Targeting class I histone deacetylase 2 in MYC amplified group 3 medulloblastoma

Introduction: Medulloblastoma (MB) is the most frequent malignant brain tumor in children. Four subgroups with distinct genetic, epigenetic and clinical characteristics have been identified. Survival remains particularly poor in patients with Group 3 tumors harbouring a MYC amplification. We herein explore the molecular mechanisms and translational implications of class I histone deacetylase (HDAC) inhibition in MYC driven MBs. Material and Methods: Expression of HDACs in primary MB subgroups was compared to normal brain tissue. A panel of MB cell lines, including Group 3 MYC amplified cell lines, were used as model systems. Cells were treated with HDAC inhibitors (HDACi) selectively targeting class I or IIa HDACs. Depletion of HDAC2 was performed. Intracellular HDAC activity, cellular viability, metabolic activity, caspase activity, cell cycle progression, RNA and protein expression were analyzed. Results: HDAC2 was found to be overexpressed in MB subgroups with poor prognosis (SHH, Group 3 and Group 4) compared to normal brain and the WNT subgroup. Inhibition of the enzymatic activity of the class I HDACs reduced metabolic activity, cell number, and viability in contrast to inhibition of class IIa HDACs. Increased sensitivity to HDACi was specifically observed in MYC amplified cells. Depletion of HDAC2 increased H4 acetylation and induced cell death. Simulation of clinical pharmacokinetics showed time-dependent on target activity that correlated with binding kinetics of HDACi compounds. Conclusions: We conclude that HDAC2 is a valid drug target in patients with MYC amplified MB. HDACi should cover HDAC2 in their inhibitory profile and timing and dosing regimen in clinical trials should take binding kinetics of compounds into consideration

Beamline-Instrumentierung und Experimentautomatisierung fuer ROBL an der ESRF/Grenoble (F)

Durch das Forschungszentrum Rossendorf wurde in den Jahren 1996-1998 ein eigenes Strahlrohr fuer Experimente mit Synchrotronstrahlung an der ESRF (European Synchrotron Radioation Facility) in Grenoble/Frankreich aufgebaut. Das Strahlrohr verfuegt ueber zwei alternativ nutzbare Messplaetze fuer die Untersuchung von radioaktiven Proben mittels Roentgenabsorptionsspektroskopie und fuer Materialstrukturuntersuchungen mit Roentgendiffraktion. Der Bericht konzentriert sich auf die Arbeiten, die fuer die Steuerung der Optik und die Nutzung der Messplaetze hinsichtlich der Elektronik, Rechentechnik und Software erforderlich waren. Nach einer Beschreibung der Randbedingungen und einer Kurzcharakteristik der geraetetechnischen Basis werden wichtige Hardwarekomponenten fuer die Instrumentierung der Systeme vorgestellt. Die rechentechnische Basis wird anschliessend beschrieben. Die angewendeten Software-Grundprinzipien werden erlaeutert und diskutiert sowie an einigen Applikationen beispielhaft verdeutlicht. Abschliessend werden spezifische Probleme bei der Programmierung von Applikationen mit grafischer Bedienoberflaeche in Verbindung mit Geraetezugriffen behandelt. Tabellen, in denen die benutzten Hardware-Module und die Softwarekomponenten zusammengestellt sind, ermoeglichen einen Ueberblick ueber das Gesamtsystem. Das Literaturverzeichnis dient als Leitfaden fuer die Detaildokumentationen

