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miR-26a-5p Protects In opposition to Drug-induced Liver Injury via Targeting Put money.
Blockade antibodies of the immunoinhibitory receptor PD-1 can stimulate the anti-tumor activity of T cells, but clinical benefit is limited to a fraction of patients. Evidence suggests that BTLA, a receptor structurally related to PD-1, may contribute to resistance to PD-1 targeted therapy, but how BTLA and PD-1 differ in their mechanisms is debated. Here, we compared the abilities of BTLA and PD-1 to recruit effector molecules and to regulate T cell signaling. While PD-1 selectively recruited SHP2 over the stronger phosphatase SHP1, BTLA preferentially recruited SHP1 to more efficiently suppress T cell signaling. Contrary to the dominant view that PD-1 and BTLA signal exclusively through SHP1/2, we found that in SHP1/2 double-deficient primary T cells, PD-1 and BTLA still potently inhibited cell proliferation and cytokine production, albeit more transiently than in wild type T cells. Thus, PD-1 and BTLA can suppress T cell signaling through a mechanism independent of both SHP1 and SHP2.Importance Clinical outcomes for glioblastoma remain poor. Treatment with immune checkpoint blockade has shown benefits in many cancer types. To our knowledge, data from a randomized phase 3 clinical trial evaluating a programmed death-1 (PD-1) inhibitor therapy for glioblastoma have not been reported. Objective To determine whether single-agent PD-1 blockade with nivolumab improves survival in patients with recurrent glioblastoma compared with bevacizumab. Design, setting, and participants In this open-label, randomized, phase 3 clinical trial, 439 patients with glioblastoma at first recurrence following standard radiation and temozolomide therapy were enrolled, and 369 were randomized. Patients were enrolled between September 2014 and May 2015. The median follow-up was 9.5 months at data cutoff of January 20, 2017. The study included 57 multicenter, multinational clinical sites. Interventions Patients were randomized 11 to nivolumab 3 mg/kg or bevacizumab 10 mg/kg every 2 weeks until confirmed disease progrce Although the primary end point was not met in this randomized clinical trial, mOS was comparable between nivolumab and bevacizumab in the overall patient population with recurrent glioblastoma. The safety profile of nivolumab in patients with glioblastoma was consistent with that in other tumor types. Trial registration ClinicalTrials.gov Identifier NCT02017717.Importance There is substantial socioeconomic and individual burden from uncorrected refractive error (URE) and chronic ocular disease. Understanding the association of visual acuity (VA) reduction with URE and the adults most likely to benefit from refraction may help support clinical decision-making in ophthalmologic care and maximize patient outcomes. Objectives To assess the magnitude of VA improvement associated with URE among adults under ophthalmic care who obtain low vision rehabilitation (LVR) services and identify the characteristics of the patients who are most likely to experience improvement. Design, setting, and participants This retrospective case series assessed patients 20 years or older who were new to the LVR clinics from August 1, 2013, to December 31, 2015, and who had habitual VA between 20/40 and counting fingers (not including) and underwent refraction. Data analysis was performed from April 4, 2018, to December 20, 2019. Exposures Patient demographics and clinical data, including habiared with white patients (OR, 1.41; 95% CI, 1.08-1.85), or patients with moderate VI compared with mild VI (OR, 1.36; 95% CI, 1.07-1.72). Conclusions and relevance The findings suggest that URE is prevalent among patients with ocular disease and accessing LVR and that refractive evaluation should be considered for patients with ocular disease and reduced VA, especially working-age adults aged 40 to less then 65 years, African American patients, and those with moderate VI.Autophagy degrades cytoplasmic cargo by its delivery to lysosomes within double membrane autophagosomes. Synthesis of the phosphoinositide PI(3)P by the autophagic class III phosphatidylinositol-3 kinase complex I (PI3KC3-C1) and conjugation of ATG8/LC3 proteins to phagophore membranes by the ATG12-ATG5-ATG16L1 (E3) complex are two critical steps in autophagosome biogenesis, connected by WIPI2. Here, we present a complete reconstitution of these events. On giant unilamellar vesicles (GUVs), LC3 lipidation is strictly dependent on the recruitment of WIPI2 that in turn depends on PI(3)P. Ectopically targeting E3 to membranes in the absence of WIPI2 is insufficient to support LC3 lipidation, demonstrating that WIPI2 allosterically activates the E3 complex. PI3KC3-C1 and WIPI2 mutually promote the recruitment of each other in a positive feedback loop. When both PI 3-kinase and LC3 lipidation reactions were performed simultaneously, positive feedback between PI3KC3-C1 and WIPI2 led to rapid LC3 lipidation with kinetics similar to that seen in cellular autophagosome formation.Importance The Merit-Based Incentive Payment System (MIPS) for Medicare is the largest pay-for-performance program in the history of health care. Although the Centers for Medicare & Medicaid Services (CMS) launched the MIPS in 2017, the participation and performance of otolaryngologists in this program remain unclear. Objective To characterize otolaryngologist participation and performance in the MIPS in 2017. Design, setting, and participants Retrospective cross-sectional analysis of otolaryngologist participation and performance in the MIPS from January 1 through December 31, 2017, using the publicly available CMS Physician Compare 2017 eligible clinician public reporting database. Main outcomes and measures The number and proportion of active otolaryngologists who participated in the MIPS in 2017 were determined. Overall 2017 MIPS payment adjustments received by participants were determined and stratified by reporting affiliation (individual, group, or alternative payment model [APM]). Payment adjustments tional performance, fewer than 70% of otolaryngologists reporting data as individuals (1124 of 1990 [56.5%]) or groups (2050 of 3033 [67.6%]) earned such bonuses. Of note, nearly all otolaryngologists incurring penalties (658 of 672 [97.9%]) were affiliated with groups. Conclusions and relevance Most otolaryngologists participating in the 2017 MIPS received performance bonuses, although variation exists within the field. check details As CMS continues to reform the MIPS and raise performance thresholds, otolaryngologists should consider adopting measures to succeed in the era of value-based care.
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