Vitamin D Receptor Activation Mitigates the Impact of Uremia on Endothelial Function in the 5/6 Nephrectomized Rats

Endothelial dysfunction increases cardiovascular disease risk in chronic kidney disease (CKD). This study investigates whether VDR activation affects endothelial function in CKD. The 5/6 nephrectomized (NX) rats with experimental chronic renal insufficiency were treated with or without paricalcitol, a VDR activator. Thoracic aortic rings were precontracted with phenylephrine and then treated with acetylcholine or sodium nitroprusside. Uremia significantly affected aortic relaxation (−50.0 ± 7.4% in NX rats versus −96.2 ± 5.3% in SHAM at 30 μM acetylcholine). The endothelial-dependent relaxation was improved to –58.2 ± 6.0%, –77.5 ± 7.3%, and –90.5 ± 4.0% in NX rats treated with paricalcitol at 0.021, 0.042, and 0.083 μg/kg for two weeks, respectively, while paricalcitol at 0.042 μg/kg did not affect blood pressure and heart rate. Parathyroid hormone (PTH) suppression alone did not improve endothelial function since cinacalcet suppressed PTH without affecting endothelial-dependent vasorelaxation. N-omega-nitro-L-arginine methyl ester completely abolished the effect of paricalcitol on improving endothelial function. These results demonstrate that VDR activation improves endothelial function in CKD

Upregulation of PKD1L2 provokes a complex neuromuscular disease in the mouse

Following a screen for neuromuscular mouse mutants, we identified ostes, a novel N-ethyl N-nitrosourea-induced mouse mutant with muscle atrophy. Genetic and biochemical evidence shows that upregulation of the novel, uncharacterized transient receptor potential polycystic (TRPP) channel PKD1L2 (polycystic kidney disease gene 1-like 2) underlies this disease. Ostes mice suffer from chronic neuromuscular impairments including neuromuscular junction degeneration, polyneuronal innervation and myopathy. Ectopic expression of PKD1L2 in transgenic mice reproduced the ostes myopathic changes and, indeed, caused severe muscle atrophy in Tg(Pkd1l2)/Tg(Pkd1l2) mice. Moreover, double-heterozygous mice (ostes/+, Tg(Pkd1l2)/0) suffer from myopathic changes more profound than each heterozygote, indicating positive correlation between PKD1L2 levels and disease severity. We show that, in vivo, PKD1L2 primarily associates with endogenous fatty acid synthase in normal skeletal muscle, and these proteins co-localize to costameric regions of the muscle fibre. In diseased ostes/ostes muscle, both proteins are upregulated, and ostes/ostes mice show signs of abnormal lipid metabolism. This work shows the first role for a TRPP channel in neuromuscular integrity and disease

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin

VEGF and Angiopoietin-1 Exert Opposing Effects on Cell Junctions by Regulating the Rho GEF Syx

Vascular endothelial growth factor (VEGF) and Ang1 (Angiopoietin-1) have opposing effects on vascular permeability, but the molecular basis of these effects is not fully known. We report in this paper that VEGF and Ang1 regulate endothelial cell (EC) junctions by determining the localization of the RhoA-specific guanine nucleotide exchange factor Syx. Syx was recruited to junctions by members of the Crumbs polarity complex and promoted junction integrity by activating Diaphanous. VEGF caused translocation of Syx from cell junctions, promoting junction disassembly, whereas Ang1 maintained Syx at the junctions, inducing junction stabilization. The VEGF-induced translocation of Syx from EC junctions was caused by PKD1 (protein kinase D1)-mediated phosphorylation of Syx at Ser806, which reduced Syx association to its junctional anchors. In support of the pivotal role of Syx in regulating EC junctions, syx−/− mice had defective junctions, resulting in vascular leakiness, edema, and impaired heart function

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN

Spatial Organization and Molecular Correlation of Tumor-Infiltrating Lymphocytes Using Deep Learning on Pathology Images