Targeting class I histone deacetylase 2 in MYC amplified group 3 medulloblastoma

Introduction: Medulloblastoma (MB) is the most frequent malignant brain tumor in children. Four subgroups with distinct genetic, epigenetic and clinical characteristics have been identified. Survival remains particularly poor in patients with Group 3 tumors harbouring a MYC amplification. We herein explore the molecular mechanisms and translational implications of class I histone deacetylase (HDAC) inhibition in MYC driven MBs. Material and Methods Expression of HDACs in primary MB subgroups was compared to normal brain tissue. A panel of MB cell lines, including Group 3 MYC amplified cell lines, were used as model systems. Cells were treated with HDAC inhibitors (HDACi) selectively targeting class I or IIa HDACs. Depletion of HDAC2 was performed. Intracellular HDAC activity, cellular viability, metabolic activity, caspase activity, cell cycle progression, RNA and protein expression were analyzed. Results: HDAC2 was found to be overexpressed in MB subgroups with poor prognosis (SHH, Group 3 and Group 4) compared to normal brain and the WNT subgroup. Inhibition of the enzymatic activity of the class I HDACs reduced metabolic activity, cell number, and viability in contrast to inhibition of class IIa HDACs. Increased sensitivity to HDACi was specifically observed in MYC amplified cells. Depletion of HDAC2 increased H4 acetylation and induced cell death. Simulation of clinical pharmacokinetics showed time-dependent on target activity that correlated with binding kinetics of HDACi compounds. Conclusions: We conclude that HDAC2 is a valid drug target in patients with MYC amplified MB. HDACi should cover HDAC2 in their inhibitory profile and timing and dosing regimen in clinical trials should take binding kinetics of compounds into consideration. Electronic supplementary material The online version of this article (doi:10.1186/s40478-015-0201-7) contains supplementary material, which is available to authorized users

Low level of exosomal long non-coding RNA HOTTIP is a prognostic biomarker in colorectal cancer

Molecular risk stratification of colorectal cancer can improve patient outcome. A panel of lncRNAs (H19, HOTTIP, HULC and MALAT1) derived from serum exosomes of patients with non-metastatic CRC and healthy donors was analyzed. Exosomes from healthy donors carried significantly more H19, HULC and HOTTIP transcripts in comparison to CRC patients. Correlation analysis between lncRNAs and clinical data revealed a statistical significance between low levels of exosomal HOTTIP and poor overall survival. This was confirmed by multivariate analysis that HOTTIP is an independent prognostic marker for overall survival (HR: 4.5, CI: 1.69–11.98, p = 0.0027). Here, HOTTIP poses to be a valid biomarker for patients with a CRC to predict post-surgical survival time. © 2019, © 2019 Informa UK Limited, trading as Taylor & Francis Group

Regional networks, alliance portfolio configuration, and innovation performance

To maintain and enhance innovation performance, many firms nowadays look for resources from external sources such as strategic alliances and regional network embeddedness. While considering the important interdependencies among different alliances, research has established an alliance portfolio perspective. From an alliance portfolio perspective, firms can consciously configure the dimensions of their alliance portfolios such as partner characteristics, relational properties, or structural properties. However, within the context of alliance portfolio configuration, the role of regional networks has been largely overlooked. As most high-tech firms are regionally clustered, this is an important research gap. In addressing this gap, this study explores the link between regional network density, alliance portfolio configuration, and its contribution to firm innovation performance. We examine how regional network density and alliance partner diversity influences firm level innovation output. We also investigate the moderating effect of overall network partner status and partner diversity on the link between regional network density and innovation performance. Our empirical evidence is derived from a longitudinal quantitative study of 1,233 German biotechnology firms. We find that regional network density and alliance partner diversity has an inverted U-shape effect on firm level innovation performance. However, overall network status as well as alliance partner diversity negatively moderates the link between regional network density and innovation output. Thus, our study contributes to a better understanding of the link between regional networks, alliance portfolio configuration, and firm level innovation performance

More is More? Total Pancreatectomy for Periampullary Cancer as an Alternative in Patients with High-Risk Pancreatic Anastomosis: A Propensity Score-Matched Analysis

