Apoptotic Signaling Pathways in Glioblastoma and Therapeutic Implications

Glioblastoma multiforme (GBM) is the most hostile type of brain cancer. Its aggressiveness is due to increased invasion, migration, proliferation, angiogenesis, and a decreased apoptosis. In this review, we discuss the role of key regulators of apoptosis in GBM and glioblastoma stem cells. Given their importance in the etiology and pathogenesis of GBM, these signaling molecules may represent potential therapeutic targets.

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DNA Damage as a Driver for Growth Delay: Chromosome Instability Syndromes with Intrauterine Growth Retardation

DNA is constantly exposed to endogenous and exogenous mutagenic stimuli that are capable of producing diverse lesions. In order to protect the integrity of the genetic material, a wide array of DNA repair systems that can target each specific lesion has evolved. Despite the availability of several repair pathways, a common general program known as the DNA damage response (DDR) is stimulated to promote lesion detection, signaling, and repair in order to maintain genetic integrity. The genes that participate in these pathways are subject to mutation; a loss in their function would result in impaired DNA repair and genomic instability. When the DDR is constitutionally altered, every cell of the organism, starting from development, will show DNA damage and subsequent genomic instability. The cellular response to this is either uncontrolled proliferation and cell cycle deregulation that ensues overgrowth, or apoptosis and senescence that result in tissue hypoplasia. These diverging growth abnormalities can clinically translate as cancer or growth retardation; both features can be found in chromosome instability syndromes (CIS). The analysis of the clinical, cellular, and molecular phenotypes of CIS with intrauterine growth retardation allows inferring that replication alteration is their unifying feature.

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Infusion of leukocytes from HLA haplo-identical familial donors as an adjuvant in the HLH-2004 protocol to treat the virus-associated adult hemophagocytic lymphohistiocytosis: a retrospective study of 26 patients

Abstract

Adult hemophagocytic lymphohistiocytosis (HLH) is a fatal disease with poor survival and a limited role of drug therapies. To help to recognize virus and enhance survival, we infused leukocytes derived from human leukocyte antigen (HLA) haplo-identical familial donors to patients. We retrospectively investigated 26 adult virus-associated hemophagocytic syndrome (VAHS) patients' medical records from 2006–2017. Eleven of the 26 patients accepted relatives' derived leukocytes infusions in addition to drug therapies recommended in the HLH-2004 protocol. The leukocyte doses ranged from 0.75 to 3.30×10⁸ per kilogram of body weight. The other 15 patients accepted immunosuppressive and supportive therapies referred to in the HLH-2004 protocol. We compared the treatment outcomes of the two groups of patients. Patients in the cell infusion group had a lower viral load (P = 0.023) and better laboratory results and prolonged overall survival (60.44 vs. 20.18 weeks, P = 0.047). A factor that might relate to overall survival is platelet count (P = 0.032), except for the leukocyte infusions (P = 0.012). For patients without acceptable donors, infusions of leukocytes from HLA haplo-identical familial donors could be a feasible treatment to prolong overall survival as an adjuvant to drug therapies.

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Advances in Microbiology Vol.7,No.10 (October 2017)

Role of Fungal Biomass in N-Hexane Biofiltration
Biofiltration, N-Hexane, Trickle Bed Air Biofilter (TBAB), VOCs, Fungi
Paper Information Full Paper: PDF (Size:787KB)
DOI: 10.4236/aim.2017.710053

Age Does Not Affect the Induction of Mortality by the Foodborne Pathogen Salmonella enterica in Caenorhabditis elegans
Salmonella enterica, Caenorhabditis elegans, Aging, Infection
Paper Information Full Paper: PDF (Size:362KB)
DOI: 10.4236/aim.2017.710054

Treatment with Enterococcus faecalis CECT7121 Is Not Effective as Therapy in Mice with an Established Allergy Status
Enterococcus faecalis CECT7121, Ovalbumin-Allergy Murine Model, Immunoglobulin E, Th2 Cytokines, Probiotics
Paper Information Full Paper: PDF (Size:502KB)
DOI: 10.4236/aim.2017.710055

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Decreased Helios Expression in Regulatory T Cells in Acute Coronary Syndrome

Regulatory T cells (Tregs) play an essential role in acute coronary syndrome (ACS). However, there is debate about which Treg subsets are truly critical to ACS. Helios, a transcription factor, was recently reported to be a bona fide marker for natural Tregs or activated Tregs with a suppression function, but little is known about its role in ACS. We therefore examined Helios+ Tregs in patients with ACS, patients with stable angina, and control subjects. 73 patients with ACS, 30 patients with stable angina, and 48 control subjects were enrolled. The frequencies and estimated absolute numbers of different Treg subsets in peripheral blood were measured by flow cytometry. Plasma cytokine level was measured by ELISA. The mRNA expression of Foxp3 and Helios in purified CD4+ T cells was determined by RT-PCR. Helios+ Tregs was decreased significantly in patients with ACS. The frequency and estimated absolute numbers of CD4+Foxp3+Helios+ Tregs were negatively correlated with IL-6 and positively correlated with circulating level of TGF-beta1 and HDL-C. The mRNA expression of Foxp3 and Helios was decreased in CD4+ T cells from patients with ACS. In summary, Helios+ Tregs was downregulated in patients with ACS and may play a role in ACS.

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Enhancement of Angiogenesis by Ultrasound-Targeted Microbubble Destruction Combined with Nuclear Localization Signaling Peptides in Canine Myocardial Infarction

Objective. This study aimed to develop a gene delivery system using ultrasound-targeted microbubbles destruction (UTMD) combined with nuclear localization signal (NLS) and investigate its efficacy and safety for therapeutic angiogenesis in canine myocardial infarction (MI) model. Methods. Fifty MI dogs were randomly divided into 5 groups and transfected with Ang-1 gene plasmid: (i) group A: only injection of microbubbles and Ang-1 plasmid; (ii) group B: only UTMD mediated gene transfection; (iii) group C: UTMD combined with classical NLS mediated gene transfection; (iv) group D: UTMD combined with mutational NLS mediated transfection; and (v) group E: UTMD combined with classical NLS in the presence of a nucleus transport blocker. The mRNA and protein expression of Ang-1 gene, microvessel density (MVD) cardiac troponin I (cTnI), and cardiac function were determined after transfection. Results. The expression of mRNA and protein of Ang-1 gene in group C was significantly higher than that of the other groups (all P

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Efficacy and Safety of Compound Kushen Injection on Patients with Advanced Colon Cancer: A Meta-Analysis of Randomized Controlled Trials

Objective. The efficacy and safety of Compound Kushen Injection (CKI) on advanced colon cancer remain controversial. We undertook a systematic meta-analysis of randomized controlled clinical studies on this issue. Methods. A comprehensive literature search was conducted by searching the following electronic databases: PubMed, Cochrane, Chinese Biological Medical disc, Chinese National Knowledge Infrastructure, and Wan-Fang Database in China by the end of January 31, 2017, without language restriction. Meta-analysis was performed by using the random effects model to estimate the summary odd ratio (OR) with 95% confidence interval (CI) according to the study design. Stata 12.0 software was used for data analysis. The heterogeneity, sensitivity, and publication bias were assessed, respectively. Results. A total of 14 trials met the inclusion criteria in present meta-analysis. The results suggested that CKI combined with chemotherapeutic drugs was favorable for the treatment of advanced colon cancer and could improve the patients' life quality. Funnel plot analysis and Egger's test suggested that there was not significant publication bias, and the sensitivity analysis indicated stable results. Conclusion. The current evidence suggested that CKI is favorable to improve the efficacy of chemotherapeutic drugs in patients with advanced colon cancer.

