Τετάρτη, 31 Μαΐου 2017

Responsiveness of the functioning and disability parts of the International Classification of Functioning, Disability, and Health core sets in postacute stroke patients.

To study the responsiveness of the International Classification of Functioning, Disability, and Health (ICF) core set with respect to human functioning and disability in stroke patients. Postacute stroke patients who were admitted to the convalescent rehabilitation wards were included in this observational cohort study. The comprehensive ICF core set for neurological conditions for postacute care and the ICF rehabilitation set were evaluated at admission and discharge using five-grade qualifiers. Extension indexes were calculated for entire two ICF core sets. Responsiveness was measured as change in the extension indexes in the ICF core sets. The correlation between changes in ICF core sets and improvement in the Functional Independence Measure (FIM) was analyzed using Spearman's correlation coefficient. The study included 108 poststroke patients (49 women, mean age 70.8 years, mean FIM score improvement: 23.0). The mean percentage of categories that showed changes with at least one qualifier level was 19.5% in the comprehensive ICF core set for neurological conditions for postacute care and 35.9% in the ICF rehabilitation set. Effect sizes in each ICF core set were moderate to large (0.79-0.80). Improvement in the two ICF core sets correlated significantly with changes in the FIM score. Our results indicate that functioning and disability parts of these two ICF core sets can detect changes in functioning and disability in patients who receive an inpatient rehabilitation program for postacute stroke. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Transient ischemic attacks on turning the head to one side, with immediate remission of symptoms when the head returned to the neutral position.



Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182
6948891480

Intravital investigation of rat mesenteric small artery tone and blood flow

Abstract

Functional characteristics of rat mesenteric small arteries (internal diameter ∼150–200 μm) have been extensively studied in vitro using isometric and isobaric myographs. In vivo, precapillary arterioles (internal diameter< 50 μm) have been studied, but only few studies have investigated the function of mesenteric small arteries. We here present a novel approach for intravital studies of rat mesenteric small artery segments (∼5 mm long) isolated in a chamber. The agonist-induced changes in arterial diameter and blood flow were studied using video imaging and laser speckle analysis in rats anaesthetized by isoflurane, pentobarbital, ketamine/xylazine, or by a combination of fentanyl, fluanison and midazolam (rodent mixture). The arteries had spontaneous tone. Noradrenaline added to the chamber constricted the artery in the chamber but not the downstream arteries in the intestinal wall. The constriction was smaller when rats were anaesthetised by rodent mixture in comparison with other anaesthetics, where responses were qualitatively similar to those reported in vitro. The contraction was associated with reduction of blood flow, but no flow reduction was seen in the downstream arteries in the intestinal wall. The magnitude of different endothelium-dependent relaxation pathways was dependent on the anaesthesia. Vasomotion was present under all forms of anaesthesia with characteristics similar to in vitro. We have established an intravital method for studying the tone and flow in rat mesenteric arteries. The reactivity of the arteries was qualitatively similar to the responses previously obtained under in vitro conditions, but the choice of anaesthetic affects the magnitude of responses.

This article is protected by copyright. All rights reserved



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Coupling of excitation to Ca2+ release is modulated by dysferlin

Abstract

Dysferlin concentrates in the transverse tubules of skeletal muscle and stabilizes Ca2+ transients when muscle fibres are subjected to osmotic shock injury (OSI). We show here that voltage-induced Ca2+ transients elicited in dysferlin-null A/J myofibers are smaller than control A/WySnJ fibres. Regional expression of Venus-dysferlin chimeras in A/J fibres restores the full amplitude of the Ca2+ transients and protects against OSI. We also show that drugs that target ryanodine receptors (RyR1: dantrolene, tetracaine, S107) and L-type Ca2+ channels (LTCC: nifedipine, verapamil, diltiazem) prevent the decrease in Ca2+ transients in A/J fibres following OSI. Diltiazem specifically increases transients by ∼20% in uninjured A/J fibres, restoring them to control values. The fact that both RyR1s and LTCCs are involved in OSI-induced damage suggests that damage is mediated by increased Ca2+ leak from the sarcoplasmic reticulum (SR) through the RyR1. Congruent with this, injured A/J fibres produced Ca2+ sparks and Ca2+ waves. S107 (stabilizer of RyR1-FKBP coupling that reduces Ca2+ leak) or local expression of Venus-dysferlin prevented OSI-induced Ca2+ waves. Our data suggest that dysferlin modulates SR Ca2+ release in skeletal muscle, and that in its absence OSI causes increased RyR1-mediated Ca2+ leak from the SR into the cytoplasm.

This article is protected by copyright. All rights reserved



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Movement-Dependent Spatial Expansion of Visual Receptive Fields of Neurons of the Extrastriate Cortex

The spatial structure of the receptive field (RF) of a visually sensitive neuron, as defined by presentation of stationary visual stimuli, predetermines in most cases central processing of visual information concerning moving visual images. In our study, properties of a group of neurons in the extrastriate cortical area 21a (≈18% of the examined sampling) with extremely small RF sizes (≈1.5 deg2) determined by stationary visual stimuli were investigated. It was found that spatial dimensions of each neuronal RFs may undergo manifold expansions; the neuronal response profiles depended strongly on the size, shape, and contrast of the applied moving stimuli. As a result, a high degree of diversification of neuronal response patterns depending of the shapes and contrasts of applied moving stimuli was observed. These data confirm the suggestion that the RFs of neurons in the extrastriate area 21a undergo temporary dynamic changes due to activation of surrounding neuronal groups/networks by moving visual stimuli. Thus, it is evident that processing of visual information in the course of visual image recognition is realized by integrated activity of a complex of the corresponding cortical networks of visually sensitive neurons.



