10910 results for "fc 26 coins u7buy Visit Buyfc26coins.com Megkaptam az FC 26 érméket a garantált idő előtt. Mindig bonuszként!.HNTf"

in 16.14 milliseconds.

• Assessment of cannabidiol and Δ9-tetrahydrocannabiol in mouse models of medulloblastoma

  Phytocannabinoids Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) have been demonstrated to exhibit anti-cancer activity in preclinical models of brain cancer leading to new clinical trials for adults with glioblastoma. We describe here the first report that has investigated a role for THC and CBD in paediatric brain cancer. Cannabinoids had cytotoxic activity against medulloblastoma and ependymoma cells in vitro, functioning in part through the inhibition of cell cycle progression and the induction of autophagy. Despite these effects in vitro, when tested in orthotopic mouse models of medulloblastoma or ependymoma, no impact on animal survival was observed. Furthermore, cannabinoids neither enhanced nor impaired conventional chemotherapy in a medulloblastoma mouse model. These data show that while THC and CBD do have some effects on medulloblastoma and ependymoma cells, are well tolerated and have minimal adverse effects, they do not appear to elicit any survival benefit in preclinical models of paediatric brain cancer.

  Study EGAS00001004963

• Mult-omics Palbociclib Resistance Study in HR+/HER2– Metastatic Breast Cancer

  Resistance to CDK4/6 inhibitors and endocrine therapy (ET) are common and poorly understood since they have been real game changer in patients with HR-positive and HER2-negative MBC. A comprehensive genomic and transcriptomic analysis of pre-treatment and post-treatment tumors from patients treated with palbociclib plus ET identified novel markers associated with poor prognosis such as genomic scar features caused by homologous repair deficiency (HRD), estrogen response signatures, and four unique prognostic clusters with distinct molecular features. Tumors with TP53 mutations co-occurring with a unique HRD-high cluster responded poorly. By comparing genomic and transciptomic profiles of paired samples, tumors were found to be further enriched in HRD genomic scars and many had switched to aggressive molecular subtypes. Furthermore, we identified high frequencies of acquired genomic alterations upon disease progression in RB1, ESR1, PTEN, and KMT2C. Our findings provide new insight into potential predictive biomarkers that could be targeted to overcome resistance. (NCT03401359)

  Study EGAS00001005736

• Accumulation of copy number alterations and clinical progression across advanced prostate cancer

  The burden of copy number alterations positively associated with radiologically-evident distant metastases at diagnosis (P=0.00006) and showed a non-linear relationship with clinical outcome on univariable and multivariable analysis, characterised by a sharp increase in the relative risk of progression (P=0.003) and death (P=0.045) for each unit increase, stabilising into more modest increases with higher burdens. This association between copy number burden and outcome was similar in each of the four metastatic states. Copy number loss occurred significantly more frequently than gain at the lowest copy number burden quartile (q=4.1X10-6). Loss of segments in chromosome 5q21-22 and gains at 8q21-24, respectively including CHD1 and cMYC, occurred more frequently in cases with higher copy number alteration (for either region: Kolmogorov–Smirnov distance, 0.5; adjusted P<0.0001). Copy number alterations showed variability across tumor regions in the same prostate. This variance associated with increased risk of distant metastases (Kruskal-Wallis test P=0.037).

