Die Interaktion des Kernrezeptors PPARγ mit der Lipidphosphatase MTMR7 im kolorektalen Karzinom

Der Kernrezeptor Peroxisom-Proliferator-aktivierter Rezeptor-γ (PPARγ) stellt einen bedeutenden Faktor an der Schnittstelle zwischen Lebensstil, Metabolismus und Entzündung einerseits und der individuellen genetischen Prädisposition andererseits dar, die zu Karzinogenese und Tumorprogression im kolorektalen Karzinom beitragen. Insbesondere die enge funktionelle Verknüpfung mit der Ras-Raf-MAPK-vermittelten Signalkaskade auf genomischer wie nicht-genomischer Ebene macht den Kernrezeptor zu einem interessanten Ansatzpunkt im Kontext kolorektaler Tumore, sind es doch aktivierende Mutationen eben jener Signalkaskade, die einen limitierende Faktoren in der zielgerichteten Therapie dieser und anderer Tumorentitäten darstellen. Dabei hat die Aktivierung des Ras-Raf-MAPK-Signalwegs eine subzelluläre Lokalisationsänderung des Kernrezeptors von nukleär nach zytosolisch zur Folge, die die antiproliferative genomische Aktivität von PPARγ reduziert. Die zytosolische Funktion des Rezeptors ist jedoch nach wie vor unklar. In diesem Zusammenhang konnte das „myotubularin related“ Protein 7 (MTMR7) von der Arbeitsgruppe Burgermeister als zytosolischer Bindepartner des Kernrezeptors identifiziert werden, eine Phosphatase, deren physiologische Funktion jedoch noch weitgehend unbekannt ist und die den das zelluläre Überleben fördernden Faktoren zugerechnet werden. In dieser Arbeit, gefördert durch Ca158 (DKFZ-MOST) konnte gezeigt werden, dass MTMR7 sowohl die Insulin- und EGF-vermittelte Aktivierung der „extracellular signal regulated“-Kinasen 1/2 (ERK1/2) hemmt - Zielproteinen der Ras-Raf-MAPK-Kaskade – als auch die des PI3K-AKT-mTORC1/2-Signalwegs, was zu einem verminderten Wachstum und Überleben humaner, kolorektaler Karzinomzelllinien mit aktivierenden Ras- und PI3K-Mutationen führt. Die Effekte der Überexpression des Proteins konnten durch Inkubation mit dem PPARγ-Agonisten Rosiglitazone verstärkt werden. Gleichzeitig hemmte die MTMR7-Überexpression die Rosiglitazone vermittelte ERK1/2-Aktivierung, ein Mechanismus, der für die mit PPARγ-Agonisten assoziierten karzinogenen Effekte mitverantwortlich gemacht wird. Mit Blick auf die Rolle der MTMR7-Expression im kolorektalen Karzinom konnte ein Expressionsverlust in einer signifikanten Anzahl von kolorektalen Karzinom-Präparaten nachgewiesen werden. Als Risikofaktoren für den MTMR7 Verlust konnten ein Typ 2 Diabetes mellitus und „loss of imprinting“ des IGF2-Gens identifiziert werden, Konditionen, die eine vermehrte Insulinrezeptoraktivität mit sich bringen. Eine durch die MTMR7-Überexpression bedingte Verminderung des proproliferativen Effekts der Hyperinsulinämie konnte in kolorektalen Karzinomzelllinien gezeigt werden. Zusätzlich konnte eine Expression der MTMR7-mRNA in sämtlichen untersuchten murinen Geweben nachgewiesen werden, so dass das bereits bekannte MTMR7-Expressionsprofil erweitert werden konnte. Der Einfluss einer hyperinsulinämischen metabolischen Situation auf die MTMR7-mRNA-Expression wurde mit Hilfe des db/db-Mausmodells untersucht. Hier zeigte sich in Dickdarm und Hirn-Gewebe eine signifikant gesteigerte mRNA-Expression in den für die Leptinrezeptormutation homozygoten Tieren verglichen mit der Kontrollgruppe. Diese Arbeit beschreibt mit MTMR7 einen neuen Baustein an der Schnittstelle zwischen Metabolismus und Tumorbiologie. Insbesondere eine Bedeutung unter Bedingungen des metabolischen Syndroms lässt sich vermuten. In den durchgeführten Experimenten zeigte sich eine bisher nicht vorbeschriebene Funktion der Phosphatase als dualer Ras- und mTORC-Inhibitor, die durch einen bereits verfügbaren Wirkstoff verstärkt werden kann. Die kolorektale MTMR7-Expressionsverlustrate von etwa 50% unterstreicht die Bedeutung für die Biologie des Karzinoms. Gleichzeitig bleibt die Phosphatase ein mögliches Ziel in der Therapie eines ausreichend großen Patientenkollektivs, insbesondere in Zusammenhang mit aktivierenden Mutationen des Ras- und PI3K-Signalwegs