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Effect of Night Shift-Related Tiredness on Eye Saccades

Parameters of saccades (latency, amplitude, duration, and velocity) were measured using a saccadometer in 32 nurses (30 women and 2 men) before and after a night shift. The mean latency of saccades was found to significantly increase after this period (209.6 ± 6.84 vs. 188.6 ± 6.08 msec, P = 0.002); the same was found with respect to the saccade duration (55.0 ± 0.97 vs. 54.2 ± 1.23 msec, P < 0.05). Thus, stress and sleep deprivation noticeably influence the parameters of saccades; the latter, nonetheless, remain within a physiological range. Considering that a number of brain structures are involved in the control of saccade parameters, the above-described modulations of saccades can be potentially used as generalized indices characterizing the level of brain tiredness.



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Short- and Long-Term Effects of Methylphenidate on Cost-Benefit Decision Making in Adult Rats

Decision making is one of the most complicated and controversial topics in neuroscience. Today, there are important classes of chemicals that increase cognitive performance; in particular these are psychostimulants (e.g., methylphenidate, MPH). However, the long-term effects of MPH on cost-benefit decision making in healthy animals remain unknown. Therefore, we aimed to compare the short- and long-term effects of MPH in adult healthy male rats on the decision making in two distinct T-maze tasks and the ability of the animals to adjust the height of the obstacle in a T-maze or to process information on the reward amount. We found that short-term effects of MPH (2 weeks) played a significant role in making the correct decision in T-maze tasks, while the respective effects of long-term administration (12 weeks) were much weaker. These data suggest that chronic application of MPH has short- but not long-term effects on cost-benefit decision making in healthy adult animals.



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Effects of Stereotactic Introduction of Baclofen in the Medullary Cardiovascular Nuclei of Rats

In rats anesthetized with urethane (1.7 g/kg, i. p.), we investigated the effects of stereotaxic microinjections of baclofen into the medullary nuclei involved in the neural control of cardiovascular activity (nuclei paramedianus, ambiguus, and reticularis lateralis). Changes in the hemodynamic parameters (systolic and diastolic blood pressure and heart rate) were measured. Injections of the above GABAB receptor agonist (10–7, 10–6, or 10–5 M, 0.1 μl) into the medullary cardiovascular nuclei was accompanied by changes in the blood pressure, the magnitude and direction of which depended not only on the baclofen concentration but also on the site of injection (into one nucleus or another). Injections of the agent into the nucl. ambiguus at a 10–7 M concentration resulted in an increase in the blood pressure, but a 10–5 M concentration provided significant reduction of the systolic and diastolic blood pressure. If baclofen was injected into the nucl. reticularis lat., the blood pressure also increased or decreased but the concentration dependence was opposite to the above described. Injections of the agent into the nucl. paramedianus were always accompanied by significant increases in the blood pressure. Changes in the heart rate following baclofen injections into the nuclei under study were insignificant. The specificities of the baclofen-induced effects are probably related to peculiarities of the functioning of GABAB receptors, the activation of which may mediate the effects of multiple neuronal mechanisms.



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Denaturing gradient gel electrophoresis profiles of bacteria from the saliva of twenty four different individuals form clusters that showed no relationship to the yeasts present

Publication date: October 2017
Source:Archives of Oral Biology, Volume 82
Author(s): Manjula M Weerasekera, Chris H Sissons, Lisa Wong, Sally A Anderson, Ann R Holmes, Richard D Cannon
ObjectivesThe aim was to investigate the relationship between groups of bacteria identified by cluster analysis of the DGGE fingerprints and the amounts and diversity of yeast present.MethodsBacterial and yeast populations in saliva samples from 24 adults were analysed using denaturing gradient gel electrophoresis (DGGE) of the bacteria present and by yeast culture.ResultsEubacterial DGGE banding patterns showed considerable variation between individuals. Seventy one different amplicon bands were detected, the band number per saliva sample ranged from 21 to 39 (mean±SD=29.3±4.9). Cluster and principal component analysis of the bacterial DGGE patterns yielded three major clusters containing 20 of the samples. Seventeen of the 24 (71%) saliva samples were yeast positive with concentrations up to 103cfu/mL. Candida albicans was the predominant species in saliva samples although six other yeast species, including Candida dubliniensis, Candida tropicalis, Candida krusei, Candida guilliermondii, Candida rugosa and Saccharomyces cerevisiae, were identified. The presence, concentration, and species of yeast in samples showed no clear relationship to the bacterial clusters.ConclusionDespite indications of in vitro bacteria-yeast interactions, there was a lack of association between the presence, identity and diversity of yeasts and the bacterial DGGE fingerprint clusters in saliva. This suggests significant ecological individual-specificity of these associations in highly complex in vivo oral biofilm systems under normal oral conditions.

Graphical abstract

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Agomelatine, a MT1/MT2 melatonergic receptor agonist with serotonin 5-HT2C receptor antagonistic properties, suppresses Prevotella intermedia lipopolysaccharide-induced production of proinflammatory mediators in murine macrophages