  Study EGAS00001006251

• 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

• Metagenomic Epidemiology of Antibiotic Resistance in Infectious Diarrhea

  The study of antimicrobial resistance (AMR) in infectious diarrhea has generally been limited to cultivation, antimicrobial susceptibility testing and targeted PCR assays. When individual strains of significance are identified, whole genome shotgun (WGS) sequencing of important clones and clades is performed. Genes that encode resistance to antibiotics have been detected in environmental, insect, human and animal metagenomes and are known as "resistomes". While metagenomic datasets have been mined to characterize the healthy human gut resistome in the Human Microbiome Project and MetaHIT and in a Yanomani Amerindian cohort, directed metagenomic sequencing has not been used to examine the epidemiology of AMR. Especially in developing countries where sanitation is poor, diarrhea and enteric pathogens likely serve to disseminate antibiotic resistance elements of clinical significance. Unregulated use of antibiotics further exacerbates the problem by selection for acquisition of resistance. This is exemplified by recent reports of multiple antibiotic resistance in Shigella strains in India, in Escherichia coli in India and Pakistan, and in nontyphoidal Salmonella (NTS) in South-East Asia. We propose to use deep metagenomic sequencing and genome level assembly to study the epidemiology of AMR in stools of children suffering from diarrhea. Here the epidemiology component will be surveillance and analysis of the microbial composition (to the bacterial species/strain level where possible) and its constituent antimicrobial resistance genetic elements (such as plasmids, integrons, transposons and other mobile genetic elements, or MGEs) in samples from a cohort where diarrhea is prevalent and antibiotic exposure is endemic. The goal will be to assess whether consortia of specific mobile antimicrobial resistance elements associate with species/strains and whether their presence is enhanced or amplified in diarrheal microbiomes and in the presence of antibiotic exposure. This work could potentially identify clonal complexes of organisms and MGEs with enhanced resistance and the potential to transfer this resistance to other enteric pathogens. We have performed WGS, metagenomic assembly and gene/protein mapping to examine and characterize the types of AMR genes and transfer elements (transposons, integrons, bacteriophage, plasmids) and their distribution in bacterial species and strains assembled from DNA isolated from diarrheal and non-diarrheal stools. The samples were acquired from a cohort of pediatric patients and controls from Colombia, South America where antibiotic use is prevalent. As a control, the distribution and abundance of AMR genes can be compared to published studies where resistome gene lists from healthy cohort sequences were compiled. Our approach is more epidemiologic in nature, as we plan to identify and catalogue antimicrobial elements on MGEs capable of spread through a local population and further we will, where possible, link mobile antimicrobial resistance elements with specific strains within the population.

  Study phs001260

• Brain Arteriovenous Malformation Genetics Study

  The Predictors of Spontaneous Cerebral AVM Hemorrhage study was designed to identify genetic markers that predict adverse outcomes in brain arteriovenous malformation (BAVM) patients, examine race-ethnicity influences on BAVM hemorrhage risk, and use genome-wide association analysis to identify novel genetic predictors of AVM and hemorrhage using the Affymetrix GeneChip. We performed the first genome-wide association study (GWAS) (PMID: 26818729) of sporadic BAVM to investigate association of common single nucleotide polymorphisms (SNPs) with risk of sporadic BAVM in the international, multicenter Genetics of Arteriovenous Malformation (GEN-AVM) consortium. The study included a Caucasian discovery cohort of 515 BAVM cases and 1,191 controls genotyped using Affymetrix genome-wide SNP arrays. The Phase 1 discovery cohort comprised of 338 BAVM cases (154 male) and 504 controls genotyped using the Affymetrix Genome-Wide Human SNP Array 6.0. The molecular data (individual genetic data) for the Phase 1 discovery cohort 338 BAVM cases (self-reported Caucasian) recruited at University of California, San Francisco, or Kaiser Permanente of Northern California (KPNC) are included in the dbGaP Study Report: Brain Arteriovenous Malformation Genetics Study, with the additional BAVM case phenotypic and sample attribute characteristics: sex, race, age at BAVM diagnosis, hemorrhagic presentation, BAVM size. Written informed consent was obtained from all participants and the study was approved by the respective Institutional Review Boards. The molecular dataset for this study in dbGaP is based on the genotypes obtained for the initial set of 906,600 SNPs for cases and controls called together using Birdseed v2 algorithm in Affymetrix Genotyping Console Software. The final QC'd dataset includes 717,335 markers as SNPs with MAF<0.01 or deviating from Hardy-Weinberg equilibrium (P<0.00001) in controls were excluded. After QC, the average genotyping call rate was 99%. The discovery phase GWAS identified 57 top BAVM-associated SNPs which were tested in a replication cohort including 608 BAVM cases and 744 controls. The molecular dataset for these 338 BAVM cases was also included in a report investigating common and rare genome-wide copy number variation for association with BAVM (PMID: 24098321), which included a total sample size of 371 sporadic Caucasian BAVM cases and 563 Caucasian controls. This study identified a CNV region on 1p36.13 (NBPF1 locus) that was significantly enriched with duplications in BAVM cases compared to controls, although this association did not replicate in an independent cohort of 184 sporadic BAVM cases and 182 controls. This resource will help researchers to better understand the genetic risk factors for BAVM and/or hemorrhage. These data may be applied to examine the genetic contributions to arteriovenous malformation, stroke, and related vascular disorders and may help generate hypotheses regarding the genetics of cerebrovascular disease.

