Abstract Although numerous genetic variants affecting aging and mortality have been identified, for example, apolipoprotein E ε4, the genetic component influencing cognitive aging has not been fully ...defined yet. A better knowledge of the genetics of aging will prove helpful in understanding the underlying biological processes. Here, we describe the whole genome sequences of 2 female octogenarians. We provide the repertoire of genomic variants that the 2 octogenarians have in common. We also describe the overlap with the previously reported genomes of 2 supercentenarians—individuals aged ≥110 years. We assessed the genetic disease propensities of the octogenarians and non-aged control genomes and could not find support for the hypothesis that long-lived healthy individuals might exhibit greater genetic fitness than the general population. Furthermore, there is no evidence for an accumulation of previously described variants promoting longevity in the 2 octogenarians. These findings suggest that genetic fitness, as currently defined, is not the sole factor enabling an increased life span. We identified a number of healthy-cognitive-aging candidate genetic loci awaiting confirmation in larger studies.
Cerebral palsy (CP) is a group of nonprogressive disorders of movement and posture caused by abnormal development of, or damage to, motor control centers of the brain. A single nucleotide ...polymorphism (SNP), rs1800795, in the promoter region of the interleukin-6 (IL6) gene has been implicated in the pathogenesis of CP by mediating IL-6 protein levels in amniotic fluid and cord plasma and within brain lesions. This SNP has been associated with other neurological, vascular, and malignant processes as well, often as part of a haplotype block.
To refine the regional genetic association with CP, we sequenced (Sanger) the IL6 gene and part of the promoter region in 250 infants with CP and 305 controls.
We identified a haplotype of 7 SNPs that includes rs1800795. In a recessive model of inheritance, the variant haplotype conferred greater risk (OR = 4.3, CI = 2.0-10.1, p = 0.00007) than did the lone variant at rs1800795 (OR = 2.5, CI = 1.4-4.6, p = 0.002). The risk haplotype contains one SNP (rs2069845, CI = 1.2-4.3, OR = 2.3, p = 0.009) that disrupts a methylation site.
The risk haplotype identified in this study overlaps with previously identified haplotypes that include additional promoter SNPs. A risk haplotype at the IL6 gene likely confers risk to CP, and perhaps other diseases, via a multi-factorial mechanism.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract Microglia phagocytic activity for apoptotic glioma cells is hardly analysed inspite of its relevance to tissue damage prevention. We provide evidence for a phosphatidylserine-independent ...clearance of mouse glioma cells at an advanced stage of death, suggesting microglia recognition of late apoptotic markers. Dying cells were immediately cleared or stayed for hours in that stage before engulfment occurred. This phagocytic activity was restricted to a microglia subset representing 30 to 70% of the population according to the used strain. Expression of receptors involved in late apoptotic markers recognition therefore seems confined to a subpopulation of microglia and to be strain-dependent.
BackgroundAtezolizumab (anti-PD-L1) has demonstrated robust clinical activity in UBC 1. Elevated PD-L1 expression on tumor-infiltrating immune cells (IC) is associated with increased clinical ...efficacy; however, the contribution of other immune biomarkers is unknown. In this study, we explored tumor-based and circulating biomarkers and their correlation with clinical benefit in atezolizumab-treated patients with UBC.MethodsPatients from the UBC cohort (n = 92) of the Phase Ia atezolizumab trial PCD4989g (NCT01375842) served as source population for tumor specimens, plasma and PBMC. Baseline tumor PD-L1 expression was assessed by immunohistochemistry using the SP142 antibody assay optimized to detect PD-L1 on both tumor cells (TC) and IC. RNA gene expression on tumor and PBMC samples was interrogated with a NanoString panel of 800 immune and cancer genes. Sequential blood draws assessed dynamic changes in circulating immune biomarkers in plasma (RBM, Multi-Analyte Platform). Correlation between biomarker expression and 6-month progression-free survival (PFS; as a measure of clinical benefit) was assessed.ResultsBaseline gene expression in tumors revealed an effector T cell signature (including CD8A, GZMA, IFNG) and NK gene signature (NKG2 family members) associated with clinical benefit. In contrast, disease progression was associated with either a concomitant presence of the immune signature and an opposing stromal signature (PDPN, COL5A1, etc) or the absence of both signatures. Expression of T cell effector and immune checkpoint genes (CTLA4, PD-1, TIGIT, LAG3) correlated with PD-L1 expression on IC but not TC. Increased expression of myeloid-derived cytokines (IL-6 and IL-8) in the plasma was associated with lack of clinical benefit. Moreover, on-treatment sampling revealed an increased plasma HCG, CA15-3 and TIMP-1 to be correlated with disease progression. Immune biomarkers associated with PBMC, as well as tumor biomarkers associated with various tumor subtypes, will also be discussed.ConclusionsOur findings indicate that clinical benefit (as defined by 6-month PFS) from atezolizumab is influenced by a pre-existing CD8+ effector T cell and NK cytolytic gene signature in the tumor, which correlated with IC PD-L1 expression. Increased stromal and myeloid-derived cytokine expression in tumor and plasma, respectively, were associated with lack of clinical benefit, underscoring the complex interplay among immunological components in UBC. These components may be conceivable targets to overcome potential resistance and promote response to atezolizumab.ClinicalTrials.gov Identifier: NCT01375842
Provider: - Institution: - Data provided by Europeana Collections- Heidelberg, Univ., Diss., 2010- All metadata published by Europeana are available free of restriction under the Creative Commons CC0 ...1.0 Universal Public Domain Dedication. However, Europeana requests that you actively acknowledge and give attribution to all metadata sources including Europeana
PDF