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Publication date: October 2017
Source:Archives of Oral Biology, Volume 82
Author(s): Jin-Yi Hyeon, Eun-Young Choi, So-Hui Choe, Hae Ryoun Park, Jeom-Il Choi, In Soon Choi, Sung-Jo Kim
ObjectiveThis study was performed in an attempt to examine the influence of agomelatine in mitigating the generation of proinflammatory mediators in RAW264.7 murine macrophages exposed to lipopolysaccharide (LPS) obtained from Prevotella intermedia, a gram-negative anaerobic bacterium that is related with various types of periodontal diseases, and the molecular mechanisms behind its effects.DesignLPS from P. intermedia strain ATCC 25611 was prepared employing the conventional phenol-water procedure. Conditioned culture media were analyzed for the levels of nitric oxide (NO), interleukin-1β (IL-1β) and IL-6. Real-time PCR analysis was carried out to determine the mRNA levels of inducible NO synthase (iNOS), IL-1β, IL-6 and SOCS1. Protein expression levels were evaluated by immunoblot test. NF-κB-dependent SEAP reporter assay was performed using a reporter cell line. DNA-binding activities of NF-κB subunits were analyzed utilizing the ELISA-based kits.ResultsAgomelatine was found to down-regulate significantly the generation of iNOS-derived NO, IL-1β and IL-6 as well as the expression of their mRNAs in cells activated with P. intermedia LPS. Agomelatine decreased NF-κB-dependent SEAP release caused by P. intermedia LPS. Agomelatine did not inhibit NF-κB transcription induced by LPS at the level of IκB-α degradation. Instead, LPS-induced nuclear translocation and DNA binding of NF-κB p50 subunit was blocked by agomelatine. P. intermedia LPS-elicited activation of STAT1 and STAT3 was reduced notably by co-treatment with agomelatine. Agomelatine showed a tendency to enhance mRNA level of SOCS1 in LPS-activated cells as well.ConclusionsAgomelatine merits further evaluation to reveal its usefulness on the host modulation of periodontal disease.



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Aims & Scope/Editorial board

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Publication date: August 2017
Source:Archives of Oral Biology, Volume 80





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Editorial Board



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Angiotensin II and skeletal muscle abnormalities



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Malignant Duodenal GIST in a Patient with Situs Inversus Totalis—a Rare Association and Brief Review of Literature



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A magnetic resonance imaging study of gastric motor function in patients with dyspepsia associated with Ehlers-Danlos Syndrome-Hypermobility Type: A feasibility study

Abstract

Background

The clinical use of Magnetic Resonance Imaging (MRI) for investigating gastric motor function in dyspepsia is limited, largely due to protocol complexity, cost and limited availability. In this study, we explore the feasibility of a sub 60-minute protocol using a water challenge to assess gastric emptying, motility and accommodation in a cohort of Ehlers-Danlos Syndrome-Hypermobility type (EDS-HT) patients presenting with dyspepsia.

Methods

Nine EDS-HT patients (mean age 33, range: 26-50 all female) with a history of dyspepsia were recruited together with nine-matched controls. Subjects fasted for 6 hours prior to MRI. A baseline anatomical and motility scan was performed after which the subjects ingested 300 mL water. The anatomical and motility scans were then repeated every 10 minutes to a total of 60 minutes. Gastric emptying time, motility, and accommodation were calculated based on the observations of two observers for each EDS-HT subject and compared to their matched control using paired statistics.

Key Results

Median motility increase following the water challenge was lower in EDS-HT subjects (11%, range: 0%-22%) compared to controls (22%, range: 13%-56%), P=.03. Median gastric emptying time was non-significantly decreased in EDS-HT subjects (12.5 minutes, range: 6-27) compared to controls (20 minutes, range: 7-30), P=.15. Accommodation was non-significantly reduced in EDS-HT subjects (56% increase, range: 32%-78%) compared to healthy controls (67% increase, range: 52%-78%), P=.19.

Conclusions & Inferences

This study demonstrates the feasibility of a water challenge MRI protocol to evaluate gastric physiology in the clinical setting. Motility differences between EDS-HT and controls are worthy of further investigation.

Thumbnail image of graphical abstract

Aberrant gastric motility, accommodation, transit time likely play a role in dyspepsia. MRI has the ability to quantitatively evaluate these processes but remains underused due the length of existing protocols and uncertainly regarding its role in the clinical care pathway. In this study, we propose a 60 minutes protocol using a water stimulus which reveals differences between Ehlers Danlos patients with dyspepsia and healthy matched controls.



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Protective Strategies Against Dysphonia in Teachers: Preliminary Results Comparing Voice Amplification and 0.9% NaCl Nebulization

This study aimed to compare the effects of two protective strategies, voice amplification (VA) and 0.9% NaCl nebulization (NEB), on teachers' voice in the work setting.

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Comparison of Effects Produced by Physiological Versus Traditional Vocal Warm-up in Contemporary Commercial Music Singers

The present study aimed to observe whether physiological warm-up and traditional singing warm-up differently affect aerodynamic, electroglottographic, acoustic, and self-perceived parameters of voice in Contemporary Commercial Music singers.

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Multinuclear NMR and MRI Reveal an Early Metabolic Response to mTOR Inhibition in Sarcoma

Biomarkers predicting rapalog responses in sarcomas where PI3K and mTOR are often hyperactivated could improve the suitable recruitment of responsive patients to clinical trials. PI3K/mTOR pathway activation drives energy production by regulating anaerobic glycolysis in cancer cells, suggesting a route toward a monitoring strategy. In this study, we took a multimodality approach to evaluate the phenotypic effects and metabolic changes that occur with inhibition of the PI3K/mTOR pathway. Its central role in regulating glycolysis in human sarcomas was evaluated by short- and long-term rapamycin treatment in sarcoma cell lines. We observed an overall decrease in lactate production in vitro, followed by cell growth inhibition. In vivo, we observed a similar quantitative reduction in lactate production as monitored by hyperpolarized MRI, also followed by tumor size changes. This noninvasive imaging method could distinguish reduced cell proliferation from induction of cell death. Our results illustrate the use of hyperpolarized MRI as a sensitive technique to monitor drug-induced perturbation of the PI3K/mTOR pathway in sarcomas. Cancer Res; 77(11); 3113–20. ©2017 AACR.