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Effects of Shizhifang on NLRP3 Inflammasome Activation and Renal Tubular Injury in Hyperuricemic Rats

Objective. Uric acid (UA) activates the NLRP3-ASC-caspase-1 axis and triggers cascade inflammatory that leads to hyperuricemic nephropathy and hyperuricemia-induced renal tubular injury. The original study aims to verify the positive effects of the traditional Chinese medicinal formula Shizhifang (SZF) on ameliorating the hyperuricemia, tubular injury, and inflammasome infiltration in the kidneys of hyperuricemic lab rats. Method. Twenty-eight male Sprague-Dawley rats were divided into four groups: control group, oxonic acid potassium (OA) model group, OA + SZF group, and OA + Allopurinol group. We evaluated the mediating effects of SZF on renal mitochondrial reactive oxygen species (ROS) and oxidative stress (OS) products, protein expression of NLRP3-ASC-caspase-1 axis, and downstream inflammatory factors IL-1β and IL-18 after 7 weeks of animals feeding. Result. SZF alleviated OA-induced hyperuricemia and inhibited OS in hyperuricemic rats (). SZF effectively suppressed the expression of gene and protein of the NLRP3-ASC-caspase-1 axis through accommodating the ROS-TXNIP pathway (). Conclusion. Our data suggest that SZF alleviates renal tubular injury and inflammation infiltration by inhibiting NLRP3 inflammasome activation triggered by mitochondrial ROS in the kidneys of hyperuricemic lab rats.

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Value of oxyneurography, based on near infrared spectroscopy, in the diagnosis of carpal tunnel syndrome in comparison to provocative clinical diagnostic tests and nerve conduction studies

Near Infrared (NIR) is a form of electromagnetic radiation of the wavelength of 700-1000 nanometers. It is positioned within range of the infrared waves, between visible light and radio waves. Tissues absorb photons of NIR radiation with an aid of the molecules called chromophores that include haemoglobin (85-88%), myoglobin (10%) and oxidase of cytochrome C (2-5%) (Boushel and Piantadosi, 2000; Boushel et al., 2001). Oxidation state i.e. oxygenation of the chromophores changes the intensity of the absorbed light.

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What is the optimal frequency range for quantifying slow EEG activity in neonates? Insights from power spectra

Several weeks before and following term age, intermittent anterior slow waves in the delta frequency range (<4 Hz) are a normative neonatal EEG feature (e.g., Clancy et al., 2014; Fig.1A). Various quantitative electroencephalographic (qEEG) studies of infants born preterm have analyzed relative power of delta and other frequency bands. For example, across 60 healthy infants born at 26-41 weeks and assessed with EEG on the third day, Bell et al. (1991) reported gestational age (GA) was negatively correlated with relative "lower-delta" (0.25-1 Hz) power.

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Oxyneurography: A non-invasive NIRS technique to measure nerve oxygenation

Few people doubt the importance of cerebral blood flow integrity for the preservation of neural tissue. Blood flow compromise, causing a cerebro-vascular accident (CVA), results in nervous tissue damage or stroke.

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Detection of proximal conduction blocks using a triple stimulation technique improves the early diagnosis of Guillain–Barré syndrome

Guillain–Barré syndrome (GBS) is an acute autoimmune peripheral neuropathy with different subtypes (Wakerley et al., 2014). The diagnostic criteria include: clinical presentation (Van der Meché et al., 2001; Wakerley et al., 2014; Fokke et al., 2014), electrophysiological data, (Ho et al., 1995; Hadden et al., 1998; Van den Bergh and Piéret, 2004; Rajabally et al., 2015) and biological clues (Wakerley et al., 2014).

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Is This Urgency an Emergency?.....Sometimes

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Prostatic Adenocarcinoma in the Setting of Persistent Müllerian Duct Syndrome: A Case Report

Persistent Müllerian Duct Syndrome (PMDS) is a form of disordered sex development in which rudimentary Müllerian structures are identified in phenotypically and genotypically normal males. It is caused by defects in the anti-Müllerian hormone (AMH) system.Since patients with PMDS present with undescended testes, testosterone production by Leydig cells later in life is often decreased.The role of androgens in prostate cancerogenesis is well known. Cryptorchid testes and diminished testosterone levels in post pubertal life in patients with PMDS play a protective role against prostate cancer, and hence, prostate cancer is a rare event in patients with PMDS.

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The Notch pathway is activated in neoplastic progression in esophageal squamous cell carcinoma

The Notch signaling pathway is integral to normal human development and homeostasis and has a deterministic function on cell differentiation. Recent studies suggest aberrant Notch signaling may contribute to neoplastic progression by an increase in stem cell survival, chemoresistance, and the promotion of epithelial to mesenchymal transition. The goals of our study were to determine, utilizing quantitative technologies, the expression of activated Notch 1 in esophageal squamous cell carcinoma (SCC) and to determine the relationship between Notch 1 expression and various clinicopathologic parameters.

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EM Nerd-The Case of the Man Made of Straw Continues

We often view the results of a trial from the perspective of our own preconceived notions. We extrapolate the results far beyond the limits of the data based on our own system of beliefs, using p-values and confidence intervals as statistical armor to substantiate our positions. It is with this in mind that we turn […]

EMCrit by Rory Spiegel.

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In Vivo Imaging of Cx3cr1gfp/gfp Reporter Mice with Spectral-domain Optical Coherence Tomography and Scanning Laser Ophthalmoscopy

This protocol describes how high-resolution imaging techniques such as spectral domain optical coherence tomography and scanning laser ophthalmoscopy can be utilized in small rodents, using an ophthalmic imaging platform system, to obtain information on retinal thickness and microglial cell distribution, respectively.

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Slice Patch Clamp Technique for Analyzing Learning-Induced Plasticity

The slice patch clamp technique is an effective method for analyzing learning-induced changes in the intrinsic properties and plasticity of excitatory or inhibitory synapses.

