BET protein inhibition sensitizes glioblastoma cells to temozolomide treatment by attenuating MGMT expression.

Bromodomain and extra-terminal tail (BET) proteins have been identified as potential epigenetic targets in cancer, including glioblastoma. These epigenetic modifiers link the histone code to gene transcription that can be disrupted with small molecule BET inhibitors (BETi). With the aim of developing rational combination treatments for glioblastoma, we analyzed BETi-induced differential gene expression in glioblastoma derived-spheres, and identified 6 distinct response patterns.

DNA methylation-based age acceleration observed in IDH wild-type glioblastoma is associated with better outcome-including in elderly patients.

Elderly patients represent a growing proportion of individuals with glioblastoma, who however, are often excluded from clinical trials owing to poor expected prognosis. We aimed at identifying age-related molecular differences that would justify and guide distinct treatment decisions in elderly glioblastoma patients. The combined DNA methylome (450 k) of four IDH wild-type glioblastoma datasets, comprising two clinical trial cohorts, was interrogated for differences based on the patients' age, DNA methylation (DNAm) age acceleration (DNAm age "Horvath-clock" minus patient age), DNA methylation-based tumor classification (Heidelberg), entropy, and functional methylation of DNA damage response (DDR) genes.

BET inhibitors repress expression of interferon-stimulated genes and synergize with HDAC inhibitors in glioblastoma.

Background: The development of rational combination therapies is key to overcome inherent treatment resistance of glioblastoma (GBM). We aim at identifying new druggable targets by disturbing GBM cells with inhibitors of bromodomain and extra-terminal motif (BET) proteins to reveal cancer-relevant vulnerabilities that may sensitize to a second drug. BET proteins are epigenetic modulators and have been associated with proto-oncogene overexpression in cancer.

The DNA methylome of DDR genes and benefit from RT or TMZ in IDH mutant low-grade glioma treated in EORTC 22033.

The optimal treatment for patients with low-grade glioma (LGG) WHO grade II remains controversial. Overall survival ranges from 2 to over 15 years depending on molecular and clinical factors. Hence, risk-adjusted treatments are required for optimizing outcome and quality of life.

Ubiquitin Specific Peptidase 15 (USP15) suppresses glioblastoma cell growth via stabilization of HECTD1 E3 ligase attenuating WNT pathway activity.

Expression based prediction of new genomic alterations in glioblastoma identified the de-ubiquitinase Ubiquitin Specific Peptidase 15 () as potential tumor suppressor gene associated with genomic deletions (11%). Ectopic expression of USP15 in glioblastoma cell-lines reduced colony formation and growth in soft agar, while overexpression of its functional mutant had the opposite effect. Evaluation of the protein binding network of USP15 by Mass Spectrometry in glioblastoma cells uncovered eight novel interacting proteins, including HECT Domain Containing E3 Ubiquitin Protein Ligase 1 (HECTD1), whose mouse homologue has been associated with an inhibitory effect on the WNT-pathway.

Phase II Study of Radiotherapy and Temsirolimus versus Radiochemotherapy with Temozolomide in Patients with Newly Diagnosed Glioblastoma without MGMT Promoter Hypermethylation (EORTC 26082).

Purpose: EORTC 26082 assessed the activity of temsirolimus in patients with newly diagnosed glioblastoma harboring an unmethylated O6 methylguanine-DNA-methyltransferase (MGMT) promoter.

Experimental Design: Patients (n = 257) fulfilling eligibility criteria underwent central MGMT testing. Patients with MGMT unmethylated glioblastoma (n = 111) were randomized 1:1 between standard chemo-radiotherapy with temozolomide or radiotherapy plus weekly temsirolimus (25 mg).

Sensitivity Analysis of the MGMT-STP27 Model and Impact of Genetic and Epigenetic Context to Predict the MGMT Methylation Status in Gliomas and Other Tumors.

The methylation status of the O(6)-methylguanine-DNA methyltransferase (MGMT) gene is an important predictive biomarker for benefit from alkylating agent therapy in glioblastoma. Our model MGMT-STP27 allows prediction of the methylation status of the MGMT promoter using data from the Illumina's Human Methylation BeadChips (HM-27K and HM-450K) that is publically available for many cancer data sets. Here, we investigate the impact of the context of genetic and epigenetic alterations and tumor type on the classification and report on technical aspects, such as robustness of cutoff definition and preprocessing of the data.