Background!#!Postpancreatectomy morbidity remains significant even in high-volume centers and frequently results in delay or suspension of indicated adjuvant oncological treatment. This study investigated the short-term and long-term outcome after primary total pancreatectomy (PTP) and pylorus-preserving pancreaticoduodenectomy (PPPD) or Whipple procedure, with a special focus on administration of adjuvant therapy and oncological survival.!##!Methods!#!Patients who underwent PTP or PPPD/Whipple for periampullary cancer between January 2008 and December 2017 were retrospectively analyzed. Propensity score-matched analysis was performed to compare perioperative and oncological outcomes. Correspondingly, cases of rescue completion pancreatectomy (RCP) were analyzed.!##!Results!#!In total, 41 PTP and 343 PPPD/Whipple procedures were performed for periampullary cancer. After propensity score matching, morbidity (Clavien-Dindo classification (CDC) ≥ IIIa, 31.7% vs. 24.4%; p = 0.62) and mortality rates (7.3% vs. 2.4%, p = 0.36) were similar in PTP and PPPD/Whipple. Frequency of adjuvant treatment administration (76.5% vs. 78.4%; p = 0.87), overall survival (513 vs. 652 days; p = 0.47), and progression-free survival (456 vs. 454 days; p = 0.95) did not significantly differ. In turn, after RCP, morbidity (CDC ≥ IIIa, 85%) and mortality (40%) were high, and overall survival was poor (median 104 days). Indicated adjuvant therapy was not administered in 77%.!##!Conclusions!#!In periampullary cancers, PTP may provide surgical and oncological treatment outcomes comparable with pancreatic head resections and might save patients from RCP. Especially in selected cases with high-risk pancreatic anastomosis or preoperatively impaired glucose tolerance, PTP may provide a safe treatment alternative to pancreatic head resection

Selective Decontamination of the Digestive Tract in Pancreatic Head Resections—A Propensity Score-Matched Analysis

(1) Background: The postoperative morbidity rate after pancreatic head resection remains high, partly due to infectious complications. The primary aim of this study was to analyze the influence of selective decontamination of the digestive tract (SDD) on the postoperative infection rate after pancreatic surgery. (2) Methods: From January 2019, the standard of care for patients undergoing pancreatic head resections at the Department for Visceral, Thoracic, and Vascular Surgery, University Hospital Dresden was the preoperative oral administration of SDD. The influence of SDD was evaluated for patients operated on between January 2019 and June 2020 in comparison to a propensity score-matched cohort, extracted from an existing database including all pancreatic resections from 2012 to 2018. The primary endpoint of the study was the shift of the bacterial load on the intraoperative bile swab test. The secondary endpoint was the association of SDD with postoperative complications. (3) Results: In total, 200 patients either with SDD (n = 100; 50%) or without SDD (non-SDD, n = 100; 50%) were analyzed. In the patient group without a preoperative biliary stent, 44% (n = 11) of the non-SDD group displayed positive bacterial results, whereas that was the case for only 21.7% (n = 10) in the SDD group (p = 0.05). Particularly, Enterobacter species (spp.) were reduced from 41.2% (n = 14) (non-SDD group) to 23.5% (n = 12) (SDD group) (p = 0.08), and Citrobacter spp. were reduced by 13.7% (p = 0.09) from the non-SDD to the SDD cohort. In patients with a preoperative biliary stent, the Gram-negative Enterobacter spp. were significantly reduced from 52.2% (n = 12) in the non-SDD group to 26.8% (n = 11) in the SDD group (p = 0.04). Similarly, Citrobacter spp. decreased by 20.6% from 30.4% (n = 7) to 9.8% (n = 4) in the non-SDD compared to the SDD group (p = 0.04). In general, deep fluid collection and abscesses occurred more frequently in the non-SDD group (36%; n = 36 vs. 27%; n = 27; p = 0.17). (4) Conclusions: Adoption of SDD before pancreatic head surgery may reduce the bacterial load in bile fluid. SDD administration does not significantly affect the postoperative infectious complication rate after pancreatic head resections