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A New DAWN for Imaging-Based Selection in the Treatment of Acute Stroke

Two years ago, the publication of the MR CLEAN trial (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands), which investigated endovascular mechanical thrombectomy for the treatment of acute ischemic stroke, was called "a first step in the…

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Thrombectomy 6 to 24 Hours after Stroke with a Mismatch between Deficit and Infarct

Previous randomized trials that involved patients with acute stroke showed that endovascular thrombectomy had a clinical benefit when it was performed within 6 hours after the onset of stroke symptoms and that the benefit diminished as the interval between the time that the patient was last known…

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A New DAWN for Imaging-Based Selection in the Treatment of Acute Stroke

Two years ago, the publication of the MR CLEAN trial (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands), which investigated endovascular mechanical thrombectomy for the treatment of acute ischemic stroke, was called "a first step in the…

http://ift.tt/2mga5NI

Thrombectomy 6 to 24 Hours after Stroke with a Mismatch between Deficit and Infarct

Previous randomized trials that involved patients with acute stroke showed that endovascular thrombectomy had a clinical benefit when it was performed within 6 hours after the onset of stroke symptoms and that the benefit diminished as the interval between the time that the patient was last known…

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Naphthoquinones: a continuing source for discovery of therapeutic antineoplastic agents

Abstract

Naturally occurring naphthoquinones, usually in forms of botanical extracts, have been implicated with human life since ancient time, far earlier than their isolation and identification in modern era. The long use history of naphthoquinones has witnessed their functional shift from the original purposes as dyes and ornaments towards medicinal benefits. Hitherto, numerous studies have been carried out to elucidate the pharmacological profile of both natural and artificial naphthoquinones. A number of entities have been identified with promising therapeutic potential. Apart from the traditional effects of wound healing, anti-inflammatory, hemostatic, antifertility, insecticidal and antimicrobial, etc., the anticancer potential of naphthoquinones either in combination with other treatment approaches or on their own is being more and more realized. The molecular mechanisms of naphthoquinones in cells mainly fall into two categories as inducing oxidant stress by ROS (reactive oxygen species) generation, or directly interacting with traditional therapeutic targets in a non-oxidant mechanism. Based on this knowledge, optimized agents with naphthoquinones scaffold have been acquired and further tested. Hereby, we summarize the explored biological mechanisms of naphthoquinones in cells and review the application perspective of promising naphthoquinones in cancer therapies.

This article is protected by copyright. All rights reserved.

The explored biological mechanisms of naphthoquinones in cellular and the application perspective of promising naphthoquinones in cancer therapies were reviewed.

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Synthetic piperine amide analogues with antimycobacterial activity

Abstract

Piperine amide analogues are synthesized by replacement of the piperidine moiety with different types of cyclic amines, including adamantyl and monoterpene derived fragments. The compounds are screened for activity against Mycobacterium tuberculosis H37Rv. The most potent compounds are the 1-adamantyl and the monoterpene derived hybrids, which combine nanomolar antimycobacterial activity with low cytotoxicity against human cells. The presence of quaternary carbon atom as main structural requirement for anti-TB activity is pointed out by a QSAR study. The most promising compound is the (+)-isopinocampheylamine derived amide which is characterized with selectivity index of 1387.8.

This article is protected by copyright. All rights reserved.

A series of Piperine amide analogues are synthesized by replacing piperidine moiety with different types of cyclic amines, including cyclohexyl, bicyclo[2.2.1]heptyl, adamantyl and monoterpene derived fragments. The hybrid analogues with 1-adamantyl and the monoterpene fragments displayed nanomolar antimycobacterial activity with low cytotoxicity against human cells. A QSAR study pointed out the presence of quaternary carbon atom as main structural requirement for the activity. The most promising compound is the (+)-isopinocampheylamine derived amide, with selectivity index of 1387.8.

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Comparative Evaluation of 68Ga-labeled NODAGA, DOTAGA and HBED-CC conjugated cNGR Peptide Chelates as Tumor Targeted Molecular Imaging Probes

Abstract

The biological behavior of ⁶⁸Ga-based radiopharmaceuticals can be significantly affected by the chelators' attributes (size, charge, lipophilicity). Thus this study aimed at examining the influence of three different chelators, DOTAGA, NODAGA and HBED-CC on the distribution pattern of ⁶⁸Ga-labeled NGR peptides targeting CD13 receptors. ⁶⁸Ga-DOTAGA-c(NGR), ⁶⁸Ga-NODAGA-c(NGR) and ⁶⁸Ga-HBED-CC-c(NGR) were observed to be hydrophilic with respective log P values being -3.5±0.2, –3.3±0.08 and -2.8±0.14. The three radiotracers exhibited nearly similar uptake in human fibrosarcoma HT-1080 tumor cells with 86, 63 and 33% reduction during blocking studies with unlabeled cNGR peptide for ⁶⁸Ga-DOTAGA-c(NGR), ⁶⁸Ga-NODAGA-c(NGR) and ⁶⁸Ga-HBED-CC-c(NGR) respectively indicating higher receptor specificity of the first two radiotracers. The neutral radiotracer ⁶⁸Ga-NODAGA-c(NGR) demonstrated better target-to-non-target ratios during in vivo studies compared to its negatively charged counterparts, ⁶⁸Ga-DOTAGA-c(NGR) and ⁶⁸Ga-HBED-CC-c(NGR). The three radiotracers had similar HT-1080 tumor uptake and being hydrophilic exhibited renal excretion with minimal uptake in non-target organs. Significant reduction (p<0.005) in HT-1080 tumor uptake of the radiotracers was observed during blocking studies. It may be inferred from these studies that the three radiotracers are promising probes for in vivo imaging of CD13 receptor expressing cancer sites however ⁶⁸Ga-NODAGA-c(NGR) is a better candidate.

This article is protected by copyright. All rights reserved.

The goal of this study was to determine the influence of three different chelators, DOTAGA, NODAGA and HBED-CC on pharmacokinetics and biodistribution pattern of ⁶⁸Ga-labeled NGR peptides targeting CD13 receptors.

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A Structure-based Strategy toward the Development of Novel Candidates for Antimycobacterial Activity: Synthesis, Biological evaluation and Docking study

Abstract

Bacterial resistance to most of the available antibiotics has stimulated the discovery of novel efficacious antibacterial agents. Bedaquiline is first of its type that has been specifically introduced for the management of MDR-TB in combination with other drugs. In the current study, a series of isoniazid/ethambutol/pyrazinamide -quinoline conjugates based on the structures of Bedaquiline were designed and synthesized. Biological activity tests revealed that some of isoniazid/ethambutol-quinoline conjugates have useful antibiotic activity against MTB H37Rv (MIC: 2.0-8.0μg/mL). Furthermore, molecular docking calculations were performed for the most potent inhibitor to show its binding interactions within the active site of the possible target protein. Overall, these compounds represent novel valuable starting point with potent antimycobacterial activity and deserve further structural modifications.

This article is protected by copyright. All rights reserved.

In the current study, a series of isoniazid/ethambutol/pyrazinamide -quinoline conjugates based on the structures of Bedaquiline were designed and synthesized. Biological evaluation indicated that some of isoniazid/ethambutol-quinoline conjugates have useful activity against MTB H37Rv (MIC: 2.0-8.0μg/mL).

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A variant in PPP4R3A protects against Alzheimer-related metabolic decline

Abstract

Objectives: A reduction in glucose metabolism in the posterior cingulate cortex (PCC) predicts conversion to Alzheimer's disease (AD) and tracks disease progression, signifying its importance in AD. We aimed to use decline in PCC glucose metabolism as a proxy for the development and progression of AD to discover common genetic variants associated with disease vulnerability.

Methods: We performed a genome-wide association study (GWAS) of decline in PCC [¹⁸F] FDG PET measured in Alzheimer's Disease Neuroimaging Initiative (ADNI) participants (n=606). We then performed follow-up analyses to assess the impact of significant single nucleotide polymorphisms (SNPs) on disease risk and longitudinal cognitive performance in a large independent dataset (n=870). Lastly, we assessed whether significant SNPs influence gene expression using two RNA sequencing (RNA-Seq) datasets (n=210 & n=159).

