Elevated neutrophil to lymphocyte ratio (NLR) has been reported as a marker for chronic inflammation, associated with poor prognosis in ischemic stroke patients, but there has been no study that investigated its association with ischemic stroke risk. This study was conducted to investigate elevated NLR as an independent risk factor for ischemic stroke incidence. Our retrospective cohort study included 24,708 generally healthy subjects aged 30–75 who received self-referred health screening at Seoul National University Hospital. Data on ischemic stroke incidence was retrieved from national medical claims registry. Median follow-up time was 5.9 years (interquartile range 4.2 years). Adjusted for major cardiovascular risk factors, compared to subjects with NLR<1.5, subjects with 2.5≤NLR<3.0, 3.0≤NLR<3.5, and NLR≥3.5 had elevated risk for ischemic stroke incidence with aHR (95% CI) of 1.76 (1.09–2.84), 2.21 (1.21–4.04), and 2.96 (1.57–5.58), respectively. NLR showed significant improvement in discrimination for ischemic stroke incidence compared to traditional cardiovascular risk factors (C-index 0.748 vs. 0.739, P = 0.025). There was significant net improvement in reclassification in Framingham risk for ischemic stroke incidence after addition of NLR, with IDI 0.0035 (P<0.0001), and NRI 6.02% (P = 0.0015). This reclassification for ischemic stroke incidence by NLR was markedly pronounced among subjects with atrial fibrillation with CHA2DS2-VASc<2 (NRI 42.41%, P = 0.056). Our study suggests elevated NLR to be an independent risk factor for ischemic stroke incidence in generally healthy adults. Future studies are needed to validate our results and further assess how subjects with elevated NLR should be managed within current guidelines.
Zeta-chain associated protein kinase-70 (Zap70), a Syk family tyrosine kinase, has been reported to be present exclusively in normal T cells, Natural Killer (NK) cells, and B cells, serving as a pivotal regulator of antigen-mediated receptor signaling and development. In this study, we report that Zap70 is expressed in undifferentiated mouse embryonic stem cells (mESCs) and may critically regulate self-renewal and pluripotency in mESCs. We found that Zap70 knocked-down mESCs (Zap70KD) show sustained self-renewal and defective differentiation. In addition, we present evidence that the sustained self-renewal in Zap70KD is associated with enhanced Jak/Stat3 signaling and c-Myc induction. These altered signaling appears to result from up-regulated LIFR and down-regulated SHP-1 phosphatase activity. Based on these results, we propose that, in undifferentiated mESCs, Zap70 plays important roles in modulating the balance between self-renewal capacity and pluripotent differentiation ability as a key regulator of the Jak/Stat3/c-Myc signaling pathway.
The therapeutic potential of human embryonic stem cells (hESCs) has long been appreciated, and the recent FDA approval of hESC derivatives for cell-based therapy encourages the clinical application of hESCs. Here, using CHA3-hESCs with normal and abnormal karyotypes, we report the importance of maintaining normal chromosomes during in vitro culture and the differentiation of hESCs for minimization of posttransplantation complications. We found that undifferentiated CHA3-hESCs with trisomy chromosome 12 undergo abnormal cell division with multiple spindles in comparison to the bipolar cell division of the karyotypically normal CHA3-hESCs. Transplanted karyotypically abnormal CHA3-hESC derivatives formed a tumor-like tissue 6weeks after transplantation in two out of seven mice tested. Our results demonstrate that the preservation of normal chromosomes is indispensable for maintaining the true properties of hESCs in vitro and abolishing adverse effects posttransplantation. Thus, the development of optimized techniques for stabilizing the chromosome state during in vitro hESC culture is a prerequisite for the therapeutic application of hESCs.
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