Variations in the Stellar IMF: from Bottom to Top

We use a recently-developed analytic model for the ISM structure from scales of GMCs through star-forming cores to explore how the pre-stellar core mass function (CMF) and, by extrapolation, stellar initial mass function (IMF) should depend on both local and galactic properties. If the ISM is supersonically turbulent, the statistical properties of the density field follow from the turbulent velocity spectrum, and the excursion set formalism can be applied to analytically calculate the mass function of collapsing cores on the smallest scales on which they are self-gravitating (non-fragmenting). Two parameters determine the model: the disk-scale Mach number M_h (which sets the shape of the CMF), and the absolute velocity (to assign an absolute scale). For 'normal' variation in disk properties and core gas temperatures in the MW and local galaxies, there is almost no variation in the predicted high-mass behavior of the CMF/IMF. The slope is always close to Salpeter down to <1 M_sun. We predict modest variation in the sub-solar regime, mostly from variation in M_h, but within the observed scatter in sub-solar IMFs in local regions. For fixed galaxy properties, there is little variation in shape or 'upper mass limit' with parent GMC mass. However, in extreme starbursts (e.g. ULIRGs) we predict a bottom-heavy CMF. This agrees with the IMF inferred for the centers of Virgo ellipticals, believed to form in such a nuclear starburst. The CMF is bottom heavy despite the gas temperature being an order of magnitude larger, because M_h is also much larger. Larger M_h values make the 'parent' cloud mass (turbulent Jeans mass) larger, but promote fragmentation to smaller scales; this steepens the slope of the low-mass CMF and shifts the turnover mass. The model may predict a top-heavy CMF for the sub-pc disks around Sgr A*, but the relevant input parameters are uncertain.Comment: 7 pages, 3 figures, MNRAS accepted (revised to match published version

Comprehensive biomarker analysis of long-term response to trastuzumab in patients with HER2-positive advanced gastric or gastroesophageal adenocarcinoma

Background A subgroup of patients with HER2-positive metastatic gastric and gastroesophageal junction cancers shows long-term response under trastuzumab maintenance monotherapy. Obviously, HER2 status alone is not able to identify these patients. We performed this study to identify potential new prognostic biomarkers for this long-term responding patient group. Patients and methods Tumor samples of 19 patients with HER2-positive metastatic gastric and gastroesophageal junction cancer who underwent trastuzumab treatment were retrospectively collected from multiple centers. Patients were divided into long-term responding (n=7) or short-term responding group (n=12) according to progression-free survival (PFS≥12 months vs. PFS<12 months). Next generation sequencing and microarray-based gene expression analysis were performed along with HER2 and PD-L1 immunohistochemistry. Results Long-term responding patients had significantly higher PD-L1 combined positive scores (CPS) and CPS correlated with longer progression-free survival. PD-L1 positivity (CPS≥1) was further associated with an increased CD4+ memory T-cell score. The ERBB2 copy number as well as the tumor mutational burden could not discriminate between short-term and long-term responding patients. Genetic alterations and co-amplifications in HER2 pathway associated genes such as EGFR, which were connected to trastuzumab resistance, were present in 10% of the patients and equally distributed between the groups. Conclusion The study highlights the clinical relevance of PD-L1 testing also in the context of trastuzumab treatment and offers a biological rational by demonstrating elevated CD4+ memory T-cells scores in the PD-L1-positive group

WMO evaluation of northern hemispheric coldest temperature: −69.6 °C at Klinck, Greenland, 22 December 1991

A World Meteorological Organization (WMO) Extremes Evaluation Committee investigated an observation of −69.6 °C by Klinck Automatic Weather Station (AWS) in Greenland on 22 December 1991 as the lowest temperature observed in Greenland, thereby making it the lowest recorded near‐surface air temperature for the Northern and Western Hemispheres and for WMO Region VI. The committee examined the metadata and observations of the station as well as the regional synoptic circulation. The committee concluded that the observation is credible in terms of instrument calibration, monitoring of the station and the synoptic situation. Consequently, the WMO Rapporteur accepted the observation as the officially lowest observed near‐surface air temperature for Greenland, the Northern and Western Hemisphere and for WMO Region VI. As a supplement to this investigation, the committee also recommends that opportunities be investigated such that AWS data from Greenland can be efficiently incorporated into real‐time weather forecasts and hence into reanalysis datasets

