Allredmckinley0757

PURPOSE Malignant peripheral nerve sheath tumors (MPNSTs) are deadly sarcomas that lack effective therapies. In most MPNSTs, the retinoblastoma (RB1) tumor suppressor is disabled by hyperactivation of cyclin dependent kinases (CDKs), commonly through loss of CDK inhibitory proteins such as p27(Kip1). RABL6A is an inhibitor of RB1 whose role in MPNSTs is unknown. see more To gain insight into MPNST development and establish new treatment options, we investigated RABL6A-RB1 signaling and CDK inhibitor-based therapy in MPNSTs. EXPERIMENTAL DESIGN We examined patient-matched MPNSTs and precursor lesions by RNA-Seq and IHC. Molecular and biological effects of silencing RABL6A and/or p27 in MPNST lines and normal human Schwann cells were determined. Tumor suppressive effects of CDK inhibitors were measured in MPNST cells and orthotopic tumors. RESULTS RABL6A was dramatically upregulated in human MPNSTs compared to precursor lesions, which correlated inversely with p27 levels. Silencing RABL6A caused MPNST cell death and G1 arrest that coincided with p27 upregulation, CDK downregulation and RB1 activation. The growth suppressive effects of RABL6A loss, and its regulation of RB1, were largely rescued by p27 depletion. Importantly, reactivation of RB1 using a CDK4/6 inhibitor (palbociclib) killed MPNST cells in vitro in a RABL6A-dependent manner and suppressed MPNST growth in vivo. Low-dose combination of drugs targeting multiple RB1 kinases (CDK4/6, CDK2) had enhanced anti-tumorigenic activity associated with potential MPNST cell re-differentiation. CONCLUSIONS RABL6A is a new driver of MPNST pathogenesis that acts in part through p27-RB1 inactivation. Our results suggest RB1 targeted therapy with multiple pathway drugs may effectively treat MPNSTs. Copyright ©2020, American Association for Cancer Research.PURPOSE Immune checkpoint inhibitors (ICI) are a significant advance to the treatment of advanced non-small cell lung cancer (NSCLC), however, their initiation is associated with heterogeneity in outcomes. This study aimed to develop and validate a prognostic tool of survival in advanced NSCLC patients treated with ICIs. EXPERIMENTAL DESIGN A pre-treatment prognostic model was developed and validated using clinicopathological data. Development data consisted of advanced NSCLC patients treated with atezolizumab from the randomised trials OAK and POPLAR (n=751). Data from the single-arm atezolizumab trials BIRCH and FIR (n=797) were used for external validation. Prognostic scores were categorised into low, intermediate-low, intermediate, intermediate-high and high-risk prognostic groups. The primary outcome was overall survival (OS), with progression-free survival (PFS) secondary. RESULTS Pre-treatment C-reactive protein (CRP) was the most predictive variable for OS. The prognostic tool was optimally defined by CRP, lactate dehydrogenase, derived neutrophil-to-lymphocyte ratio, albumin, PD-L1 expression, performance status, time since metastatic diagnosis, and metastatic sites count. Prognostic groups had significantly different OS (c-statistic=0.72), with median OS ranging from >24 to 3 months for the low to high-risk groups. Performance was maintained on validation (c=0.76). Findings were similar for PFS, with median PFS ranging from 5 to 1 month for the low to high-risk groups. Benefit of atezolizumab (versus docetaxel) was greatest in the low-risk group (>3 months median OS improvement), with little benefit apparent for the highest-risk group. CONCLUSIONS A prognostic tool was developed and validated to identify patient groups with distinctly different survival following atezolizumab initiation for advanced NSCLC. Copyright ©2020, American Association for Cancer Research.Many paediatricians will be faced with a sick infant who on investigation is found to have hyponatraemia and hyperkalaemia at some time in their career. The focus of initial management includes the treatment of potentially life-threatening hyperkalaemia with concurrent investigation aiming to elucidate whether the underlying cause reflects a primarily renal or endocrine pathology. We describe the presentation of two infants who each presented with one of the more common underlying diagnoses that led to this biochemical disturbance and discuss the approach to immediate treatment, diagnostic work-up and longer term management. © Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.Scientific research traditionally has been the domain of graduate school training, and it is based on higher cognitive levels associated with reflective thought. Such skills differ markedly from those needed to train competent respiratory therapists at the undergraduate level. Trainees at the undergraduate level need to acquire, comprehend, and apply large amounts of functional knowledge within a relatively brief time period. As a consequence, there is a pragmatic restriction on the level of complexity that characterizes pathophysiology, therapeutics, and associated technology that can be taught without causing confusion and thereby impeding the learning process. The era of evidence-based medicine is characterized both by the increasing complexity of medical technology and therapeutics. Because respiratory care is fundamentally a technology-driven profession, cultivating research skills among a select group of motivated practitioners is essential. Moreover, it is incumbent on all respiratory therapists to possess a rudimentary understanding of scientific methodology and a familiarity with the processes of reflective thought to become more discerning consumers of medical information. Organizing and implementing a research program within a respiratory care department or training program require forethought and devoted leadership. Crucial to this endeavor is developing mentors to guide those with little or no exposure to scientific inquiry. This article provides an overview of the pedagogical issues that underlie this predicament and then describes practical steps that can be taken to slowly build such a program. Copyright © 2020 by Daedalus Enterprises.