Results: We demonstrate a novel genome-wide significant association between rs2273647-T in the gene PPP4R3A and reduced [¹⁸F] FDG decline (p= 4.44 x 10⁻⁸). In a follow-up analysis using an independent dataset, we demonstrate a protective effect of this variant against risk of conversion to MCI or AD (p=0.038) and against cognitive decline in individuals who develop dementia (p = 3.41 x 10⁻¹⁵). Furthermore, this variant is associated with altered gene expression in peripheral blood and altered PPPP4R3A transcript expression in temporal cortex, suggesting a role at the molecular level.

Interpretations: PPP4R3A is a gene involved in AD risk and progression. Given the protective effect of this variant PPP4R3A should be further investigated as a gene of interest in neurodegenerative diseases and as a potential target for AD therapies. This article is protected by copyright. All rights reserved.

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Heterogenous migraine aura symptoms correlate with visual cortex fMRI responses

Abstract

Objective: Migraine aura is sparsely studied due to the highly challenging task of capturing patients during aura. Cortical spreading depression (CSD) is likely the underlying phenomenon of aura. The possible correlation between the multifaceted phenomenology of aura symptoms and the effects of CSD on the brain has not been ascertained.

Methods: Five migraine patients were studied during various forms of aura symptoms induced by hypoxia, sham or physical exercise and photostimulation. The blood oxygenation level-dependent (BOLD) functional MRI (fMRI) signal response to visual stimulation was measured in retinotopic mapping defined visual cortex area V1 - V4.

Results: We found reduced BOLD response in patients reporting scotoma and increased response in patients who only experienced positive symptoms. Furthermore, patients with bilateral visual symptoms had corresponding bi-hemispherical changes in BOLD response.

Interpretation: These findings suggest that different aura symptoms reflect different types of cerebral dysfunction, which correspond to specific changes in BOLD signal reactivity. Furthermore, we provide evidence of bilateral CSD recorded by fMRI during bilateral aura symptoms. This article is protected by copyright. All rights reserved.

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A localized pallidal physiomarker in cervical dystonia

Abstract

Objective: Deep brain stimulation (DBS) allows for direct recordings of neuronal activity from the human basal ganglia. In Parkinson's disease, a disease-specific physiomarker was identified that is now used to investigate adaptive closed-loop stimulation in first studies. In dystonia such a physiomarker is missing.

Methods: Pallidal oscillations were recorded from 153 contact pairs in 27 patients. We investigated whether power amplitudes in theta and beta bands correlate with dystonic symptom severity across patients. We then projected theta power from each contact pair onto standard subcortical anatomy. This way, we defined a theta hot spot on a group level and investigated whether proximity of the active DBS contacts to it correlates with clinical improvement.

Results: Dystonic symptom severity significantly correlated with theta, but not beta oscillatory amplitudes (ρ=0.4; P=0.009) and interhemispheric coherence (ρ=0.5; P=0.002). The sweet spot of theta activity localized to the posterior third of the internal pallidum and theta power correlated with proximity to this location (ρ=0.23; P=0.002), which coincided with three previously published coordinates describing optimal stimulation targets. Finally, motor improvement through pallidal long term DBS correlated with theta peak amplitude (ρ=0.38; P=0.018).

Interpretation: Our findings suggest that theta oscillations in the internal pallidum are robustly associated with dystonic symptoms in cervical dystonia and may be a useful biomarker for adaptive closed-loop stimulation. Furthermore, theta oscillatory activity may have a predictive value for the clinical benefit after chronic DBS that could be used to improve intraoperative neurophysiological target mapping during electrode implantation. This article is protected by copyright. All rights reserved.

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Feeding the microbiota: transducer of nutrient signals for the host

In this episode Mairi McLean, Associate Editor of Gut journal, talks to Fergus Shanahan, Professor and Chair of the Department of Medicine at University College Cork. They discuss his recent paper in Gut entitled "Feeding the microbiota: transducer of nutrient signals for the host"

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Profiles of Women in Science: Prof. Ingrid Olson of Temple University

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Endoscopic submucosal dissection of early gastric neoplasms in the fornix using the newly developed scissors-type SB knife GX

Endoscopic submucosal dissection (ESD) using a scissors-type knife, the Stag-Beetle knife (SB knife, Sumitomo Bakelite, Tokyo, Japan), is considered technically easy and safe due to its ability to grasp the target tissue to allow controlled resection without the complex endoscopic tip control required with conventional ESD devices. There are two types of SB knife (short-type and Jr-type), used mainly for esophageal and colorectal neoplasms (1-3). Recently, a new type, SB knife GX, has been developed for gastric ESD. The ridged base of the blades helps grasp tissue more tightly. More details about the characteristics of SB knife GX and comparison with another scissors-type knife, Clutch Cutter (Fujifilm, Tokyo, Japan) (4), are described in the video.

This article is protected by copyright. All rights reserved.

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Tips for endoscopic stone-extraction using new short type double balloon endoscope for common bile duct stones in patients with surgically altered gastrointestinal anatomy

The endoscopic approach to pancreatobiliary diseases in postoperative patients had been difficult (1). Percutaneous or surgical interventions were applied as the first line policy. However, using double balloon endoscopes (DBE), especially the short-type DBE, radically made it practical and safe (2, 3). In this study, endoscopic technical tips using the newly developed short-type DBE (EI-580 BT; FUJIFILM Co, Tokyo, Japan) for stone-extraction via papilla for common bile duct stones in patients with Roux-en Y reconstruction post gastrectomy will be introduced.

This article is protected by copyright. All rights reserved.

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The Akkermansia-muciniphila is a gut microbiota signature in psoriasis

Abstract

Psoriasis is an immune-mediated chronic inflammatory skin disease. Although its pathogenesis is not fully understood, Th17 cells and the cytokines they produce, such as IL-17, IL-22 and IL-23, play critical roles in the pathogenesis of psoriasis. Evidence has demonstrated that psoriasis has some common features, including immune responses (due to Th17 cells) and inflammatory cytokine profiles, with systematic diseases including inflammatory bowel diseases (IBDs) and obesity. Recently, studies have demonstrated that the gut microbiota plays a crucial role in host homeostasis and immune response, particular in Th17 cells, but the role of the gut microbiota in psoriasis remains unclear. To study the relationship between gut microbiota and psoriasis, we analyzed microbiota profiles in psoriasis using a 16S rDNA sequencing platform, and we found that the abundance of Akkermansia muciniphila was significantly reduced in psoriatic patients. Akkermansia muciniphila is believed to have an important function in the pathogenesis of IBD and obesity; therefore, Akkermansia muciniphila, which is an indicator of health status, may be a key node for psoriasis as well as IBD and obesity. Taken together, our study identified that gut microbiota signature and function are significantly altered in the gut of psoriatic patients, which provides a novel angle to understanding the pathogenesis of psoriasis.

This article is protected by copyright. All rights reserved.

