancestry component and significantly increased in offspring of consanguineous parents, with a pronounced difference between 3rd and 4th-degree relatedness. Investigation of cumulative AFs of variants causing Mendelian diseases highlighted genes related to alpha- and beta-thalassemia (HBB, HBA2). It showed a high burden of variants causing severe recessive diseases, metabolic and retinal disorders, and hearing loss. In summary, EGP represents a landmark effort in characterizing the genetic diversity of the Emirati population, leveraging the largest Middle Eastern cohort reported to date.

  Study EGAS50000001071

• Gene expression signatures associated with chronic endometritis revealed by RNA sequencing

  Chronic endometritis (CE) is a persistent inflammatory condition of the endometrium characterized by the infiltration of plasma cells. CD138 immunohistochemistry is considered to improve the CE diagnosis rate. Using the number of CD138-positive cells equal or greater than five as a diagnostic criterion for CE, we identified 24 CE and 33 non-CE cases among women with infertility. We conducted RNA-sequencing analysis for these 57 cases in total as an attempt to elucidate the molecular pathogenesis of CE and to search for new biomarkers for CE. By comparing CE and non-CE groups, we identified 20 genes upregulated in the endometria of CE patients, including 12 immunoglobulin-related genes and eight non-immunoglobulin genes as differentially expressed genes. The eight genes were MUC5AC, LTF, CAPN9, MESP1, ACSM1, TVP23A, ALOX15, and MZB1. By analyzing samples in the proliferative and secretory phases of the menstrual cycle separately, we also identified four additional non-immunoglobulin genes upregulated in CE endometria: CCDC13 by comparing the samples in the proliferative phase, and OVGP1, MTUS2, and CLIC6 by comparing the samples in the secretory phase. Although the genes upregulated in CE may serve as novel diagnostic markers of CE, many of them were upregulated only in a limited number of CE cases showing an extremely high number of CD138-positive cells near or over one hundred. Exceptionally, TVP23A was upregulated in the majority of CE cases regardless of the number of CD138-positive cells. The upregulation of TVP23A in the endometria of CE cases may reflect the pathophysiology of a cell-type or cell-types intrinsic to the endometrium rather than the accumulation of plasma cells. Our data, consisting of clinical and transcriptomic information for CE and non-CE cases, helped us identify gene expression signatures associated with CE.

  Study JGAS000621

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

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

  Study JGAS000022

• Na?ve Treg-specific genomic DNA hypomethylation for autoimmune disease susceptibility

  Naturally occurring regulatory T (Treg) cells, which are specifically expressing the transcription factor FOXP3, CD25 and CTLA-4, are indispensable for the maintenance of immunological self-tolerance and homeostasis. Mutations of the FOXP3, CD25 and CTLA4 genes compromise the function of natural FOXP3+CD25+CD4+ Treg cells and cause severe autoimmune diseases showing Mendelian inheritance. Also, altered Treg-specific epigenetic changes, such as DNA hypomethylation and enhancer activation, impair the expression of these molecules in developing Treg cells, causing autoimmune diseases. It is obscure, however, whether Treg cells significantly contribute to the development of polygenic common autoimmune diseases (such as type 1 diabetes and rheumatoid arthritis), which afflict ~10% of the population. Recent genome-wide association study (GWAS) of common autoimmune diseases has revealed many autoimmune disease-associated single nucleotide polymorphisms (SNPs) in enhancer regions of immune cells, for example, in non-coding regions of T cell activation-associated genes such as CD25 and CTLA4. These findings, especially the involvement of common T-cell genes in the functions of both Treg cells and effector T cells, prompt one to ask whether autoimmune disease-associated causative SNPs impact on the functions of either disease-causing effector T cells or disease-suppressing Treg cells. Here, we have explored epigenetic profiles of human Treg and conventional T (Tconv) cells in na?ve or activated states, and found that autoimmune disease-associated SNPs are predominantly enriched in Treg-specific CpG demethylated regions (Treg-DRs), which were mostly included in Treg-specific super-enhancers. Treg-DRs are developmentally established in na?ve Treg cells before antigenic stimulation, distinct from activation-induced CpG hypomethylation in Treg or Tconv cells, and highly associated with Treg cell-specific transcriptional and epigenetic changes. Taken together, genetic variants affecting endogenous development of natural Treg cells and their Treg-intrinsic functions are causative of common autoimmune diseases, indicating natural Treg cells as a key target for their treatment and prevention.