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TAM Receptor Tyrosine Kinases in Cancer Drug Resistance

Receptor tyrosine kinases (RTK) are major regulators of key biological processes, including cell growth, survival, and differentiation, and were established early on as proto-oncogenes, with aberrant expression linked to tumor progression in many cancers. Therefore, RTKs have emerged as major targets for selective therapy with small-molecule inhibitors. However, despite improvements in survival rates, it is now apparent that the targeting of RTKs with selective inhibitors is only transiently effective, as the majority of patients eventually become resistant to therapy. As chemoresistance is the leading cause of cancer spread, progression, and mortality, there is an increasing need for understanding the mechanisms by which cancer cells can evade therapy-induced cell death. The TAM (Tyro3, Axl, Mer) subfamily of RTKs in particular feature in a variety of cancer types that have developed resistance to a broad range of therapeutic agents, including both targeted as well as conventional chemotherapeutics. This article reviews the roles of TAMs as tumor drivers and as mediators of chemoresistance, and the potential effectiveness of targeting them as part of therapeutic strategies to delay or combat resistance. Cancer Res; 77(11); 2775–8. ©2017 AACR.

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Expression of Neuroendocrine Factor VGF in Lung Cancer Cells Confers Resistance to EGFR Kinase Inhibitors and Triggers Epithelial-to-Mesenchymal Transition

Mutations in EGFR drive tumor growth but render tumor cells sensitive to treatment with EGFR tyrosine kinase inhibitors (TKI). Phenotypic alteration in epithelial-to-mesenchymal transition (EMT) has been linked to the TKI resistance in lung adenocarcinoma. However, the mechanism underlying this resistance remains unclear. Here we report that high expression of a neuroendocrine factor termed VGF induces the transcription factor TWIST1 to facilitate TKI resistance, EMT, and cancer dissemination in a subset of lung adenocarcinoma cells. VGF silencing resensitized EGFR-mutated lung adenocarcinoma cells to TKI. Conversely, overexpression of VGF in sensitive cells conferred resistance to TKIs and induced EMT, increasing migratory and invasive behaviors. Correlation analysis revealed a significant association of VGF expression with advanced tumor grade and poor survival in patients with lung adenocarcinoma. In a mouse xenograft model of lung adenocarcinoma, suppressing VGF expression was sufficient to attenuate tumor growth. Overall, our findings show how VGF can confer TKI resistance and trigger EMT, suggesting its potential utility as a biomarker and therapeutic target in lung adenocarcinoma. Cancer Res; 77(11); 3013–26. ©2017 AACR.

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Therapeutic IgE Antibodies: Harnessing a Macrophage-Mediated Immune Surveillance Mechanism against Cancer

IgG monoclonal antibodies have made significant contributions to cancer therapy, but suffer from several limitations that restrict their effectiveness in unleashing host immune system components against tumors. The development of monoclonal antibodies of an alternative class, namely IgE, may offer enhanced immune surveillance and superior effector cell potency against cancer cells. In our recent article, we elaborate our proof-of-concept studies of a mouse/human chimeric IgE antibody (MOv18 IgE), which is specific for the cancer-associated antigen folate receptor alpha. We demonstrate superior antitumor efficacy for IgE compared with an otherwise identical IgG in a syngeneic immunocompetent animal, and we identify TNFα/MCP-1 signaling as an IgE-mediated mechanism of monocyte and macrophage activation and recruitment to tumors. These findings draw parallels with powerful macrophage-activating functions employed by IgE against parasites, rather than allergic IgE mechanisms. The potential clinical application of IgE-derived drugs in clinical oncology is clear if the antitumor activity of MOv18 IgE in these preclinical experiments can be replicated in patients. In particular, different IgE antibodies with specificity for many other antigens already validated as targets for IgG suggest a wide potential for development of a novel class of antibody therapy. Cancer Res; 77(11); 2779–83. ©2017 AACR.

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A Squalene-Based Nanomedicine for Oral Treatment of Colon Cancer

Nanotechnology offers many possibilities to improve drug treatments, including with regard to drug pharmacology. The current study reports a simple approach to improve cisplatin efficacy in the treatment of colon cancer through the creation of orally administered squalenoylated nanoparticles loaded with cisplatin (SQ-CDDP NP). Cytotoxic effects of SQ-CDDP NP were assessed in human colonic cells and in mouse models of intestinal cancer. In cell culture, SQ-CDDP NP exhibited at least 10-fold greater cytotoxic potency compared with uncomplexed cisplatin, reflecting an enhancement in intracellular accumulation and DNA platination. Mechanistic investigations showed that SQ-CDDP NP stimulated ROS production, expression of heavy metal–inducible and stress-inducible genes, stress kinase cascades, and apoptosis. In ApcMin/+ mice, a model of intestinal tumorigenesis, oral administration of SQ-CDDP NP curtailed spontaneous tumor formation and azoxymethane-induced colon carcinogenesis with no apparent evidence of tissue toxicity. Our results offer preclinical validation of a nanocarrier formulation that can safely improve chemotherapeutic efficacy, address risks of drug resistance, and improve patient compliance by enabling oral administration. Cancer Res; 77(11); 2964–75. ©2017 AACR.