Cilengitide in newly diagnosed glioblastoma: biomarker expression and outcome.

Integrins αvβ3 and αvβ5 regulate angiogenesis and invasiveness in cancer, potentially by modulating activation of the transforming growth factor (TGF)-β pathway. The randomized phase III CENTRIC and phase II CORE trials explored the integrin inhibitor cilengitide in patients with newly diagnosed glioblastoma with versus without O6-methylguanine DNA methyltransferase (MGMT) promoter methylation. These trials failed to meet their primary endpoints.

Mir-21-Sox2 Axis Delineates Glioblastoma Subtypes with Prognostic Impact.

Unlabelled: Glioblastoma (GBM) is the most aggressive human brain tumor. Although several molecular subtypes of GBM are recognized, a robust molecular prognostic marker has yet to be identified. Here, we report that the stemness regulator Sox2 is a new, clinically important target of microRNA-21 (miR-21) in GBM, with implications for prognosis.

Genome-wide DNA methylation detection by MethylCap-seq and Infinium HumanMethylation450 BeadChips: an independent large-scale comparison.

Two cost-efficient genome-scale methodologies to assess DNA-methylation are MethylCap-seq and Illumina's Infinium HumanMethylation450 BeadChips (HM450). Objective information regarding the best-suited methodology for a specific research question is scant. Therefore, we performed a large-scale evaluation on a set of 70 brain tissue samples, i.

Chromosome 7 gain and DNA hypermethylation at the HOXA10 locus are associated with expression of a stem cell related HOX-signature in glioblastoma.

Background: HOX genes are a family of developmental genes that are expressed neither in the developing forebrain nor in the normal brain. Aberrant expression of a HOX-gene dominated stem-cell signature in glioblastoma has been linked with increased resistance to chemo-radiotherapy and sustained proliferation of glioma initiating cells. Here we describe the epigenetic and genetic alterations and their interactions associated with the expression of this signature in glioblastoma.

MGMT methylation analysis of glioblastoma on the Infinium methylation BeadChip identifies two distinct CpG regions associated with gene silencing and outcome, yielding a prediction model for comparisons across datasets, tumor grades, and CIMP-status.

The methylation status of the O(6)-methylguanine-DNA methyltransferase (MGMT) gene is an important predictive biomarker for benefit from alkylating agent therapy in glioblastoma. Recent studies in anaplastic glioma suggest a prognostic value for MGMT methylation. Investigation of pathogenetic and epigenetic features of this intriguingly distinct behavior requires accurate MGMT classification to assess high throughput molecular databases.

DNA fingerprinting of glioma cell lines and considerations on similarity measurements.

Glioma cell lines are an important tool for research in basic and translational neuro-oncology. Documentation of their genetic identity has become a requirement for scientific journals and grant applications to exclude cross-contamination and misidentification that lead to misinterpretation of results. Here, we report the standard 16 marker short tandem repeat (STR) DNA fingerprints for a panel of 39 widely used glioma cell lines as reference.

Presence of an oligodendroglioma-like component in newly diagnosed glioblastoma identifies a pathogenetically heterogeneous subgroup and lacks prognostic value: central pathology review of the EORTC_26981/NCIC_CE.3 trial.

Glioblastoma (GBM) is a morphologically heterogeneous tumor type with a median survival of only 15 months in clinical trial populations. However, survival varies greatly among patients. As part of a central pathology review, we addressed the question if patients with GBM displaying distinct morphologic features respond differently to combined chemo-radiotherapy with temozolomide.

Pathway analysis of glioblastoma tissue after preoperative treatment with the EGFR tyrosine kinase inhibitor gefitinib--a phase II trial.

Amplification of the epidermal growth factor receptor (EGFR) gene is one of the most common oncogenic alterations in glioblastoma (45%) making it a prime target for therapy. However, small molecule inhibitors of the EGFR tyrosine kinase showed disappointing efficacy in clinical trials for glioblastoma. Here we aimed at investigating the molecular effects of the tyrosine kinase inhibitor gefitinib on the EGFR signaling pathway in human glioblastoma.