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Comprehensive study of three novel cases of TFEB-amplified renal cell carcinoma and review of the literature: evidence for a specific entity with poor outcome

Abstract

The first case of TFEB-amplified renal cell carcinoma was published in 2014. Since then, 29 additional cases have been described. The prognostic and therapeutic implications of this rare entity remain to be determined. We describe here the clinical, histological and genetic features of three novel cases, as well as the first complete literature review. Four tumors were examined from three patients selected from the large collection of genetically characterized renal tumors in our institution. The pathological and immunohistochemical features were centrally reviewed by a uropathologist. Quantitative and structural genomic abnormalities were analyzed using comparative genomic hybridization, fluorescence in situ hybridization and next generation sequencing. The three cases showed high-level amplification but no translocation of TFEB. Histologically, two tumors showed a papillary or pseudopapillary architecture. They did not show similarities with renal cell carcinoma harboring translocation of TFEB. The tumors were locally advanced high-grade lesions. They exhibited a metastatic course, which was rapidly leading to death in one patient. A second patient developed metastatic disease that did not respond to four lines of targeted treatments. The third patient had a protracted history of pulmonary and cardiac metastases. Complete clinical and biological data were examined and compared to those of the reported cases. Within the classification of renal tumors, TFEB-amplified renal cell carcinoma may constitute a novel entity characterized histologically by high grade, papillary or pseudopapillary architecture and necrotic remodeling and clinically by a poor outcome. Its pathogenesis has to be further characterized in order to develop appropriate targeted therapy. This article is protected by copyright. All rights reserved.

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Population representation among anatomical donors and the implication for medical student education

Abstract

Introduction: Dissection provides a unique opportunity to integrate anatomical and clinical education. Commonly, cadavers are randomly assigned to courses, which may result in skewed representation of patient populations. The primary aim of this study was to determine if the anatomical donors studied by students at Medical School (MS) accurately represent the disease burden of the local patient population. Materials and methods: This cross-sectional study compared Medical Center patient claims data and body donation data from the Anatomical Gift Program (AGP). This study examined age, race, sex and morbidities within a 10-year timeframe in 401,258 patients and 859 anatomical donors who met inclusion criteria. An independent t-test was conducted to compare the mean ages of the two populations. Chi square analysis was conducted on race, sex, and 10 morbidity categories. A Fischer's Exact test was conducted for two morbidity categories with n<10. Results: Demographic analysis showed a significant difference in age, and racial representation between the populations. No statistical difference was found regarding sex. Morbidities were separated into 22 ICD-10 categories. 12 categories were excluded and 10 were analyzed for population comparison. Two categories were over represented and seven were under-represented in the AGP population. One category showed no significant difference between populations. Conclusions: Targeted selection of cadavers in anatomy courses would improve morbidity variability in the anatomy lab. In addition, AGP acceptance guidelines should be evaluated to increase disease variation among the donor population. This article is protected by copyright. All rights reserved.

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Salivary uric acid and C-reactive protein associations with hypertensionin Midwestern Latino preadolescents and their parents

Abstract

Latino families face increased risk for hypertension. Serum-based uric acid and C-reactive protein have been linked to hypertension. However, a paucity of salivary biomarker data exists in this area for Latino families. Using salivary biomarkers enables less invasive options for biomedical and biosocial research, which is especially important among vulnerable populations facing increased health disparities. This study examined the associations between salivary uric (sUA) acid, salivary C-reactive protein (sCRP), and hypertension among 151 participants (57 children, 57 mothers, 37 fathers) from 57 Midwestern Latino families. Participants self-administered the salivary samples, and blood pressure was measured by researchers. Results showed sUA was associated across family members, and child hypertension was related to parents′ hypertension. sCRP was only related to sUA in fathers. Findings highlight the family-level health connections, along with the importance for further investigations using salivary biomarkers with Latinos, and the need for a robust sUA cut-off for hyperuricemia.

http://ift.tt/2i4VU9F

Mechanisms underpinning sympathetic nervous activity and its modulation using transcutaneous vagus nerve stimulation

Abstract

The autonomic nervous system, consisting of the sympathetic and parasympathetic branches, is a major contributor to maintaining cardiovascular variables within homeostatic limits. As we age or in certain pathological conditions, the balance between the two branches changes such that sympathetic activity is more dominant and this change in dominance negatively correlates with prognosis in conditions such as heart failure. We have shown that non-invasive stimulation of the tragus of the ear increases parasympathetic activity and reduces sympathetic activity and that extent of this effect is correlated with the baseline cardiovascular parameters of different subjects. The effects could be due to activation of the afferent branch of the vagus and potentially other sensory nerves in that region. This indicates that tragus stimulation may be a viable treatment in disorders where autonomic activity to the heart is compromised.

This article is protected by copyright. All rights reserved

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Liver X receptor activation inhibits SGLT2-mediated glucose transport in human renal proximal tubular cells

Abstract

Liver X receptors (LXRs) are members of a nuclear receptor family consisting of two isoforms, LXR-α and LXR-β. They play a major role in energy metabolism including lipid and glucose metabolism. Recent studies reported LXRs regulate plasma glucose although the mechanism is still uncertain. The present study investigated whether LXR activation regulates sodium glucose cotransporter2 (SGLT2) in human renal proximal tubular cells. LXR agonists, T0901317 and GW3965, inhibited SGLT2-mediated glucose uptake in concentration-dependent manners. The effect of T0901317 and GW3965 was attenuated by a LXR antagonist, fenofibrate. Activation of retinoid X receptor (RXR) agonist, bexarotene, potentiates the inhibitory effect of these ligands. Thus, the inhibitory effect of LXR agonists on SGLT2 was mediated and facilitated by LXR and RXR activation, respectively. In addition, the inhibitory effect of LXR agonists was not mediated by cytotoxicity. Exposing HK-2 cells, renal proximal tubular cell line, to LXR agonists significantly reduced the maximal transport rate (J_max) of SGLT2 without any effect on transporter affinity. Western blot analysis revealed LXR activation significantly decreased protein expression of SGLT2 with no change in mRNA level. In addition, LXR activation inhibited canagliflozin-sensitive short-circuits current which represents SGLT2-mediated glucose transport in polarized human renal proximal tubular cell monolayer. Furthermore, LXR activation inhibited transport function of SGLT2 in hyperglycemic conditions. As such, this study represents the evidence of LXR activation's inhibitory effect on glucose transport in human renal proximal tubular cells.

This article is protected by copyright. All rights reserved

http://ift.tt/2mgwryE

South African cactus pear seed oil: a comprehensive study on 42 spineless Burbank Opuntia ficus-indica and O. robusta cultivars

Abstract

Cactus pear fruit seeds contain oil that can be utilized for human consumption. Fourty-two South African cultivars were evaluated over two seasons for seed oil content and fatty acid composition in an attempt to ascertain the best oil yielding cultivar. Seed oil content varied among cultivars and seasons and the yield ranged between 4.09 and 8.76% of seed mass. The unsaturated fatty acids were the most prominent and were dominated by linoleic acid, which varied between 56.86 and 65.21%, followed by oleic acid (16.44 and 22.51%), while the saturated fatty acids palmitic and stearic acid content ranged from 12.72 to 16.05% and from 2.21 to 3.39%, respectively. Cultivar and variation in rainfall had a statistically significant effect on cactus pear seed oil content and fatty acid composition. Principal Component Analysis showed that certain cultivars were exclusively associated with specific characteristics. This was the most comprehensive study of the seed oil characteristics of the available cultivars in South Africa ever to be performed. The American Giant cultivar had the highest seed oil yield.