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Widespread Use of Misidentified Cell Line KB (HeLa): Incorrect Attribution and Its Impact Revealed through Mining the Scientific Literature

Continuous cell lines are widely used, but can result in invalid, irreproducible research data. Cell line misidentification is a common problem that can be detected by authentication testing; however, misidentified cell lines continue to be used in publications. Here we explore the impact of one misidentified cell line, KB (HeLa), on the scientific literature. We identified 574 articles between 2000 and 2014 that provided an incorrect attribution for KB, in accordance with its false identity as oral epidermoid carcinoma, but only 57 articles that provided a correct attribution for KB, as HeLa or cervical adenocarcinoma. Statistical analysis of 57 correct and 171 incorrect articles showed that the number of citations to these articles increased over time. Content analysis of 200 citing articles showed there was a tendency to describe the cell line in accordance with the description in the cited paper. Analysis of journal impact factor showed no significant difference between correct and incorrect groups. Articles using KB or citing that usage were most frequently published in the subject areas of pharmacology, pharmacy, oncology, and medicinal chemistry. These findings are important for science policy and support the need for journals to require authentication testing as a condition of publication. Cancer Res; 77(11); 2784–8. ©2017 AACR.

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Combination Therapy Targeting BCL6 and Phospho-STAT3 Defeats Intratumor Heterogeneity in a Subset of Non-Small Cell Lung Cancers

Oncogene-specific changes in cellular signaling have been widely observed in lung cancer. Here, we investigated how these alterations could affect signaling heterogeneity and suggest novel therapeutic strategies. We compared signaling changes across six human bronchial epithelial cell (HBEC) strains that were systematically transformed with various combinations of TP53, KRAS, and MYC—oncogenic alterations commonly found in non–small cell lung cancer (NSCLC). We interrogated at single-cell resolution how these alterations could affect classic readouts (β-CATENIN, SMAD2/3, phospho-STAT3, P65, FOXO1, and phospho-ERK1/2) of key pathways commonly affected in NSCLC. All three oncogenic alterations were required concurrently to observe significant signaling changes, and significant heterogeneity arose in this condition. Unexpectedly, we found two mutually exclusive altered subpopulations: one with STAT3 upregulation and another with SMAD2/3 downregulation. Treatment with a STAT3 inhibitor eliminated the upregulated STAT3 subpopulation, but left a large surviving subpopulation with downregulated SMAD2/3. A bioinformatics search identified BCL6, a gene downstream of SMAD2/3, as a novel pharmacologically accessible target of our transformed HBECs. Combination treatment with STAT3 and BCL6 inhibitors across a panel of NSCLC cell lines and in xenografted tumors significantly reduced tumor cell growth. We conclude that BCL6 is a new therapeutic target in NSCLC and combination therapy that targets multiple vulnerabilities (STAT3 and BCL6) downstream of common oncogenes, and tumor suppressors may provide a potent way to defeat intratumor heterogeneity. Cancer Res; 77(11); 3070–81. ©2017 AACR.

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BRCA2 Hypomorphic Missense Variants Confer Moderate Risks of Breast Cancer

Breast cancer risks conferred by many germline missense variants in the BRCA1 and BRCA2 genes, often referred to as variants of uncertain significance (VUS), have not been established. In this study, associations between 19 BRCA1 and 33 BRCA2 missense substitution variants and breast cancer risk were investigated through a breast cancer case–control study using genotyping data from 38 studies of predominantly European ancestry (41,890 cases and 41,607 controls) and nine studies of Asian ancestry (6,269 cases and 6,624 controls). The BRCA2 c.9104A>C, p.Tyr3035Ser (OR = 2.52; P = 0.04), and BRCA1 c.5096G>A, p.Arg1699Gln (OR = 4.29; P = 0.009) variant were associated with moderately increased risks of breast cancer among Europeans, whereas BRCA2 c.7522G>A, p.Gly2508Ser (OR = 2.68; P = 0.004), and c.8187G>T, p.Lys2729Asn (OR = 1.4; P = 0.004) were associated with moderate and low risks of breast cancer among Asians. Functional characterization of the BRCA2 variants using four quantitative assays showed reduced BRCA2 activity for p.Tyr3035Ser compared with wild-type. Overall, our results show how BRCA2 missense variants that influence protein function can confer clinically relevant, moderately increased risks of breast cancer, with potential implications for risk management guidelines in women with these specific variants. Cancer Res; 77(11); 2789–99. ©2017 AACR.

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Correction: Chromosome Instability Modulated by BMI1-AURKA Signaling Drives Progression in Head and Neck Cancer



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Mathematical Modeling Links Pregnancy-Associated Changes and Breast Cancer Risk

Recent debate has concentrated on the contribution of bad luck to cancer development. The tight correlation between the number of tissue-specific stem cell divisions and cancer risk of the same tissue suggests that bad luck has an important role to play in tumor development, but the full extent of this contribution remains an open question. Improved understanding of the interplay between extrinsic and intrinsic factors at the molecular level is one promising route to identifying the limits on extrinsic control of tumor initiation, which is highly relevant to cancer prevention. Here, we use a simple mathematical model to show that recent data on the variation in numbers of breast epithelial cells with progenitor features due to pregnancy are sufficient to explain the known protective effect of full-term pregnancy in early adulthood for estrogen receptor–positive (ER+) breast cancer later in life. Our work provides a mechanism for this previously ill-understood effect and illuminates the complex influence of extrinsic factors at the molecular level in breast cancer. These findings represent an important contribution to the ongoing research into the role of bad luck in human tumorigenesis. Cancer Res; 77(11); 2800–9. ©2017 AACR.