Beyond sample curation and basic pathologic characterization, the digitized H&E-stained images of TCGA samples remain underutilized. To highlight this resource, we present mappings of tumorinfiltrating lymphocytes (TILs) based on H&E images from 13 TCGA tumor types. These TIL maps are derived through computational staining using a convolutional neural network trained to classify patches of images. Affinity propagation revealed local spatial structure in TIL patterns and correlation with overall survival. TIL map structural patterns were grouped using standard histopathological parameters. These patterns are enriched in particular T cell subpopulations derived from molecular measures. TIL densities and spatial structure were differentially enriched among tumor types, immune subtypes, and tumor molecular subtypes, implying that spatial infiltrate state could reflect particular tumor cell aberration states. Obtaining spatial lymphocytic patterns linked to the rich genomic characterization of TCGA samples demonstrates one use for the TCGA image archives with insights into the tumor-immune microenvironment

Minimal in vivo efficacy of iminosugars in a lethal Ebola virus guinea pig model

The antiviral properties of iminosugars have been reported previously in vitro and in small animal models against Ebola virus (EBOV); however, their effects have not been tested in larger animal models such as guinea pigs. We tested the iminosugars N-butyl-deoxynojirimycin (NB-DNJ) and N-(9-methoxynonyl)-1deoxynojirimycin (MON-DNJ) for safety in uninfected animals, and for antiviral efficacy in animals infected with a lethal dose of guinea pig adapted EBOV. 1850 mg/kg/day NB-DNJ and 120 mg/kg/day MON-DNJ administered intravenously, three times daily, caused no adverse effects and were well tolerated. A pilot study treating infected animals three times within an 8 hour period was promising with 1 of 4 infected NB-DNJ treated animals surviving and the remaining three showing improved clinical signs. MON-DNJ showed no protective effects when EBOV-infected guinea pigs were treated. On histopathological examination, animals treated with NB-DNJ had reduced lesion severity in liver and spleen. However, a second study, in which NB-DNJ was administered at equally-spaced 8 hour intervals, could not confirm drug-associated benefits. Neither was any antiviral effect of iminosugars detected in an EBOV glycoprotein pseudotyped virus assay. Overall, this study provides evidence that NB-DNJ and MON-DNJ do not protect guinea pigs from a lethal EBOV-infection at the dose levels and regimens tested. However, the one surviving animal and signs of improvements in three animals of the NB-DNJ treated cohort could indicate that NB-DNJ at these levels may have a marginal beneficial effect. Future work could be focused on the development of more potent iminosugars

Resisting Sleep Pressure:Impact on Resting State Functional Network Connectivity

In today's 24/7 society, sleep restriction is a common phenomenon which leads to increased levels of sleep pressure in daily life. However, the magnitude and extent of impairment of brain functioning due to increased sleep pressure is still not completely understood. Resting state network (RSN) analyses have become increasingly popular because they allow us to investigate brain activity patterns in the absence of a specific task and to identify changes under different levels of vigilance (e.g. due to increased sleep pressure). RSNs are commonly derived from BOLD fMRI signals but studies progressively also employ cerebral blood flow (CBF) signals. To investigate the impact of sleep pressure on RSNs, we examined RSNs of participants under high (19 h awake) and normal (10 h awake) sleep pressure with three imaging modalities (arterial spin labeling, BOLD, pseudo BOLD) while providing confirmation of vigilance states in most conditions. We demonstrated that CBF and pseudo BOLD signals (measured with arterial spin labeling) are suited to derive independent component analysis based RSNs. The spatial map differences of these RSNs were rather small, suggesting a strong biological substrate underlying these networks. Interestingly, increased sleep pressure, namely longer time awake, specifically changed the functional network connectivity (FNC) between RSNs. In summary, all FNCs of the default mode network with any other network or component showed increasing effects as a function of increased 'time awake'. All other FNCs became more anti-correlated with increased 'time awake'. The sensorimotor networks were the only ones who showed a within network change of FNC, namely decreased connectivity as function of 'time awake'. These specific changes of FNC could reflect both compensatory mechanisms aiming to fight sleep as well as a first reduction of consciousness while becoming drowsy. We think that the specific changes observed in functional network connectivity could imply an impairment of information transfer between the affected RSNs

Tofacitinib for Treating Rheumatoid Arthritis After the Failure of Disease-Modifying Anti-rheumatic Drugs: An Evidence Review Group Perspective of a NICE Single Technology Appraisal

