BRAF mutations may identify a clinically distinct subset of glioblastoma

Glioblastoma (GBM) is the most common primary malignant brain tumor in adults. Prior studies examining the mutational landscape of GBM revealed recurrent alterations in genes that regulate the same growth control pathways. To this regard, ~ 40% of GBM harbor EGFR alterations, whereas BRAF variants are rare. Existing data suggests that gain-of-function mutations in these genes are mutually exclusive. This study was designed to explore the clinical, pathological, and molecular differences between EGFR- and BRAF-mutated GBM. We reviewed retrospective clinical data from 89 GBM patients referred for molecular testing between November 2012 and December 2015. Differences in tumor mutational profile, location, histology, and survival outcomes were compared in patients with EGFR- versus BRAF-mutated tumors, and microarray data from The Cancer Genome Atlas was used to assess differential gene expression between the groups. Individuals with BRAF-mutant tumors were typically younger and survived longer relative to those with EGFR-mutant tumors, even in the absence of targeted treatments. BRAF-mutant tumors lacked distinct histomorphology but exhibited unique localization in the brain, typically arising adjacent to the lateral ventricles. Compared to EGFR- and IDH1-mutant tumors, BRAF-mutant tumors showed increased expression of genes related to a trophoblast-like phenotype, specifically HLA-G and pregnancy specific glycoproteins, that have been implicated in invasion and immune evasion. Taken together, these observations suggest a distinct clinical presentation, brain location, and gene expression profile for BRAF-mutant tumors. Pending further study, this may prove useful in the stratification and management of GBM

Crohn\u27s disease-associated ATG16L1 T300A genotype is associated with improved survival in gastric cancer

BACKGROUND: A non-synonymous single nucleotide polymorphism of the ATG16L1 gene, T300A, is a major Crohn\u27s disease (CD) susceptibility allele, and is known to be associated with increased apoptosis induction in the small intestinal crypt base in CD subjects and mouse models. We hypothesized that ATG16L1 T300A genotype also correlates with increased tumor apoptosis and therefore could lead to superior clinical outcome in cancer subjects. METHODS: T300A genotyping by Taqman assay was performed for gastric carcinoma subjects who underwent resection from two academic medical centers. Transcriptomic analysis was performed by RNA-seq on formalin-fixed paraffin-embedded cancerous tissue. Tumor apoptosis and autophagy were determined by cleaved caspase-3 and p62 immunohistochemistry, respectively. The subjects\u27 genotypes were correlated with demographics, various histopathologic features, transcriptome, and clinical outcome. FINDINGS: Of the 220 genotyped subjects, 163 (74%) subjects carried the T300A allele(s), including 55 (25%) homozygous and 108 (49%) heterozygous subjects. The T300A/T300A subjects had superior overall survival than the other groups. Their tumors were associated with increased CD-like lymphoid aggregates and increased tumor apoptosis without concurrent increase in tumor mitosis or defective autophagy. Transcriptomic analysis showed upregulation of WNT/β-catenin signaling and downregulation of PPAR, EGFR, and inflammatory chemokine pathways in tumors of T300A/T300A subjects. INTERPRETATION: Gastric carcinoma of subjects with the T300A/T300A genotype is associated with repressed EGFR and PPAR pathways, increased tumor apoptosis, and improved overall survival. Genotyping gastric cancer subjects may provide additional insight for clinical stratification

Model Convolution: A Computational Approach to Digital Image Interpretation

Digital fluorescence microscopy is commonly used to track individual proteins and their dynamics in living cells. However, extracting molecule-specific information from fluorescence images is often limited by the noise and blur intrinsic to the cell and the imaging system. Here we discuss a method called “model-convolution,” which uses experimentally measured noise and blur to simulate the process of imaging fluorescent proteins whose spatial distribution cannot be resolved. We then compare model-convolution to the more standard approach of experimental deconvolution. In some circumstances, standard experimental deconvolution approaches fail to yield the correct underlying fluorophore distribution. In these situations, model-convolution removes the uncertainty associated with deconvolution and therefore allows direct statistical comparison of experimental and theoretical data. Thus, if there are structural constraints on molecular organization, the model-convolution method better utilizes information gathered via fluorescence microscopy, and naturally integrates experiment and theory