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SFK/FAK Signaling Attenuates Osimertinib Efficacy in Both Drug-Sensitive and Drug-Resistant Models of EGFR-Mutant Lung Cancer

Mutant-selective EGFR tyrosine kinase inhibitors (TKI), such as osimertinib, are active agents for the treatment of EGFR-mutant lung cancer. Specifically, these agents can overcome the effects of the T790M mutation, which mediates resistance to first- and second-generation EGFR TKI, and recent clinical trials have documented their efficacy in patients with EGFR-mutant lung cancer. Despite promising results, therapeutic efficacy is limited by the development of acquired resistance. Here we report that Src family kinases (SFK) and focal adhesion kinase (FAK) sustain AKT and MAPK pathway signaling under continuous EGFR inhibition in osimertinib-sensitive cells. Inhibiting either the MAPK pathway or the AKT pathway enhanced the effects of osimertinib. Combined SFK/FAK inhibition exhibited the most potent effects on growth inhibition, induction of apoptosis, and delay of acquired resistance. SFK family member YES1 was amplified in osimertinib-resistant EGFR-mutant tumor cells, the effects of which were overcome by combined treatment with osimertinib and SFK inhibitors. In conclusion, our data suggest that the concomitant inhibition of both SFK/FAK and EGFR may be a promising therapeutic strategy for EGFR-mutant lung cancer. Cancer Res; 77(11); 2990–3000. ©2017 AACR.

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Tissue-Specific Signaling Networks Rewired by Major Somatic Mutations in Human Cancer Revealed by Proteome-Wide Discovery

Massive somatic mutations discovered by large cancer genome sequencing projects provide unprecedented opportunities in the development of precision oncology. However, deep understanding of functional consequences of somatic mutations and identifying actionable mutations and the related drug responses currently remain formidable challenges. Dysfunction of protein posttranslational modification plays critical roles in tumorigenesis and drug responses. In this study, we proposed a novel computational oncoproteomics approach, named kinome-wide network module for cancer pharmacogenomics (KNMPx), for identifying actionable mutations that rewired signaling networks and further characterized tumorigenesis and anticancer drug responses. Specifically, we integrated 746,631 missense mutations in 4,997 tumor samples across 16 major cancer types/subtypes from The Cancer Genome Atlas into over 170,000 carefully curated nonredundant phosphorylation sites covering 18,610 proteins. We found 47 mutated proteins (e.g., ERBB2, TP53, and CTNNB1) that had enriched missense mutations at their phosphorylation sites in pan-cancer analysis. In addition, tissue-specific kinase–substrate interaction modules altered by somatic mutations identified by KNMPx were significantly associated with patient survival. We further reported a kinome-wide landscape of pharmacogenomic interactions by incorporating somatic mutation-rewired signaling networks in 1,001 cancer cell lines via KNMPx. Interestingly, we found that cell lines could highly reproduce oncogenic phosphorylation site mutations identified in primary tumors, supporting the confidence in their associations with sensitivity/resistance of inhibitors targeting EGF, MAPK, PI3K, mTOR, and Wnt signaling pathways. In summary, our KNMPx approach is powerful for identifying oncogenic alterations via rewiring phosphorylation-related signaling networks and drug sensitivity/resistance in the era of precision oncology. Cancer Res; 77(11); 2810–21. ©2017 AACR.

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ATM Deficiency Is Associated with Sensitivity to PARP1- and ATR Inhibitors in Lung Adenocarcinoma

Defects in maintaining genome integrity are a hallmark of cancer. The DNA damage response kinase ATM is frequently mutated in human cancer, but the significance of these events to chemotherapeutic efficacy has not been examined deeply in whole organism models. Here we demonstrate that bi-allelic Atm deletion in mouse models of Kras-mutant lung adenocarcinoma does not affect cisplatin responses. In marked contrast, Atm-deficient tumors displayed an enhanced response to the topoisomerase-II poison etoposide. Moreover, Atm-deficient cells and tumors were sensitive to the PARP inhibitor olaparib. This actionable molecular addiction to functional PARP1 signaling was preserved in models that were proficient or deficient in p53, resembling standard or high-risk genetic constellations, respectively. Atm deficiency also markedly enhanced sensitivity to the ATR inhibitor VE-822. Taken together, our results provide a functional rationale to profile human tumors for disabling ATM mutations, particularly given their impact on PARP1 and ATR inhibitors. Cancer Res; 77(11); 3040–56. ©2017 AACR.

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Variability in Chromatin Architecture and Associated DNA Repair at Genomic Positions Containing Somatic Mutations

Dynamic chromatin structures result in differential chemical reactivity to mutational processes throughout the genome. To identify chromatin features responsible for mutagenesis, we compared chromatin architecture around single-nucleotide variants (SNV), insertion/deletions (indels), and their context-matched, nonmutated positions. We found epigenetic differences between genomic regions containing missense SNVs and those containing frameshift indels across multiple cancer types. Levels of active histone marks were higher around frameshift indels than around missense SNV, whereas repressive histone marks exhibited the reverse trend. Accumulation of repressive histone marks and nucleosomes distinguished mutated positions (both SNV and indels) from the context-matched, nonmutated positions, whereas active marks were associated with substitution- and cancer type–specific mutagenesis. We also explained mutagenesis based on genome maintenance mechanisms, including nucleotide excision repair (NER), mismatch repair (MMR), and DNA polymerase epsilon (POLE). Regional NER variation correlated strongly with chromatin features; NER machineries exhibited shifted or depleted binding around SNV, resulting in decreased NER at mutation positions, especially at sites of recurrent mutations. MMR-deficient tumors selectively acquired SNV in regions with high active histone marks, especially H3K36me3, whereas POLE-deficient tumors selectively acquired indels and SNV in regions with low active histone marks. These findings demonstrate the importance of fine-scaled chromatin structures and associated DNA repair mechanisms in mutagenesis. Cancer Res; 77(11); 2822–33. ©2017 AACR.