Practical applications: In a semi-arid country such as South Africa, the value of by-products and waste products from a drought resistant plant such as cactus pear should be emphasized. Cactus pear seed oil is a novel and expensive essential oil. The emergence of many small-holding farms and small-scale processing facilities necessitated a comprehensive investigation into the oil composition of all the available cactus pear cultivars. Essential knowledge regarding cultivar choice in terms of oil-production and specific fatty acid composition, as well as seasonal effects thereon, was generated with this research. This research indicated that the American Giant (Opuntia ficus-indica) cultivar had the highest oil yield wheras the Roly Poly cultivar had the highest linoleic acid content. This data will enable processors to make recommendations to producers to use cultivars with optimum yield and oil quality as production target.

http://ift.tt/2yRvYsy

Does more favourable handling of the cerebrospinal fluid increase the diagnostic sensitivity of Borrelia burgdorferi sensu lato-specific PCR in Lyme neuroborreliosis?

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http://ift.tt/2mfEOdG

Vaccine responses in newborns.

Vaccine responses in newborns.

Semin Immunopathol. 2017 Nov 09;:

Authors: Saso A, Kampmann B

Abstract
Immunisation of the newborn represents a key global strategy in overcoming morbidity and mortality due to infection in early life. Potential limitations, however, include poor immunogenicity, safety concerns and the development of tolerogenicity or hypo-responsiveness to either the same antigen and/or concomitant antigens administered at birth or in the subsequent months. Furthermore, the neonatal immunological milieu is polarised towards Th2-type immunity with dampening of Th1-type responses and impaired humoral immunity, resulting in qualitatively and quantitatively poorer antibody responses compared to older infants. Innate immunity also shows functional deficiency in antigen-presenting cells: the expression and signalling of Toll-like receptors undergo maturational changes associated with distinct functional responses. Nevertheless, the effectiveness of BCG, hepatitis B and oral polio vaccines, the only immunisations currently in use in the neonatal period, is proof of concept that vaccines can be successfully administered to the newborn via different routes of delivery to induce a range of protective mechanisms for three different diseases. In this review paper, we discuss the rationale for and challenges to neonatal immunisation, summarising progress made in the field, including lessons learnt from newborn vaccines in the pipeline. Furthermore, we explore important maternal, infant and environmental co-factors that may impede the success of current and future neonatal immunisation strategies. A variety of approaches have been proposed to overcome the inherent regulatory constraints of the newborn innate and adaptive immune system, including alternative routes of delivery, novel vaccine configurations, improved innate receptor agonists and optimised antigen-adjuvant combinations. Crucially, a dual strategy may be employed whereby immunisation at birth is used to prime the immune system in order to improve immunogenicity to subsequent homologous or heterologous boosters in later infancy. Similarly, potent non-specific immunomodulatory effects may be elicited when challenged with unrelated antigens, with the potential to reduce the overall risk of infection and allergic disease in early life.

PMID: 29124321 [PubMed - as supplied by publisher]

http://ift.tt/2md75BL

A temperature sensitive Mycobacterium paragordonae induces enhanced protective immune responses against mycobacterial infections in the mouse model.

A temperature sensitive Mycobacterium paragordonae induces enhanced protective immune responses against mycobacterial infections in the mouse model.

Sci Rep. 2017 Nov 09;7(1):15230

Authors: Kim BJ, Kim BR, Kook YH, Kim BJ

Abstract
Recently, we introduced a temperature sensitive Mycobacterium spp., Mycobacterium paragordonae (Mpg). Here, we checked its potential as a candidate for live vaccination against Mycobacterium tuberculosis and Mycobacterium abscessus. Intravenous infections of mice with Mpg led to lower colony forming units (CFUs) compared to infection with BCG, suggesting its usefulness as a live vaccine. The analyses of immune responses indicated that the highly protective immunity elicited by Mpg was dependent on effective dendritic maturation, shift of cytokine patterns and antibody production toward a Th1 phenotype, and enhanced cytotoxic T cell response. Compared to BCG, Mpg showed a more effective protective immune response in the vaccinated mice against challenges with 2 different mycobacterial strains, M. tuberculosis H37Ra or M. abscessus Asan 50594. Our data suggest that a temperature sensitive Mpg may be a potentially powerful candidate vaccine strain to induce enhanced protective immune responses against M. tuberculosis and M. abscessus.

PMID: 29123166 [PubMed - in process]

http://ift.tt/2yrcYwH

Novel grid combined with peripheral distortion correction for ultra-widefield image grading of age-related macular degeneration

http://ift.tt/2zAycMb

Cetuximab/TPF/radiotherapy in oesophageal cancer

Abstract

Background

Pre-operative chemoradiotherapy using a 5-fluorouracil (5-FU)/cisplatin backbone is widely used to improve surgical outcomes in locoregional oesophageal cancer patients, despite a non-negligible failure rate.

Objective

We evaluated intensification of this approach to improve patient outcomes by adding cetuximab to induction 5-FU/cisplatin/docetaxel (TPF) and to chemoradiotherapy in a phase II study.

Patients and Methods

Between November 2006 and April 2009, 50 patients with stage II–IVa squamous cell carcinoma (SCC) or adenocarcinoma of the oesophagus or gastro-oesophageal junction initiated three TPF/cetuximab cycles. Six weeks later, patients with response or stabilisation initiated 6 weeks of cisplatin/cetuximab/radiotherapy, followed by surgery. The primary objective was the clinical complete response (cCR) rate after induction therapy plus chemoradiotherapy in intent-to-treat patients.

Results

Thirty-eight patients were evaluable after chemoradiotherapy, 84% of whom showed disease control. Six patients (12%) achieved a cCR, with a 54% overall response rate. Twenty-seven patients underwent surgery, 11 of whom (22%; nine SCC, two adenocarcinoma) had a pathological CR (41%). Fifteen patients were alive after a median follow-up of 23.2 months. Median progression-free survival was 12.2 months (95% confidence interval [CI] 1.7–22.8). Median overall survival was 23.4 months (95% CI 12.2–36.6) and was significantly longer among the 22 patients with complete resection than in the five patients without (42.1 vs. 24.9 months; p = 0.02, hazard ratio: 3.6, 95% CI 1.1–11.6). The toxicity profile was acceptable.

Conclusions

Neoadjuvant cetuximab/TPF followed by chemoradiotherapy in locoregional oesophageal carcinoma patients is feasible and offers a modest response rate in this trial. The results of combining trimodality neoadjuvant treatment with cetuximab are consistent with the literature.

