Actionable FGFR1 and BRAF mutations in adult circumscribed gliomas.

Purpose: Circumscribed gliomas -pilocytic astrocytomas (PA), gangliogliomas (GG), ependymomas (EP)- are mostly low-grade tumours but may progress to anaplasia and sometimes surgery can be challenging due to deep anatomical localization. Because of the high frequency of MAPK-pathway alterations and availability of targeted therapies for FGFR1 and BRAF-mutated tumors, we investigated these mutational hotspots in a cohort of adult circumscribed gliomas.

Methods: Adult patients (>15 years) with diagnosis of PA, GG, EP and DNET were retrospectively identified from two institutions databases.

DNA repair complex licenses acetylation of H2A.Z.1 by KAT2A during transcription.

Post-translational modifications of histone variant H2A.Z accompany gene transactivation, but its modifying enzymes still remain elusive. Here, we reveal a hitherto unknown function of human KAT2A (GCN5) as a histone acetyltransferase (HAT) of H2A.

CD34 Identifies a Subset of Proliferating Microglial Cells Associated with Degenerating Motor Neurons in ALS.

Amyotrophic lateral sclerosis (ALS) is characterized by degeneration of upper and lower motor neurons accompanied by proliferation of reactive microglia in affected regions. However, it is unknown whether the hematopoietic marker CD34 can identify a subpopulation of proliferating microglial cells in the ALS degenerating spinal cord. Immunohistochemistry for CD34 and microglia markers was performed in lumbar spinal cords of ALS rats bearing the SOD1 mutation and autopsied ALS and control human subjects.

TRIM33 deficiency in monocytes and macrophages impairs resolution of colonic inflammation.

Background: Mature myeloid cells play a crucial role in Crohn's disease (CD) but the molecular players that regulate their functions in CD are not fully characterized. We and others have shown that TRIM33 is involved in the innate immune response and in the inflammatory response but TRIM33 role in intestinal inflammation is not known. In this study, we investigated the role of TRIM33 in myeloid cells during dextran sulfate sodium (DSS)-induced colitis.

qDSB-Seq is a general method for genome-wide quantification of DNA double-strand breaks using sequencing.

DNA double-strand breaks (DSBs) are among the most lethal types of DNA damage and frequently cause genome instability. Sequencing-based methods for mapping DSBs have been developed but they allow measurement only of relative frequencies of DSBs between loci, which limits our understanding of the physiological relevance of detected DSBs. Here we propose quantitative DSB sequencing (qDSB-Seq), a method providing both DSB frequencies per cell and their precise genomic coordinates.

TFIIE orchestrates the recruitment of the TFIIH kinase module at promoter before release during transcription.

In eukaryotes, the general transcription factors TFIIE and TFIIH assemble at the transcription start site with RNA Polymerase II. However, the mechanism by which these transcription factors incorporate the preinitiation complex and coordinate their action during RNA polymerase II transcription remains elusive. Here we show that the TFIIEα and TFIIEβ subunits anchor the TFIIH kinase module (CAK) within the preinitiation complex.

Polyploidy spectrum: a new marker in HCC classification.

Objectives: Polyploidy is a fascinating characteristic of liver parenchyma. Hepatocyte polyploidy depends on the DNA content of each nucleus (nuclear ploidy) and the number of nuclei per cell (cellular ploidy). Which role can be assigned to polyploidy during human hepatocellular carcinoma (HCC) development is still an open question.

Obesity-induced activation of JunD promotes myocardial lipid accumulation and metabolic cardiomyopathy.

Aims: Metabolic cardiomyopathy (MC)-characterized by intra-myocardial triglyceride (TG) accumulation and lipotoxic damage-is an emerging cause of heart failure in obese patients. Yet, its mechanisms remain poorly understood. The Activator Protein 1 (AP-1) member JunD was recently identified as a key modulator of hepatic lipid metabolism in obese mice.

PML-Regulated Mitochondrial Metabolism Enhances Chemosensitivity in Human Ovarian Cancers.

High-grade serous ovarian cancer (HGSOC) remains an unmet medical challenge. Here, we unravel an unanticipated metabolic heterogeneity in HGSOC. By combining proteomic, metabolomic, and bioergenetic analyses, we identify two molecular subgroups, low- and high-OXPHOS.

Designed Surface Topographies Control ICAM-1 Expression in Tonsil-Derived Human Stromal Cells.

Fibroblastic reticular cells (FRCs), the T-cell zone stromal cell subtype in the lymph nodes, create a scaffold for adhesion and migration of immune cells, thus allowing them to communicate. Although known to be important for the initiation of immune responses, studies about FRCs and their interactions have been impeded because FRCs are limited in availability and lose their function upon culture expansion. To circumvent these limitations, stromal cell precursors can be mechanotranduced to form mature FRCs.

TRPV1 variants impair intracellular Ca signaling and may confer susceptibility to malignant hyperthermia.