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The p53/p21 Complex Regulates Cancer Cell Invasion and Apoptosis by Targeting Bcl-2 Family Proteins

The tumor suppressor p53 binds prosurvival Bcl-2 family proteins such as Bcl-w and Bcl-XL to liberate Bax, which in turn exerts proapoptotic or anti-invasive functions depending on stress context. On the basis of our previous finding that p53 interacts with p21, we investigated the possible involvement of p21 in these functions. Here, we report that although p53 can bind Bcl-w alone, it requires p21 to liberate Bax to suppress cell invasion and promote cell death. p21 bound Bcl-w, forming a p53/p21/Bcl-w complex in a manner that maintained all pairwise p53/p21, p21/Bcl-w, and p53/Bcl-w interactions. This allowed Bax liberation from the complex. Accordingly, a p53 derivative incapable of binding p21 failed to mediate radiotherapy-induced tumor cell death in mice. Bcl-XL also served as a target of the cooperative action of p53 and p21. Overall, our findings indicate that the p53/p21 complex rather than p53 itself regulates cell invasion and death by targeting Bcl-2 proteins. We propose that the p53/p21 complex is a functional unit that acts on multiple cell components, providing a new foundation for understanding the tumor-suppressing functions of p53 and p21. Cancer Res; 77(11); 3092–100. ©2017 AACR.

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SETD1B Activates iNOS Expression in Myeloid-Derived Suppressor Cells

Inducible nitric oxide synthase (iNOS) generates nitric oxide (NO) in myeloid cells that acts as a defense mechanism to suppress invading microorganisms or neoplastic cells. In tumor-bearing mice, elevated iNOS expression is a hallmark of myeloid-derived suppressor cells (MDSC). MDSCs use NO to nitrate both the T-cell receptor and STAT1, thus inhibiting T-cell activation and the antitumor immune response. The molecular mechanisms underlying iNOS expression and regulation in tumor-induced MDSCs are unknown. We report here that deficiency in IRF8 results in diminished iNOS expression in both mature CD11b+Gr1− and immature CD11b+Gr1+ myeloid cells in vivo. Strikingly, although IRF8 was silenced in tumor-induced MDSCs, iNOS expression was significantly elevated in tumor-induced MDSCs, suggesting that the expression of iNOS is regulated by an IRF8-independent mechanism under pathologic conditions. Furthermore, tumor-induced MDSCs exhibited diminished STAT1 and NF-κB Rel protein levels, the essential inducers of iNOS in myeloid cells. Instead, tumor-induced MDSCs showed increased SETD1B expression as compared with their cellular equivalents in tumor-free mice. Chromatin immunoprecipitation revealed that H3K4me3, the target of SETD1B, was enriched at the nos2 promoter in tumor-induced MDSCs, and inhibition or silencing of SETD1B diminished iNOS expression in tumor-induced MDSCs. Our results show how tumor cells use the SETD1B–H3K4me3 epigenetic axis to bypass a normal role for IRF8 expression in activating iNOS expression in MDSCs when they are generated under pathologic conditions. Cancer Res; 77(11); 2834–43. ©2017 AACR.

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Water Concentration Analysis of the Surgical Margin—Response



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GAD1 Upregulation Programs Aggressive Features of Cancer Cell Metabolism in the Brain Metastatic Microenvironment

The impact of altered amino acid metabolism on cancer progression is not fully understood. We hypothesized that a metabolic transcriptome shift during metastatic evolution is crucial for brain metastasis. Here, we report a powerful impact in this setting caused by epigenetic upregulation of glutamate decarboxylase 1 (GAD1), a regulator of the GABA neurotransmitter metabolic pathway. In cell-based culture and brain metastasis models, we found that downregulation of the DNA methyltransferase DNMT1 induced by the brain microenvironment–derived clusterin resulted in decreased GAD1 promoter methylation and subsequent upregulation of GAD1 expression in brain metastatic tumor cells. In a system to dynamically visualize cellular metabolic responses mediated by GAD1, we monitored the cytosolic NADH:NAD+ equilibrium in tumor cells. Reducing GAD1 in metastatic cells by primary glia cell coculture abolished the capacity of metastatic cells to utilize extracellular glutamine, leading to cytosolic accumulation of NADH and increased oxidative status. Similarly, genetic or pharmacologic disruption of the GABA metabolic pathway decreased the incidence of brain metastasis in vivo. Taken together, our results show how epigenetic changes in GAD1 expression alter local glutamate metabolism in the brain metastatic microenvironment, contributing to a metabolic adaption that facilitates metastasis outgrowth in that setting. Cancer Res; 77(11); 2844–56. ©2017 AACR.

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Highlights from Recent Cancer Literature



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Targeting Autocrine CCL5-CCR5 Axis Reprograms Immunosuppressive Myeloid Cells and Reinvigorates Antitumor Immunity

The tumor-promoting potential of CCL5 has been proposed but remains poorly understood. We demonstrate here that an autocrine CCL5–CCR5 axis is a major regulator of immunosuppressive myeloid cells (IMC) of both monocytic and granulocytic lineages. The absence of the autocrine CCL5 abrogated the generation of granulocytic myeloid-derived suppressor cells and tumor-associated macrophages. In parallel, enhanced maturation of intratumoral neutrophils and macrophages occurred in spite of tumor-derived CCL5. The refractory nature of ccl5-null myeloid precursors to tumor-derived CCL5 was attributable to their persistent lack of membrane-bound CCR5. The changes in the ccl5-null myeloid compartment subsequently resulted in increased tumor-infiltrating cytotoxic CD8+ T cells and decreased regulatory T cells in tumor-draining lymph nodes. An analysis of human triple-negative breast cancer specimens demonstrated an inverse correlation between "immune CCR5" levels and the maturation status of tumor-infiltrating neutrophils as well as 5-year-survival rates. Targeting the host CCL5 in bone marrow via nanoparticle-delivered expression silencing, in combination with the CCR5 inhibitor Maraviroc, resulted in strong reductions of IMC and robust antitumor immunities. Our study suggests that the myeloid CCL5–CCR5 axis is an excellent target for cancer immunotherapy. Cancer Res; 77(11); 2857–68. ©2017 AACR.