  Study phs002069

• The Genomic Landscape of Mongolian Hepatocellular Carcinoma

  Background and Hypotheses: Mongolia has the highest reported incidence of - and mortality from - hepatocellular carcinoma (HCC) in the world, which is between three and seven times higher than that observed in other high-incidence populations, such as South Korea, Thailand, and China. Although its causative factors and underlying tumor biology remain unknown, risk factors such as chronic hepatitis B virus and/or hepatitis C virus infection are highly prevalent. Moreover, Mongolia has an extraordinarily high prevalence of hepatitis delta virus (HDV), more than ten times above the global estimate, which we hypothesize as a major driver of Mongolian hepatocarcinogenesis. By performing a comprehensive and integrative genomic characterization, we aimed to identify robust molecular subclasses and driver features informative of the etiology and progression of the disease. This study, the first one of this nature ever to be conducted on a Mongolian cohort, identifies similarities to previous studies performed on other populations (which reflect general characteristics of liver carcinogenesis) as well as unique features of Mongolian HCC. Study Design and Methods: Clinical information and paired tumor/non-tumor liver tissue samples were obtained from 76 HCC patients undergoing surgery at the National Cancer Center of Mongolia. Transcriptome sequencing and whole exome sequencing were performed on all tumor and non-tumor samples, followed by bioinformatics processing and quality control. Consensus clustering and regularized Cox regression analyses were performed on transcriptome data. Driver mutations and mutational signatures were assessed. These results were compared to those from 373 HCC patients of different races and ethnicities and diverse etiologies. Furthermore, molecular subclass gene signatures from multiple previous studies were assessed for validation. Results and Conclusions: Using a transcriptomics-based unsupervised approach, we identified four molecular subclasses among Mongolian HCC cases, which were associated with different patient survival outcomes. These molecular subclasses were mapped to signatures reported in other HCC cohorts, showing significant associations consistent with survival outcomes. A supervised analysis determined risk scores strongly associated with survival, consistent with the four molecular subclasses. Mutational signature analysis using recently published COSMIC and Environmental Agents Compendia identified signatures with distinct prevalence among HDV+ and HVD- groups. Signatures differentially associated with HDV+ include mutational patterns linked to alkylating agents (such as temozolomide), tobacco chewing and exposures to 1,8-Dinitropyrene and furan, whereas HDV- appeared differentially associated with aristolochic acid II. In addition to common driver mutations (TP53, CTNNB1) frequently found in pan-cancer analysis, Mongolian HCC exhibits several unique drivers (most notably GTF2IRD2B, PNRC2, and SPTA1), the latter of which may be linked to HDV infection. These results suggest the existence of new molecular mechanisms at play in Mongolian hepatocarcinogenesis.