Registration: The study is registered at ClinicalTrials.gov (NCT00733889).

http://ift.tt/2ABmj6H

In vasculitis of small muscular arteries, activation of vessel-infiltrating CD8 T cells seems to be antigen-independent

Abstract

The etiology of polyarteritis nodosa (PAN) and localized PAN is still unknown, although a T cell-mediated immune mechanism has been considered. CD8 T cells participate not only in the antigen-dependent adaptive immune system, but also in the antigen-independent innate immune system. Non-antigen-activated CD8 T cells express a unique phenotype: granzyme B (GrB) positive /CD25 negative /programmed death-1 (PD-1) negative. The aims of this study were to assess the participation of T cells, especially innate CD8 T cells, in the development of vasculitis. Twenty-eight consecutive cases of skin biopsy specimens with cutaneous vasculitis of small muscular arteries (CVSMA) were retrieved. The series comprises of 21 cases of cutaneous arteritis, three cases of PAN, and four cases of rheumatoid vasculitis. Cases of antineutrophil cytoplasmic antibody-associated vasculitis were excluded. The phenotypes of infiltrating lymphocytes in vasculitis lesions were evaluated by immunohistochemistry. In most cases of CVSMA, the number of CD8 T cells infiltrating the intima was higher than that of CD4 T cells, and significant numbers of GrB-positive cells, which represent activated CD8 T cells, were observed. However, GrB/CD25-double-positive cells, which correspond to antigen-activated T cells, were very few in a small number of cases. Cells positive for PD-1, which is also expressed on antigen-activated CD8 T cells, were not detected. We conclude that a T cell-mediated immune mechanism, involving cytotoxic CD8 T cells, may play a role in the development of CVSMA. Low expression of CD25 in activated CD8 T cells suggests that activation was antigen-independent.

http://ift.tt/2yt2vBa

PD-1-PD-L1 immune-checkpoint blockade in malignant lymphomas

Abstract

Tumor cells can evade immune surveillance through overexpressing the ligands of checkpoint receptors on tumor cells or adjacent cells, leading T cells to anergy or exhaustion. Growing evidence of the interaction between tumor cells and microenvironment promoted the emergence of immune-checkpoint blockade. By targeting programmed cell death-1 (PD-1) pathway, cytotoxic activity of T cell is enhanced significantly and tumor cell lysis is induced subsequently. Currently, various antibodies against PD-1 and programmed death-ligand 1 (PD-L1) are under clinical studies in lymphomas. In this review, we outline the rationale for investigation of PD-1-PD-L1 immune-checkpoint blockade in lymphomas and discuss their prospect of applications in clinical treatment.

http://ift.tt/2AA9t8P

Erratum to: Treadmill exercise alters ecstasy- induced long- term potentiation disruption in the hippocampus of male rats

Abstract

In the original publication of the article, author name Masoumeh Asadbegi was incorrectly written as Masoumeh Asadbeigi. The authors regret the oversight.

http://ift.tt/2AvroN3

Erratum to: Anatomical specificity of the brain in the modulation of Neuroglobin and Cytoglobin genes after chronic bisphenol a exposure

http://ift.tt/2i3xlKo

Organosulfur compound protects against memory decline induced by scopolamine through modulation of oxidative stress and Na + /K + ATPase activity in mice

Abstract

The present study investigated the possible effect of BMMS in protecting against memory impairment in an Alzheimer's disease model induced by scopolamine in mice. Another objective was to evaluate the involvement of oxidative stress and Na⁺/K⁺ ATPase activity in cerebral cortex and hippocampus of mice. Male Swiss mice were divided into four groups: groups I and III received canola oil (10 ml/kg, intragastrically (i.g.)), while groups II and IV received BMMS (10 mg/kg, i.g.). Thirty minutes after treatments, groups III and IV received scopolamine (1 mg/kg, intraperitoneal (i.p.)), while groups I and II received saline (5 ml/kg, i.p.). Behavioral tests were performed thirty minutes after scopolamine or saline injection. Cerebral cortex and hippocampus were removed to determine the thiobarbituric acid reactive species (TBARS) levels, non-protein thiols (NPSH) content, catalase (CAT) and Na⁺/K⁺ ATPase activities. The results showed that BMMS pretreatment protected against the reduction in alternation and latency time induced by scopolamine in the Y-maze test and step-down inhibitory avoidance, respectively. In the Barnes maze, the latency to find the escape box and the number of holes visited were attenuated by BMMS. Locomotor and exploratory activities were similar in all groups. BMMS pretreatment protected against the increase in the TBARS levels, NPSH content and CAT activity, as well as the inhibition on the Na⁺/K⁺ ATPase activity caused by scopolamine in the cerebral cortex. In the hippocampus, no significant difference was observed. In conclusion, the present study revealed that BMMS protected against the impairment of retrieval of short-term and long-term memories caused by scopolamine in mice. Moreover, antioxidant effect and protection on the Na⁺/K⁺ ATPase activity are involved in the effect of compound against memory impairment in AD model induced by scopolamine.

http://ift.tt/2AusQzm

A homozygous PIGO mutation associated with severe infantile epileptic encephalopathy and corpus callosum hypoplasia, but normal alkaline phosphatase levels

Abstract

We describe two sisters from a consanguineous Arab family with global developmental delay, dystrophy, axial hypotonia, epileptic encephalopathy dominated by intractable complex partial seizures that were resistant to various anti-epileptic treatments. Dysmorphic features comprised low set ears, hypertelorism, upslanting palpebral fissures, a broad nasal bridge, and blue sclera with elongated eyelashes. Brain MRI in both children showed a corpus callosum hypoplasia that was evident already in utero and evolving cortical atrophy. Autozygosity mapping in combination with Whole Exome Sequencing revealed a homozygous missense mutation in the PIGO gene [c.765G > A, NM_032634.3] that affected a highly conserved methionine in the alkaline phosphatase-like core domain of the protein [p.(Met255Ile), NP_116023.2]. PIGO encodes the GPI-ethanolamine phosphate transferase 3, which is crucial for the final synthetic step of the glycosylphosphatidylinositol-anchor that attaches many enzymes to their cell surfaces, such as the alkaline phosphatase and granulocyte surface markers. Interestingly, measurement of serum alkaline phosphatase activities in both children was normal or only slightly elevated. Quantification of granulocyte surface antigens CD16/24/59 yielded reduced levels only for CD59. Phenotype analysis of our and other published patients with PIGO mutations reveals a more severe affectation and predominantly neurological presentation in individuals carrying a mutation in the alkaline phosphatase-like core domain thereby hinting towards a genotype-phenotype relation for PIGO gene mutations.

http://ift.tt/2i3xihG

Multidisciplinary Clinic Approach Improves Overall Survival Outcomes of Patients with Metastatic Germ Cell Tumors

Abstract

Background

To report our experience utilizing a multidisciplinary clinic (MDC) at Indiana University (IU) since the publication of the International Germ Cell Cancer Collaborative Group (IGCCCG), and to compare our overall survival to that of the National Cancer Institute (NCI) Surveillance, Epidemiology, and End Results (SEER) Program.

Patients and Methods

We conducted a retrospective analysis of all patients with metastatic germ cell tumor (GCT) seen at IU from 1998-2014. 1,611 consecutive patients were identified, of whom 704 patients received an initial evaluation by our MDC (including medical oncology, pathology, urology and thoracic surgery) and started first-line chemotherapy at IU. These 704 patients were eligible for analysis. All patients in this cohort were treated with cisplatin-etoposide based combination chemotherapy. We compared the progression-free survival (PFS) and overall survival (OS) of patients treated at IU with that of the published IGCCCG cohort. OS of the IU testis cancer primary cohort (n = 622) was further compared to the SEER data of 1283 patients labeled with "distant" disease. The Kaplan-Meier method was used to estimate progression-free survival and overall survival.