  Study JGAS000145

• After the completion of CINECA, EUCANCan, and euCanSHare. What's next?

  CINECA, EUCANCan, and euCanSHare were part of the EUCAN Cluster, made up of six projects that received funding under the same Horizon 2020 call. All EUCAN projects (CINECA, EUCANCan, EUCAN-Connect, euCanSHare, Receptor Plus, and ReCoDID) were aimed at facilitating data reuse and knowledge discovery by enhancing data exchange and long-term collaboration in the health field. Here are some highlights about EGA’s contribution to these projects. CINECA: advances in Federated discovery and infrastructure for cohorts CINECA (Common Infrastructure for National Cohorts in Europe, Canada, and Africa) developed a federated cloud-based infrastructure for making genomic and biomolecular data accessible. The project has assembled a virtual cohort of 1.4 million individuals from sources such as the EGA, CanDIG and H3Africa. The EGA–CRG co-leaded a work package Work Package 1 on Federated Data Discovery and Querying. Beacon v2, championed by Jordi Rambla and Lauren Fromont, has been one of the central elements for the discovery of human genetic and phenotypic data. The EGA-CRG contributed to the development of a model for cohort discovery inside the Beacon v2 model. The team also delivered a Discovery Portal was implemented to explore cohorts and individuals of synthetic data. It is a UI that gathers a network of Beacons, a service for query expansion, and a visualisation tool. Have a look at the Discovery Portal UI, gathering a network of Beacons. You will find entities such as the Barcelona Supercomputing Center (BSC), BioData.pt and the European Genomic Data Infrastructure (GDI), among others. euCanSHare: facilitation of data access management This joint EU-Canada project aimed to build a European and Canadian FAIR platform for cardiovascular data sharing and analysis. The EGA’s tasks contributed to the development of the data management plan and data flows, main web-portal and interoperability protocols. An important part of the EuCanShare platform is the data access manager, a tool for the data owners to control the access to their sensitive datasets. We built a user-friendly interface for data access committees (data owners) to easily manage their data requests and access credentials. The data access portal facilitates the creation and internal organization of the data access committees as well as the linkage of data usage conditions to specific datasets. The interface includes filters for browsing requests and page to visualize the request history helping with the handling of data access requests. EUCANCan: toward a federation of clinical institutions in oncology The EUropean-CAnadian CANcer Network worked towards building a federated network to advance personalized medicine in oncology, by promoting the standard analysis, management and sharing of harmonized genomic and phenotypic data. The EGA led tasks on defining data flows and preparing an adapted infrastructure for long-term data storage and sharing. One of the key contributions was the conception of the EGA communities, offering standard and interoperable solutions for data discovery, processing, and sharing to projects and institutions that would like to manage and share data in the context of the EGA ecosystem. What's Next? The participation in projects such as CINECA, EUCANCan, and euCanSHare provide us with experience for future projects. We are happy to enhance data sharing and reuse, vital for advancing clinical and genomic research. The Discovery Portal is a wonderful proof of concept for the Beacon network. Next, we will finalise both the network and the user interface, and make sure it can be applied to more clinically-centred settings like hospitals. Most data hosted at the EGA are about cancer research. Currently, we contribute to building tools and infrastructure to empower oncology research in several European projects such as EUCAIM, EUCANIMAGE and EOSC4Cancer. We also do not lose sight of initiatives in the field such as the International Cancer Genome Consortium (ICGC) with the project ARGO, whose data model was adopted in EUCanCan.

  Blog cineca-eucancan-and-eucanshare-were-concluded-in-june