As part of its Single Technology Appraisal process, the National Institute for Health and Care Excellence (NICE) invited the manufacturer (Pfizer) of tofacitinib (TOF; Xeljanz®) to submit evidence of the drug's clinical and cost-effectiveness in the treatment of rheumatoid arthritis (RA) after the failure of conventional disease-modifying antirheumatic drugs (cDMARDs). The School of Health and Related Research Technology Appraisal Group at the University of Sheffield was commissioned to act as the independent Evidence Review Group (ERG). The ERG produced a detailed review of the evidence for the clinical and cost-effectiveness of the technology, based upon the company's submission to NICE. The clinical effectiveness evidence in the company's submission for TOF is based predominantly on four randomised controlled trials (RCTs) comparing the efficacy of TOF against placebo. Three RCTs investigated TOF in combination with methotrexate (MTX), and one RCT investigated TOF monotherapy. All four RCTs compared TOF with placebo plus cDMARDs, one RCT also included adalimumab as a comparator. The study population in the four RCTs comprised patients who were MTX inadequate responders or cDMARD inadequate responders (cDMARD-IR). The company performed network meta-analyses (NMA) to assess the relative efficacy of TOF compared with biologic DMARDs (bDMARDs) in patients who were cDMARD-IR or bDMARD-IR with moderate-to-severe RA for European League Against Rheumatism (EULAR) response and change in the Health Assessment Questionnaire Disability Index at 6 months. The company's NMA concluded that TOF had comparable efficacy to bDMARDs currently recommended by NICE. The company submitted a de novo model that assessed the cost-effectiveness of TOF versus its comparators in six different populations: (1) cDMARD-IR with severe RA; (2) cDMARD-IR with severe RA for whom MTX is contraindicated or not tolerated; (3) bDMARD-IR; (4) bDMARD-IR for whom rituximab (RTX) is contraindicated or not tolerated; (5) bDMARD-IR for whom MTX is contraindicated or not tolerated; and, (6) cDMARD-IR with moderate RA. According to the company's economic analyses, in cDMARD-IR with severe RA, TOF plus MTX dominates or extendedly dominates most comparators, whilst TOF monotherapy is slightly less effective and less expensive than its comparators, with the cost saved per quality-adjusted life year (QALY) lost always higher than £50,000. In bDMARD-IR with severe RA, RTX plus MTX dominated TOF plus MTX, but in patients for whom RTX was not an option, TOF plus MTX dominated all comparators included in the analysis (four comparators recommended by NICE were not included). In cDMARD-IR with moderate RA, the cost per QALY for TOF in combination with MTX or as monotherapy compared with a sequence of cDMARDs was estimated to be greater than £50,000/QALY. The ERG identified a number of limitations in the company's analyses, including use of a fixed-effects model in the NMA and the use of treatment sequences in the cost-effectiveness model which did not reflect NICE recommendations. These limitations were addressed partly by the company during the clarification round and partly by the ERG. The exploratory analyses undertaken by the ERG resulted in similar conclusions: (1) TOF plus MTX was dominated by RTX plus MTX; (2) TOF in combination with MTX or as monotherapy dominates or extendedly dominates some of its comparators in cDMARD-IR and bDMARD-IR with severe RA for whom RTX plus MTX was not an option; and (3) in cDMARD-IR with moderate RA, the cost per QALY of TOF in combination with MTX or as a monotherapy versus cDMARDs was in excess of £47,000. The NICE Appraisal Committee consequently recommended TOF plus MTX as an option for patients whose disease has responded inadequately to intensive therapy with a combination of cDMARDs only if (1) disease is severe [a Disease Activity Score (DAS28) of more than 5.1] and (2) the company provides TOF with the discount agreed in the Patient Access Scheme (PAS). TOF plus MTX is also recommended as an option for adults whose disease has responded inadequately to, or who cannot have, other DMARDs, including at least one bDMARD, only if (1) disease is severe, (2) they cannot have RTX, and (3) the company provides TOF with the discount agreed in the PAS. For patients who are intolerant of MTX, or where MTX is contraindicated, TOF monotherapy is recommended where TOF plus MTX would be recommended