Results

With a median follow-up of 4.4 years, patients with good, intermediate, and poor risk disease by IGCCCG criteria treated at IU had 5-year PFS of 90%, 84%, and 54% and 5-year OS of 97%, 92%, and 73% respectively. The 5-year PFS for all patients in the IU cohort was 79% (95%CI, 76% to 82%). The 5-year OS for the IU cohort was 90% (95% CI, 87% to 92%). IU testis cohort had 5-year OS 94% (95% CI, 91% to 96%) vs. 75% (95% CI, 73% to 78%) for the SEER "distant" cohort between 2000-2014, P-value <0.0001.

Conclusion

The MDC approach to GCT at high-volume cancer center associated with improved overall survival outcomes in this contemporary dataset. OS is significantly higher in the IU cohort compared to the IGCCCG and SEER "distant" cohort.

http://ift.tt/2AuYj48

Expression of Glut-1 in Malignant Melanoma and Melanocytic Nevi: an Immunohistochemical Study of 400 Cases

Abstract

The glucose transporter-1 (Glut-1) is a cell membrane glycoprotein involved in glucose uptake. An increased expression of Glut-1 is an important cell adaptation mechanism against hypoxia. An upregulation of Glut-1 can be found in several types of malignant tumors, which are able to reprogram their metabolism from oxidative phosphorylation to aerobic glycolysis (Warburg effect). However, the data regarding melanocytic lesions is equivocal. We performed comprehensive immunohistochemical analysis of the Glut-1 expression in 225 malignant melanomas (MM) and 175 benign nevi. Only the membranous expression of Glut-1 was regarded as positive. The expression of Glut-1 (the cut-off for positivity was determined as H-score 15) was found in 69/225 malignant melanomas. The number of positive cases and the H-score of Glut-1 increased where there was a higher Breslow thickness (p < 0.00001) when comparing pT1- pT4 MM groups. All benign nevi were classified as negative. In conclusion, the membranous expression of Glut-1 is a common feature of a malignant melanoma but this type of expression is very rare in benign melanocytic nevi. Our results suggest that the membranous expression of Glut-1 can be used as a surrogate marker in the assessing of the biological nature of benign and malignant melanocytic lesions. However, despite its high specificity, the sensitivity of this marker is relatively low. Moreover, due to the fact that the increased expression of Glut-1 correlates with a shorter survival period (10-year disease free survival, recurrence free survival and metastasis free survival and MFS), it can be used as a prognostically adverse factor.

http://ift.tt/2i3IxXr

Minds and Machines Special Issue: Ethics and Artificial Intelligence

http://ift.tt/2zO8uot

Matching Abilities to Careers for Others and Self: Do Gender Stereotypes Matter to Students in Advanced Math and Science Classes?

Abstract

Interest in STEM (science, technology, engineering, and mathematics) careers falls off more quickly for young women than for young men over adolescence, and gender stereotypes may be partially to blame. Adolescents typically become more stereotypical in their career interests over time, yet they seem to become more flexible in applying stereotypes to others. Models of career interest propose that career decisions result from the alignment of self-perceived abilities with occupation-required skills and that gender stereotypes may influence this process. To investigate the discrepancy between applying stereotypes to self and others, we examined if these models can be applied to perceptions of others. Focusing on students from fifth grade through college enrolled in advanced STEM courses, we investigated how STEM occupational stereotypes, abilities, and efficacy affect expectations for others' and own career interests. U.S. participants (n = 526) read vignettes describing a hypothetical male or female student who was talented in math/science or language arts/social studies and then rated the student's interest in occupations requiring some of those academic skills. Participants' self-efficacy, interest, and stereotypes for STEM occupations were also assessed. Findings suggest that ability beliefs, whether for oneself or another, are powerful predictors of occupational interest, and gender stereotypes play a secondary role. College students were more stereotypical in their ratings of others, but they did not manifest gender differences in their own STEM self-efficacy and occupational interests. Experiences in specialized STEM courses may explain why stereotypes are applied differentially to the self and others.

http://ift.tt/2AupQD6

Do Sexist Mothers Change More Diapers? Ambivalent Sexism, Maternal Gatekeeping, and the Division of Childcare

Abstract

The present study examined the role of ambivalent sexist ideologies in the division of childcare responsibilities. We proposed maternal gatekeeping as a mediator through which hostile sexist attitudes toward men and women facilitate gendered division of childcare. A sample of 207 mothers with at least one child aged 6 years or younger completed extensive questionnaires. As hypothesized, the mother's hostile sexist attitudes toward men and women were positively related to maternal gatekeeping tendencies. Gatekeeping, in turn, was related to the mother's greater time investment in childcare and greater share of childcare tasks relative to the father. Finally, hostile sexist attitudes toward men and women had an indirect effect on the mothers' hours of care and relative share of childcare tasks, mediated though maternal gatekeeping. The findings underscore the importance of investigating the mechanisms through which sexist ideologies are translated into daily behaviors that help maintain a gendered social structure. They may be utilized to inform parenting interventions aimed at increasing collaborative family work and fathers' participation.

http://ift.tt/2i4w2uz

An Exploration of Black Women’s Gendered Racial Identity Using a Multidimensional and Intersectional Approach

Abstract

The current study explored the potential for an empirically supported taxonomy of gendered racial identity among Black women sampled in the United States. Drawing from Black racial identity theory (Sellers et al. 1998a), gendered racial identity was defined as the significance and qualitative meaning women attribute to their membership within Black and woman social identity groups. To assess this construct, Black women (n = 240; M _age = 35.83, SD = 11.88, range = 19–79) completed measures of racial and gender centrality as well as an opened-ended question assessing the meaning assigned to one's intersected identity. Four profiles of gendered racial identity emerged through a cluster analysis of racial and gender centrality, which were further explicated through women's qualitative descriptions of identity. The profiles included Intersectional Engaged, Race Progressive, Intersectional Aware, and Gender Expressive. We explain each profile in detail and conclude by discussing the implications of study findings in terms of theory development, future research, and practice related to Black women.

http://ift.tt/2Awn5Bg

Actionable secondary findings from whole-genome sequencing of 954 East Asians

Abstract

Recently, the American College of Medical Genetics (ACMG) recommended the return of actionable secondary findings detected from clinical sequencing. The reported frequency of secondary findings in Asian populations were highly variable and it is unclear whether the uniformity in coverage offered by whole-genome sequencing (WGS) may impact the estimate. In this analysis, we aimed to refine the rate of secondary findings on East Asians through a large-scale WGS study. We classified 1256 protein-altering or splicing variants of the 59 actionable genes detected from WGS of 954 East Asians in strict accordance with the ACMG and the Association for Molecular Pathology guidelines. A total of 21 pathogenic or likely pathogenic variants were detected in 24 of the 954 East Asian genomes with an estimate of 2.5% of East Asians carrying actionable variants. Although the overall estimate of secondary findings was consistent with those reported for non-East Asian ethnicities, genetic and allelic heterogeneity was observed. WGS offers a wider breadth of coverage over WES, which highlights the need to further investigate the variable sensitivity of WES and WGS in the detection of secondary findings. Identifying secondary findings in populations underrepresented in previous genetic literature might improve variant interpretation and has a profound impact on local decision-making with regard to the cost-effectiveness of returning the secondary findings from clinical sequencing.

http://ift.tt/2i4lNX9