Risk factor paradox: No prognostic impact of arterial hypertension and smoking in patients with ventricular tachyarrhythmias

Background: Data regarding the outcome of patients with ventricular tachyarrhythmias related to arterial hypertension (AHT) and smoking is limited. The study sought to assess the prognostic impact of AHT and smoking on survival in patients presenting with ventricular tachyarrhythmias. Methods: All consecutive patients surviving ventricular tachycardia (VT) and ventricular fibrillation (VF) upon admission to the University Medical Center Mannheim (UMM), Germany from 2002 to 2016 were included and stratified according to AHT and smoking by propensity score matching. The primary prognostic endpoint was all-cause mortality at 30 months.Results: A total of 988 AHT-matched patients (494 each, with and without AHT) and a total of 872 smoking-matched patients (436 each, with and without smoking) were included. The rates of VT and VF were similar in both groups (VT: AHT 60% vs. no AHT 60%; smokers 61% vs. non-smokers 62%; VF: AHT 35% vs. no AHT 38%; smokers 39% vs. non-smokers 38%). Neither AHT nor smoking were associated with the primary endpoint of long-term all-cause mortality at 30 months (long-term mortality rates: AHT/no AHT, 26% vs. 28%; log-rank p = 0.525; smoking/non-smoking, 22% vs. 25%; log-rank p = 0.683).Conclusions: Paradoxically, neither AHT nor smoking were associated with differences of long-term all-cause mortality in patients presenting with ventricular tachyarrhythmias

Clinicopathological and prognostic significance of EGFR, VEGF, and HER2 expression in cholangiocarcinoma

Epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), and human epidermal growth factor receptor 2 (HER2) have been considered as potential therapeutic targets in cholangiocarcinoma, but no studies have yet clarified the clinicopathological or prognostic significance of these molecules. Immunohistochemical expression of these molecules was assessed retrospectively in 236 cases of cholangiocarcinoma, as well as associations between the expression of these molecules and clinicopathological factors or clinical outcome. The proportions of positive cases for EGFR, VEGF, and HER2 overexpression were 27.4, 53.8, and 0.9% in intrahepatic cholangiocarcinoma (IHCC), and 19.2, 59.2, and 8.5% in extrahepatic cholangiocarcinoma (EHCC), respectively. Clinicopathologically, EGFR overexpression was associated with macroscopic type (P=0.0120), lymph node metastasis (P=0.0006), tumour stage (P=0.0424), lymphatic vessel invasion (P=0.0371), and perineural invasion (P=0.0459) in EHCC, and VEGF overexpression with intrahepatic metastasis (P=0.0224) in IHCC. Multivariate analysis showed that EGFR expression was a significant prognostic factor (hazard ratio (HR), 2.67; 95% confidence interval (CI), 1.52–4.69; P=0.0006) and also a risk factor for tumour recurrence (HR, 1.89; 95% CI, 1.05–3.39, P=0.0335) in IHCC. These results suggest that EGFR expression is associated with tumour progression and VEGF expression may be involved in haematogenic metastasis in cholangiocarcinoma

Thermal and Morphological Properties of Poly(L-Lactic Acid)/Poly(D-Lactic Acid)-B-Polycaprolactone Diblock Copolymer Blends

Due to the brittle nature of poly(lactic acid) many attempts have been made to flexibilize this polyester for applications such as thin films and foils. However, due to complex phase behavior, many drawbacks for plasticizer and blend components are described. To overcome miscibility, post crystallization and migration issues a principle of click-chemistry was employed to change the molecular characteristics from external to internal plasticization by fixation of a plastisizing unit with help of a stereocomplex crystallization. Hydroxyl terminated polycaprolactone oligomers were used as a macroinitiator for the ring opening polymerization of d-lactide, resulting in blockcopolymers with plasticizing unit polycaprolactone and compatibilizing poly(d-lactic acid)-blocks. The generated block copolymers were blended with a poly(l-lactic acid)-matrix and formed so called stereocomplex crystals. In comparison to unbound polycaprolactone the polycaprolactone blocks show a lower migration tendency regarding a solution test in toluene. Besides that, trapping the plasticizing units via stereocomplex also improves the efficiency of the plasticizer. In comparison to polymer blends with the same amount of non-bonded polycaprolactone oligomers of the same molecular weight, block copolymers with poly(d-lactic acid) and polycaprolactone can shift the glass transition temperature to lower values. This effect can be explained by the modulated crystallization of the polycaprolactone-blocks trapped into the matrix, so that a higher effective amount can interact with the poly(l-lactic acid)-matrix