Purpose: Malignant hyperthermia (MH) is a pharmacogenetic disorder arising from uncontrolled muscle calcium release due to an abnormality in the sarcoplasmic reticulum (SR) calcium-release mechanism triggered by halogenated inhalational anesthetics. However, the molecular mechanisms involved are still incomplete.

Methods: We aimed to identify transient receptor potential vanilloid 1 (TRPV1) variants within the entire coding sequence in patients who developed sensitivity to MH of unknown etiology.

Author Correction: IMMP2L: a mitochondrial protease suppressing cellular senescence.

We apologize for an error we just found in the paper published online on 29 May 2018. The protein SERPINB4 is mistakenly indicated as SERPIN4B for three times in the main text and once in Fig. 1.

Dependence receptors - the dark side awakens.

Transmembrane receptors are usually seen as on and off switches: when the specific ligand is bound, the receptor is on and transduces a downstream signal, whereas when the ligand is absent, the receptor is off. Over the last two decades several reports have argued for an alternative view where some receptors, depending on the context, will be active both in the presence and in the absence of ligand, being sort of on and on switch rather than on and off. These receptors have been named dependence receptors (DR) and they share the ability to actively trigger cell death when unbound by their respective ligands.

Involvement of the FOXO6 transcriptional factor in breast carcinogenesis.

In mammals, FOXO transcriptional factors form a family of four members (FOXO1, 3, 4, and 6) involved in the modulation proliferation, apoptosis, and carcinogenesis. The role of the FOXO family in breast cancer remains poorly elucidated. According to the cellular context and the stage of the disease, FOXOs can have opposite effects on carcinogenesis.

Mitochondrial MDM2 Regulates Respiratory Complex I Activity Independently of p53.

Accumulating evidence indicates that the MDM2 oncoprotein promotes tumorigenesis beyond its canonical negative effects on the p53 tumor suppressor, but these p53-independent functions remain poorly understood. Here, we show that a fraction of endogenous MDM2 is actively imported in mitochondria to control respiration and mitochondrial dynamics independently of p53. Mitochondrial MDM2 represses the transcription of NADH-dehydrogenase 6 (MT-ND6) in vitro and in vivo, impinging on respiratory complex I activity and enhancing mitochondrial ROS production.

Changes in chromatin state reveal ARNT2 at a node of a tumorigenic transcription factor signature driving glioblastoma cell aggressiveness.

Although a growing body of evidence indicates that phenotypic plasticity exhibited by glioblastoma cells plays a central role in tumor development and post-therapy recurrence, the master drivers of their aggressiveness remain elusive. Here we mapped the changes in active (H3K4me3) and repressive (H3K27me3) histone modifications accompanying the repression of glioblastoma stem-like cells tumorigenicity. Genes with changing histone marks delineated a network of transcription factors related to cancerous behavior, stem state, and neural development, highlighting a previously unsuspected association between repression of ARNT2 and loss of cell tumorigenicity.

Evidence for mast cells contributing to neuromuscular pathology in an inherited model of ALS.

Evidence indicates that neuroinflammation contributes to motor neuron degeneration in amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease leading to progressive muscular paralysis. However, it remains elusive whether inflammatory cells can interact with degenerating distal motor axons, influencing the progressive denervation of neuromuscular junctions (NMJs). By analyzing the muscle extensor digitorum longus (EDL) following paralysis onset in the SOD1G93A rat model, we have observed a massive infiltration and degranulation of mast cells, starting after paralysis onset and correlating with progressive NMJ denervation.

HTLV-1-induced leukotriene B4 secretion by T cells promotes T cell recruitment and virus propagation.

The human T-lymphotropic virus type 1 (HTLV-1) is efficiently transmitted through cellular contacts. While the molecular mechanisms of viral cell-to-cell propagation have been extensively studied in vitro, those facilitating the encounter between infected and target cells remain unknown. In this study, we demonstrate that HTLV-1-infected CD4 T cells secrete a potent chemoattractant, leukotriene B4 (LTB4).

Anticancer effects of the microbiome and its products.

The human gut microbiome modulates many host processes, including metabolism, inflammation, and immune and cellular responses. It is becoming increasingly apparent that the microbiome can also influence the development of cancer. In preclinical models, the host response to cancer treatment has been improved by modulating the gut microbiome; this is known to have an altered composition in many diseases, including cancer.

ALS Clinical Trials Review: 20 Years of Failure. Are We Any Closer to Registering a New Treatment?

Amyotrophic lateral sclerosis (ALS) is a devastating condition with an estimated mortality of 30,000 patients a year worldwide. The median reported survival time since onset ranges from 24 to 48 months. Riluzole is the only currently approved mildly efficacious treatment.

Histone H3.3 regulates mitotic progression in mouse embryonic fibroblasts.

H3.3 is a histone variant that marks transcription start sites as well as telomeres and heterochromatic sites on the genome. The presence of H3.