Notes

Supersized alcopop associated phone calls within the Nationwide Toxin Info System, 2010-2019.
A multivariable conventional Cox regression model identified continued pembrolizumab administration as a significant independent prognostic factor of all-cause mortality (hazard ratio [HR] 0.21, 95% confidence interval [CI] 0.05-0.90, P=0.036), irrespective of the time from treatment initiation to progression and concurrent clinical progression. Further, longer duration of pembrolizumab treatment beyond progression was independently associated with a reduced risk of all-cause mortality in a multivariable time-dependent Cox regression model, when used as a time-dependent variable (HR 0.07, 95% CI 0.01-0.45, P=0.006).

Continued pembrolizumab administration beyond progression might be beneficial in patients with metastatic UC who were clinically stable.
Continued pembrolizumab administration beyond progression might be beneficial in patients with metastatic UC who were clinically stable.
The superior mesenteric artery (SMA) is exposed and dissected during pancreatic resections (PR) and mesenteric vascular surgery (MVS). The resulting damage of the surrounding extrinsic and intrinsic vegetative nerve plexus can lead to a temporary or treatment refractory diarrhea.

This study aimed to provide an overview of the current status of SMA revascularization and dissection-associated diarrhea (SMARD syndrome) in Germany.

After aselective literature search (SLS) on the frequency of newly developed postoperative diarrhea after PR and MVS, an online survey was initiated.

The SLS (n = 4) confirmed that newly developed postoperative diarrhea is afrequent complication after preparation for revascularization (RV) or dissection (DIS) of the SMA (incidence approximately 62%). Treatment refractive courses were relatively uncommon with 14%. Out of 159 centers 54 took part in the survey and 63% stated that they carried out an SMA RV/DIS during PR or MVS. The average PR per center was47 in 2018 and49 in 2019. The average MVS was 5 per center in both years and on average 3 patients suffered from SMARD syndrome.

This survey recorded the current status of the SMARD syndrome in Germany for the first time. So far there are no recommendations for the treatment of such a diarrhea. The results show that initially a symptomatic treatment should be carried out. Due to the complexity of the pathophysiology, causal treatment approaches have not yet been developed.
This survey recorded the current status of the SMARD syndrome in Germany for the first time. So far there are no recommendations for the treatment of such a diarrhea. The results show that initially a symptomatic treatment should be carried out. Due to the complexity of the pathophysiology, causal treatment approaches have not yet been developed.Ionotropic glutamate receptors (iGluRs) play key roles for signaling in the central nervous system. Alternative splicing and RNA editing are well-known mechanisms to increase iGluR diversity and to provide context-dependent regulation. Earlier work on isoform identification has focused on the analysis of cloned transcripts, mostly from rodents. We here set out to obtain a systematic overview of iGluR splicing and editing in human brain based on RNA-Seq data. Using data from two large-scale transcriptome studies, we established a workflow for the de novo identification and quantification of alternative splice and editing events. We detected all canonical iGluR splice junctions, assessed the abundance of alternative events described in the literature, and identified new splice events in AMPA, kainate, delta, and NMDA receptor subunits. Notable events include an abundant transcript encoding the GluA4 amino-terminal domain, GluA4-ATD, a novel C-terminal GluD1 (delta receptor 1) isoform, GluD1-b, and potentially new GluK4 and GluN2C isoforms. C-terminal GluN1 splicing may be controlled by inclusion of a cassette exon, which shows preference for one of the two acceptor sites in the last exon. Moreover, we identified alternative untranslated regions (UTRs) and species-specific differences in splicing. In contrast, editing in exonic iGluR regions appears to be mostly limited to ten previously described sites, two of which result in silent amino acid changes. Coupling of proximal editing/editing and editing/splice events occurs to variable degree. Overall, this analysis provides the first inventory of alternative splicing and editing in human brain iGluRs and provides the impetus for further transcriptome-based and functional investigations.To clarify whether differential compartmentalization of Survivin impacts temozolomide (TMZ)-triggered end points, we established a well-defined glioblastoma cell model in vitro (LN229 and A172) and in vivo, distinguishing between its nuclear and cytoplasmic localization. Expression of nuclear export sequence (NES)-mutated Survivin (SurvNESmut-GFP) led to impaired colony formation upon TMZ. This was not due to enhanced cell death but rather due to increased senescence. Nuclear-trapped Survivin reduced homologous recombination (HR)-mediated double-strand break (DSB) repair, as evaluated by γH2AX foci formation and qPCR-based HR assay leading to pronounced induction of chromosome aberrations. Opposite, clones, expressing free-shuttling cytoplasmic but not nuclear-trapped Survivin, could repair TMZ-induced DSBs and evaded senescence. Mass spectrometry-based interactomics revealed, however, no direct interaction of Survivin with any of the repair factors. The improved TMZ-triggered HR activity in Surv-GFP was associated with enhanced mRNA and stabilized RAD51 protein expression, opposite to diminished RAD51 expression in SurvNESmut cells. Notably, cytoplasmic Survivin could significantly compensate for the viability under RAD51 knockdown. Differential Survivin localization also resulted in distinctive TMZ-triggered transcriptional pathways, associated with senescence and chromosome instability as shown by global transcriptome analysis. Orthotopic LN229 xenografts, expressing SurvNESmut exhibited diminished growth and increased DNA damage upon TMZ, as manifested by PCNA and γH2AX foci expression, respectively, in brain tissue sections. Consequently, those mice lived longer. Although tumors of high-grade glioma patients expressed majorly nuclear Survivin, they exhibited rarely NES mutations which did not correlate with survival. selleck kinase inhibitor Based on our in vitro and xenograft data, Survivin nuclear trapping would facilitate glioma response to TMZ.
Website: https://www.selleckchem.com/