Prospective study on procalcitonin and other systemic infection markers in patients with leukocytosis.

Objective: To better assess the diagnosis of an infection in patients presenting at an emergency department with peripheral blood leukocytosis (>10 x 10(9) cells/l) on laboratory testing.

Methods: We prospectively evaluated serum procalcitonin concentration (PCT), C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR). Patients were divided into two groups according to their final diagnosis: patients with infection and those without infection.

Active screening for pulmonary tuberculosis among immigrants by chest x-ray at the Swiss border.

Aim: To assess the number of immigrants with pulmonary tuberculosis detected by chest x-ray screening at the Swiss border.

Method: All adult immigrants entering Switzerland in 2004 were screened by chest x-ray (CXR). The number of radiological abnormalities suggestive of pulmonary tuberculosis, and the proportion requiring treatment for tuberculosis, were assessed retrospectively.

Brief alcohol intervention and alcohol assessment do not influence alcohol use in injured patients treated in the emergency department: a randomized controlled clinical trial.

Aims: To evaluate the effectiveness of brief alcohol intervention (BAI) in reducing alcohol use among hazardous drinkers treated in the emergency department (ED) after an injury; in addition it tests whether assessment of alcohol use without BAI is sufficient to reduce hazardous drinking.

Design: Randomized controlled clinical trial with 12-month follow-up conducted between January 2003 and June 2005.

Setting: Urban academic emergency department (ED) of the Lausanne University Hospital, Lausanne, Switzerland.

Impacts of global changes and extreme hydroclimatic events on macroinvertebrate community structures in the French Rhône River.

We assessed the temporal changes in and the relationships between the structures of the macroinvertebrate communities and the environmental conditions of the French Rhône River (the river from Lake Geneva to the Mediterranean Sea) over the last 20 years (1985-2004). Multisite environmental and biological datasets were analysed using multiple CO-inertia analysis (MCOA) and Procrustean analysis. Changes in environmental conditions were mainly marked by an improvement in water quality between 1985 and 1991 and by an increase in water temperature from 1985 onwards due to climate change.

Deletion of mu- and kappa-opioid receptors in mice changes epidermal hypertrophy, density of peripheral nerve endings, and itch behavior.

The mu- (MOR) and kappa- (KOR) opioid receptors have been implicated in the regulation of homeostasis of non-neuronal cells, such as keratinocytes, and sensations like pain and chronic pruritus. Therefore, we have studied the phenotype of skin after deletion of MOR and KOR. In addition, we applied a dry skin model in these knockout mice and compared the different mice before and after induction of the dermatitis in terms of epidermal thickness, epidermal peripheral nerve ending distribution, dermal inflammatory infiltrate (mast cells, CD4 positive lymphocytes), and scratching behavior.

At-risk drinking and drug use among patients seeking care in an emergency department.

Objective: This study reports the frequency of alcohol use and associated tobacco and drug use among emergency department (ED) patients, in order to increase physician awareness and treatment of women and men seeking care in ED settings.

Method: All adults seen in the ED at the University Hospital in Lausanne, Switzerland, between 11 AM and 11 PM were screened by direct interview for at-risk drinking, tobacco use, drug use, and depression during an 18-month period.

Results: A total of 8,599 patients (4,006 women and 4,593 men) participated in the screening procedure and provided full data on the variables in our analysis.

Deletion of delta-opioid receptor in mice alters skin differentiation and delays wound healing.

In addition to their well-known antinociceptive action, opioids can modulate non-neuronal functions, such as immune activity and physiology of different cell types. Several findings suggest that the delta-opioid receptor (DOR) and its endogenous ligands (enkephalins) are important players in cell differentiation and proliferation. Here we show the expression of DOR in mouse skin and human skin cultured fibroblasts and keratinocytes using RT-PCR.

Multiple co-inertia analysis: a tool for assessing synchrony in the temporal variability of aquatic communities.

Multitable techniques are rarely used for investigating patterns in ecological data surveys despite their ability to deal with the spatial and/or temporal stability of assemblages. Based on a covariance optimisation criterion, Multiple Co-inertia analysis (MCOA) enables the simultaneous ordination of several tables. Such analysis allows the representation of the stable vs.