ISSN exercise & sport nutrition review: research & recommendations

Sports nutrition is a constantly evolving field with hundreds of research papers published annually. For this reason, keeping up to date with the literature is often difficult. This paper is a five year update of the sports nutrition review article published as the lead paper to launch the JISSN in 2004 and presents a well-referenced overview of the current state of the science related to how to optimize training and athletic performance through nutrition. More specifically, this paper provides an overview of: 1.) The definitional category of ergogenic aids and dietary supplements; 2.) How dietary supplements are legally regulated; 3.) How to evaluate the scientific merit of nutritional supplements; 4.) General nutritional strategies to optimize performance and enhance recovery; and, 5.) An overview of our current understanding of the ergogenic value of nutrition and dietary supplementation in regards to weight gain, weight loss, and performance enhancement. Our hope is that ISSN members and individuals interested in sports nutrition find this review useful in their daily practice and consultation with their clients

Crohn's disease-associated ATG16L1 T300A genotype is associated with improved survival in gastric cancer.

BackgroundA non-synonymous single nucleotide polymorphism of the ATG16L1 gene, T300A, is a major Crohn's disease (CD) susceptibility allele, and is known to be associated with increased apoptosis induction in the small intestinal crypt base in CD subjects and mouse models. We hypothesized that ATG16L1 T300A genotype also correlates with increased tumor apoptosis and therefore could lead to superior clinical outcome in cancer subjects.MethodsT300A genotyping by Taqman assay was performed for gastric carcinoma subjects who underwent resection from two academic medical centers. Transcriptomic analysis was performed by RNA-seq on formalin-fixed paraffin-embedded cancerous tissue. Tumor apoptosis and autophagy were determined by cleaved caspase-3 and p62 immunohistochemistry, respectively. The subjects' genotypes were correlated with demographics, various histopathologic features, transcriptome, and clinical outcome.FindingsOf the 220 genotyped subjects, 163 (74%) subjects carried the T300A allele(s), including 55 (25%) homozygous and 108 (49%) heterozygous subjects. The T300A/T300A subjects had superior overall survival than the other groups. Their tumors were associated with increased CD-like lymphoid aggregates and increased tumor apoptosis without concurrent increase in tumor mitosis or defective autophagy. Transcriptomic analysis showed upregulation of WNT/β-catenin signaling and downregulation of PPAR, EGFR, and inflammatory chemokine pathways in tumors of T300A/T300A subjects.InterpretationGastric carcinoma of subjects with the T300A/T300A genotype is associated with repressed EGFR and PPAR pathways, increased tumor apoptosis, and improved overall survival. Genotyping gastric cancer subjects may provide additional insight for clinical stratification

Distinct gene expression signatures comparing latent tuberculosis infection with different routes of Bacillus Calmette-Guérin vaccination

Abstract Tuberculosis remains an international health threat partly because of limited protection from pulmonary tuberculosis provided by standard intradermal vaccination with Bacillus of Calmette and Guérin (BCG); this may reflect the inability of intradermal vaccination to optimally induce pulmonary immunity. In contrast, respiratory Mycobacterium tuberculosis infection usually results in the immune-mediated bacillary containment of latent tuberculosis infection (LTBI). Here we present RNA-Seq-based assessments of systemic and pulmonary immune cells from LTBI participants and recipients of intradermal and oral BCG. LTBI individuals uniquely display ongoing immune activation and robust CD4 T cell recall responses in blood and lung. Intradermal BCG is associated with robust systemic immunity but only limited pulmonary immunity. Conversely, oral BCG induces limited systemic immunity but distinct pulmonary responses including enhanced inflammasome activation potentially associated with mucosal-associated invariant T cells. Further, IL-9 is identified as a component of systemic immunity in LTBI and intradermal BCG, and pulmonary immunity following oral BCG