  Study phs002000

• NIDA Genetic Epidemiology of Opioid Dependence in Bulgaria (GEODB)

  The study was conducted in Bulgaria as a collaboration between the Molecular Medicine Center (Medical University, Sofia), the Bulgarian Addictions Institute (Sofia), the Initiative for Health Foundation (Sofia) and Washington University School of Medicine (Saint Louis, MO, USA). This is a case-population control study. Participants (N=2,499 interviews; N=1,995 with GWAS data) in our study are primarily active heroin users (78%) aged 18 and over, with a median 8.9 years of daily heroin use (minimum of 12 months). Virtually all participants (99.1%) qualified for a lifetime DSM-IV diagnosis of dependence, symptom endorsement probabilities ranging from 77% to 99.3%; and 61% endorsing all symptoms. 85% were heroin injectors and 97% reported using (or having used) heroin daily. Anonymized, population-representative control samples (no phenotypic data, N = 1,062 with GWAS data) were drawn from the MMC repository. Unlike other studies, where samples are clinically ascertained (e.g., from ORT programs), our participants are primarily untreated. PTSD, major depression, suicidality, mania, alcohol, nicotine and substance dependence (separating heroin and opioids) were assessed using the MAGIC (Todd et al., 2003, PMID: 14627881), a broad semi-structured psychiatric assessment tool with good reliability and prospective stability. The onset of (any) illicit drug use in this sample is not particularly remarkable (age~16), but the age of onset of heroin use is much lower than in the USA: 25% by age 16; 50% by age 19, with no differences between ethnicities or gender. This is consistent with findings from other studies in Bulgaria. In contrast, in 2008, SAMHSA estimated an average age of 23.4 for new heroin initiates in the USA. Further, progression from first use to regular use appears to be more rapid, with the majority of participants reporting onset of dependence problems within one year of initiation. Another unique aspect of this study population are the comparatively low levels of polysubstance use (outside of nicotine and alcohol). This early-use, fast-transition and monosubstance heroin pattern stands in sharp contrast to what is reported in many studies in the Western World. In our study, 47% of Ethnic Bulgarians and 66% of Roma used only opioids, even years after the onset of drug use. 15.4% of Ethnic Bulgarians and 66.2% of Roma reported heroin as the very first illicit drug used. Lifetime, 12.5% of Ethnic Bulgarians and 52.8% of Roma report never having used another illicit drug other than heroin more than five times. While both Roma and Ethnic Bulgarians certainly experiment with other drugs, abuse/dependence rates for these drugs are low in Ethnic Bulgarians (from 8.4% for inhalants to 28% for stimulants) and in the Roma population (from 1.3% for hallucinogens to 11.2% for stimulants).

  Study phs001804

• Heart Failure Network Aldosterone Targeted Neurohormonal Combined with Natriuresis Therapy - (HFN ATHENA-BioLINCC)

  ObjectiveTo assess whether high-dose spironolactone treatment for patients with acute heart failure lowers natriuretic peptide levels and improves outcomes better than usual care.BackgroundAcute heart failure (AHF) accounts for more than a million hospitalizations in the United States annually. The role of low-dose mineralocorticoid receptors antagonists (MRAs) therapy as a neurohormonal antagonist is well established for the treatment of chronic heart failure and reduced ejection fraction. However, the role of high-dose MRA therapy in AHF remained uncertain. A previous clinical trial suggested that the benefits of high-dose MRA therapy in AHF included lower natriuretic peptide levels, less congestion, better renal function, and less need for an intravenous diuretic. The use of intravenous loop diuretics can intensify secondary hyperaldosteronism among AHF patients, and hyperaldosteronism directly contributes to diuretic resistance in AHF. Elevated aldosterone levels in AHF are associated with an increased risk of cardiovascular mortality and HF readmission. Hospitalizations for heart failure are associated with increased risk of mortality and/or readmission.The HFN-ATHENA trial was conducted to determine if mineralocorticoid receptor antagonists administered at high doses relieved congestion, decreased diuretic resistance, and mitigated the effects of adverse neurohormonal activation in AHF.SubjectsThe ATHENA trial enrolled 360 participants. Of these, 178 participants were randomized to usual care treatment (placebo or low-dose spironolactone) and 182 participants were randomized to high-dose spironolactone.DesignThe study intervention was initiated within 24 hours of patients receiving the first dose of intravenous diuretics. Participants not taking spironolactone at enrollment were randomized to 100 mg spironolactone or a placebo. Participants taking low-dose spironolactone before their hospital admission were randomized to 100 mg or 25 mg per day in the usual care treatment arm. Prescription of all other medications, including diuretics, was left at the discretion of the treating physician. The study drug was discontinued after 96 hours and further MRA use was left to the treating physician's discretion. The primary end point was the proportional change in the log NT-proBNP levels from randomization to 96 hours (or at the hospital discharge if the discharge occurred earlier than 96 hours). Secondary endpoints included: (1) a clinical congestion score; (2) dyspnea relief; (3) daily cumulative net urine output for up to 96 hours; (4) net weight change from baseline to 96 hours or discharge (whichever came first); (5) furosemide equivalents of the loop diuretic dosage at discharge; and (6) the development of in-hospital worsening HF, with signs and symptoms requiring additional therapy.ConclusionsThere was no significant difference in the primary or secondary endpoints between the high-dose treatment arm and the usual care treatment arm.

