A prognostic model for overall survival of patients with early-stage non-small cell lung cancer: a multicentre, retrospective study.

Intratumoural heterogeneity has been previously shown to be related to clonal evolution and genetic instability and associated with tumour progression. Phenotypically, it is reflected in the diversity of appearance and morphology within cell populations. Computer-extracted features relating to tumour cellular diversity on routine tissue images might correlate with outcome. This study investigated the prognostic ability of computer-extracted features of tumour cellular diversity (CellDiv) from haematoxylin and eosin (H&E)-stained histology images of non-small cell lung carcinomas (NSCLCs). In this multicentre, retrospective study, we included 1057 patients with early-stage NSCLC with corresponding diagnostic histology slides and overall survival information from four different centres. CellDiv features quantifying local cellular morphological diversity from H&E-stained histology images were extracted from the tumour epithelium region. A Cox proportional hazards model based on CellDiv was used to construct risk scores for lung adenocarcinoma (LUAD; 270 patients) and lung squamous cell carcinoma (LUSC; 216 patients) separately using data from two of the cohorts, and was validated in the two remaining independent cohorts (comprising 236 patients with LUAD and 335 patients with LUSC). We used multivariable Cox regression analysis to examine the predictive ability of CellDiv features for 5-year overall survival, controlling for the effects of clinical and pathological parameters. We did a gene set enrichment and Gene Ontology analysis on 405 patients to identify associations with differentially expressed biological pathways implicated in lung cancer pathogenesis. For prognosis of patients with early-stage LUSC, the CellDiv LUSC model included 11 discriminative CellDiv features, whereas for patients with early-stage LUAD, the model included 23 features. In the independent validation cohorts, patients predicted to be at a higher risk by the univariable CellDiv model had significantly worse 5-year overall survival (hazard ratio 1·48 [95% CI 1·06-2·08]; p=0·022 for The Cancer Genome Atlas [TCGA] LUSC group, 2·24 [1·04-4·80]; p=0·039 for the University of Bern LUSC group, and 1·62 [1·15-2·30]; p=0·0058 for the TCGA LUAD group). The identified CellDiv features were also found to be strongly associated with apoptotic signalling and cell differentiation pathways. CellDiv features were strongly prognostic of 5-year overall survival in patients with early-stage NSCLC and also associated with apoptotic signalling and cell differentiation pathways. The CellDiv-based risk stratification model could potentially help to determine which patients with early-stage NSCLC might receive added benefit from adjuvant therapy. National Institue of Health and US Department of Defense

Spatially resolved proteomic profiling identifies tumor cell CD44 as a biomarker associated with sensitivity to PD-1 axis blockade in advanced non-small- cell lung cancer

Most patients with advanced non-small-cell lung cancer (NSCLC) fail to derive significant benefit from programmed cell death protein-1 (PD-1) axis blockade, and new biomarkers of response are needed. In this study, we aimed to discover and validate spatially resolved protein markers associated with sensitivity to PD-1 axis inhibition in NSCLC

Differentially altered Ca2+ regulation and Ca2+ permeability in Cx26 hemichannels formed by the A40V and G45E mutations that cause keratitis ichthyosis deafness syndrome

Mutations in GJB2, which encodes Cx26, are one of the most common causes of inherited deafness in humans. More than 100 mutations have been identified scattered throughout the Cx26 protein, most of which cause nonsyndromic sensorineural deafness. In a subset of mutations, deafness is accompanied by hyperkeratotic skin disorders, which are typically severe and sometimes fatal. Many of these syndromic deafness mutations localize to the amino-terminal and first extracellular loop (E1) domains. Here, we examined two such mutations, A40V and G45E, which are positioned near the TM1/E1 boundary and are associated with keratitis ichthyosis deafness (KID) syndrome. Both of these mutants have been reported to form hemichannels that open aberrantly, leading to “leaky” cell membranes. Here, we quantified the Ca2+ sensitivities and examined the biophysical properties of these mutants at macroscopic and single-channel levels. We find that A40V hemichannels show significantly impaired regulation by extracellular Ca2+, increasing the likelihood of aberrant hemichannel opening as previously suggested. However, G45E hemichannels show only modest impairment in regulation by Ca2+ and instead exhibit a substantial increase in permeability to Ca2+. Using cysteine substitution and examination of accessibility to thiol-modifying reagents, we demonstrate that G45, but not A40, is a pore-lining residue. Both mutants function as cell–cell channels. The data suggest that G45E and A40V are hemichannel gain-of-function mutants that produce similar phenotypes, but by different underlying mechanisms. A40V produces leaky hemichannels, whereas G45E provides a route for excessive entry of Ca2+. These aberrant properties, alone or in combination, can severely compromise cell integrity and lead to increased cell death

Ein Verfahren zum rechnerischen Lebensdauernachweis von Windkraftanlagen mittels digitaler Simulation

Leichtbau ist heute und in Zukunft eine wesentliche Grundvoraussetzung, um einerseits Material und Kosten bei der Entwicklung neuer Konstruktionen einzusparen und andererseits die masseninduzierten Belastungen zu reduzieren. Hierzu sind umfangreiche Analysen des gesamten Systemverhaltens, aber auch für jedes Bauteil bezüglich Funktion, Verformungsverhalten, Bauteilfestigkeit usw. nötig. Im Bereich der betriebsfesten Bemessung von Windkraftanlagen dient der Einsatz von Simulationstechniken überwiegend zur Ermittlung der auf die Struktur wirkenden Belastungs-Zeitfunktionen und zur Festigkeits- und Steifigkeitsanalyse bei der Bauteiloptimierung mit dem Ziel, schon direkt am Rechner den gesamten Optimierungsprozeß im Sinne des "Virtual Prototyping" zu realisieren. Die Leistungsfähigkeit kommerziell erhältlicher Software zur digitalen Simulation, die auch mitteiständischen Windkraftanlagenherstellem zugänglich ist, bietet die Möglichkeit einer standort- und betriebsspezifischen Auslegung vo n Anlagenkomponenten