Characterization of the KRN Cell Transfer Model of Rheumatoid Arthritis (KRN-CTM), a Chronic Yet Synchronized Version of the K/BxN Mouse

In this study, a chronic yet synchronized version of the K/BxN mouse, the KRN-cell transfer model (KRN-CTM), was developed and extensively characterized. The transfer of purified splenic KRN T cells into T cell-deficient B6.TCR.Cα−/−H-2b/g7 mice induced anti-glucose 6-phosphate isomerase antibody-dependent chronic arthritis in 100% of the mice with uniform onset of disease 7 days after T cell transfer. Cellular infiltrations were assessed by whole-ankle transcript microarray, cytokine and chemokine levels, and microscopic and immunohistochemical analyses 7 through 42 days after T cell transfer. Transcripts identified an influx of monocytes/macrophages and neutrophils into the ankles and identified temporal progression of cartilage damage and bone resorption. In both serum and ankle tissue there was a significant elevation in interleukin-6, whereas macrophage inflammatory protein-1 α and monocyte chemotactic protein-1 were only elevated in tissue. Microscopic and immunohistochemical analyses revealed a time course for edema, synovial hypertrophy and hyperplasia, infiltration of F4/80-positive monocytes/macrophages and myeloperoxidase-positive neutrophils, destruction of articular cartilage, pannus invasion, bone resorption, extra-articular fibroplasia, and joint ankylosis. The KRN cell transfer model replicates many features of chronic rheumatoid arthritis in humans in a synchronized manner and lends itself to manipulation of adoptively transferred T cells and characterizing specific genes and T cell subsets responsible for rheumatoid arthritis pathogenesis and progression

Effect of a Multifactorial Fall Injury Prevention Intervention on Patient Well-Being: The STRIDE Study.

Background/objectivesIn the Strategies to Reduce Injuries and Develop Confidence in Elders (STRIDE) study, a multifactorial intervention was associated with a nonsignificant 8% reduction in time to first serious fall injury but a significant 10% reduction in time to first self-reported fall injury relative to enhanced usual care. The effect of the intervention on other outcomes important to patients has not yet been reported. We aimed to evaluate the effect of the intervention on patient well-being including concern about falling, anxiety, depression, physical function, and disability.DesignPragmatic cluster-randomized trial of 5,451 community-living persons at high risk for serious fall injuries.SettingA total of 86 primary care practices within 10 U.S. healthcare systems.ParticipantsA random subsample of 743 persons aged 75 and older.MeasurementsThe well-being measures, assessed at baseline, 12 months, and 24 months, included a modified version of the Fall Efficacy Scale, Patient-Reported Outcomes Measurement Information System (PROMIS) anxiety and depression scales, and Late-Life Function and Disability Instrument.ResultsParticipants in the intervention (n = 384) and control groups (n = 359) were comparable in age: mean (standard deviation) of 81.9 (4.7) versus 81.8 (5.0) years. Mean scores were similar between groups at 12 and 24 months for concern about falling, physical function, and disability, whereas the intervention group's mean scores on anxiety and depression were .7 points lower (i.e., better) at 12 months and .6 to .8 points lower at 24 months. For each of these outcomes, differences between the groups' adjusted least square mean changes from baseline to 12 and 24 months, respectively, were quantitatively small. The overall difference in means between groups over 2 years was statistically significant only for depression, favoring the intervention: -1.19 (99% confidence interval, -2.36 to -.02), with 3.5 points representing a minimally important difference.ConclusionsSTRIDE's multifactorial intervention to reduce fall injuries was not associated with clinically meaningful improvements in patient well-being