  Study phs003506

• Pathogenesis and Immunity in Endemic Burkitt Lymphoma

  This genomic landscape of Burkitt lymphoma represents a multimodal sequencing of tumors and control tissues and individuals to better understand the etiology, and molecular pathogenesis of Burkitt lymphoma including the roles of the associated Plasmodium falciparum malaria and EBV infections. Comprehensive sequencing set includes genomic, transcriptomic, and epigenomic datasets in concert with variable clinical phenotypes and outcome information such as anatomical presentation site, in-hospital survival rates, and EBV genome type. This deposit includes additional small RNA-seq data from endemic BL (eBL) tumors and RNA-sequencing data from sorted NK cell subsets from the peripheral blood of eBL patients. The additional small RNA-seq data are from tumor specimens from 17 eBL cases, of the previously deposited polyA RNA-seq data from 28 eBL cases (phs1282.V1). The additional RNAseq data from Fluorescence-activated cell sorting (FACS) of NK cell subsets, isolated from the peripheral blood of 7 eBL cases. The additional RNAseq data are from eBL tumor samples of 5 eBL cases, BL cell lines established from these tumor samples and also NSG mouse tumors created by implanting the established BL cell lines into NSG mice. The dataset also includes RNAseq data of the NSG mouse tumors after treatment with Rituximab (RIT) and Phosphate buffered saline (PBS). The fifth batch of data includes mRNA-seq from different passages of a single eBL cell line that have variable EBV phenotypes (low passage with lytic EBV and high passage with latent EBV). This batch also includes lytic and latent lymphoblastoid cell line (LCL) clones from a single blood donor generated through infection with the strain of EBV isolated from the aforementioned eBL cell line. For initial transcriptome analysis see: Kaymaz et al. "Comprehensive Transcriptome and Mutational Profiling of Endemic Burkitt Lymphoma Reveals EBV Type-specific Difference." Molecular Cancer Research, 2017, PMID: 28465297. For initial microRNA analysis see: Oduor et al. "Human and Epstein-Barr Virus miRNA Profiling as Predictive Biomarkers for Endemic Burkitt Lymphoma." Frontiers in Microbiology 8, 2017, PMID: 28400759. For initial NK subsets RNA expression analysis see: Forconi et al. "A new hope for CD56negCD16pos NK cells as unconventional cytotoxic mediators: an adaptation to chronic diseases." Frontiers in Cellular and Infection Microbiology, 2020, PMID: 32373555.For initial eBL cell line and mouse avatar RNA expression analysis see: Saikumar et al. "Endemic Burkitt lymphoma avatar mouse models for exploring inter-patient tumor variation and testing targeted therapies." Life Science Alliance, 2023, PMID: 36878637. For general overview of cohort study see: Buckle et al. "Factors influencing survival among Kenyan children diagnosed with endemic Burkitt lymphoma between 2003 and 2011: A historical cohort study." Int J Cancer. 15:1231, 2016, PMID: 27136063.

  Study phs001282