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Prognostic value of Notch receptors in postsurgical patients with hepatitis B virus-related hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) is one of the most prevalent malignancies and a major cause of cancer involved death worldwide. Prognosis remains poor because of high recurrence rates and lack of effective relapse prevention strategies. Notch pathway plays an important role in tumor progression and metastasis, and it is associated with the prognosis of cancer. A total of 465 hepatitis B virus (HBV)-related HCC patients who underwent surgery were enrolled. Single nucleotide polymorphisms (SNP) of Notch pathway receptors were genotyped using Sanger DNA sequencing. Kaplan–Meier curves and the Cox proportional hazards regression model were adopted to analyze the association of polymorphisms and mRNA expression with clinical and pathological features, respectively. Four SNPs (rs1043996 in Notch3 and rs422951, rs520692, rs3830041 in Notch4) were significantly associated with overall survival (OS) (= 0.023, = 0.042, = 0.028, and = 0.001 respectively). Patients carrying the AA genotype in rs1043996 and TT/TC genotypes in rs422951 and rs520692 significantly decreased risks of death, compared to those carrying the AG/GG genotype in rs1043996 and CC genotype in rs422951 and rs520692, respectively. Patients carrying the TT genotype in rs3830041 showed poorer OS, compared with those carrying the TC/CC genotype. A haplotype block (rs422951 was in strong LD with rs520692, r2 = 0.843) was identified in Notch4. Notch3 mRNA expression significantly increased in tumor tissue, compared with nontumor normal tissue (< 0.0001). Moreover, higher expression of Notch3 was associated with poorer OS (HR = 2.11, 95% CI = 1.32–3.37, = 0.002) and shorter recurrence time of HBV-related HCC (HR = 1.96, 95% CI = 1.31–2.93, = 0.001). Our findings collectively indicate that Notch receptors variants (rs1043996 in Notch3 and rs422951, rs520692, rs3830041 in Notch4) are independent predictive targets for OS in HBV-related HCC patients. Notch3 expression is a potential prognostic biomarker of OS and recurrence-free survival (RFS) prediction in HBV-related HCC patients following surgical treatment.

Thumbnail image of graphical abstract

Our study aims to investigate the prognostic value of Notch receptors in postsurgical patients with hepatitis B virus-related hepatocellular carcinoma. Our findings collectively indicate that Notch receptors variants (rs1043996 in Notch3 and rs422951, rs520692, rs3830041 in Notch4) are independent predictive targets for overall survival (OS) in HBV-related HCC patients. Notch3 expression is a potential prognostic biomarker of OS and recurrence-free survival (RFS) prediction in HBV-related HCC patients following surgical treatment.



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Balloon cells in metastatic melanoma



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Myeloid sarcoma identified on liquid-based cervical cytology samples: A report of two cases

The purpose of the Papanicolaou (Pap) smear is to detect primary squamous lesions of the uterine cervix. Although most successful at detection of squamous lesions, the Pap may also detect metastatic carcinomas, sarcomas, and melanomas. We report two rare cases of myeloid sarcoma (MS) of the uterine cervix identified on screening Pap smears with concurrent confirmatory cervical biopsies. The purpose of our study is to identify and report cytologic features of MS on Pap smears utilizing a liquid-based ThinPrep method, which has not been previously documented in literature. Two Pap smears were identified from the pathology laboratory information system, both with positive cervical biopsy findings of MS. Both women, age 40 and 39, presented with ureteral obstruction, hydronephrosis, and past medical histories significant for acute myeloid leukemia (AML). On imaging, cervical masses were identified, and subsequent work-up with Pap smears and biopsies were performed. Cytologic examination of the ThinPrep Pap smears were negative for squamous intraepithelial lesion. Atypical hematologic cells were seen in the background with irregular nuclear contours, increased nuclear to cytoplasmic ratios, variably prominent nucleoli, and variable amounts of agranular cytoplasm. The biopsy confirmed these findings to represent MS. MS is defined as a tumor mass of myeloblasts or immature myeloid cells occurring in an extramedullary site. This rarely involves the female genital tract, about 50 reported cases. Although very rare, MSs in the setting of a history of AML are able to be identified on liquid-based ThinPrep smears.



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Physical and functional interactions between nuclear receptor LXRα and the forkhead box transcription factor FOXA2 regulate the response of the human lipoprotein lipase gene to oxysterols in hepatic cells

Publication date: Available online 31 May 2017
Source:Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms
Author(s): Maria Kanaki, Ioanna Tiniakou, Efstathia Thymiakou, Dimitris Kardassis
Lipoprotein lipase (LPL) catalyzes the hydrolysis of triglycerides from triglyceride-rich lipoproteins such as VLDL and chylomicrons in the circulation. Mutations in LPL or its activator apolipoprotein C-II cause hypertriglyceridemia in humans and animal models. The levels of LPL in the liver are low but they can be strongly induced by a high cholesterol diet or by synthetic ligands of Liver X Receptors (LXRs). However, the mechanism by which LXRs activate the human LPL gene is unknown. In the present study we show that LXR agonists increased the mRNA and protein levels as well as the promoter activity of human LPL in HepG2 cells. A promoter deletion analysis defined the proximal -109/-28 region, which contains a functional FOXA2 element, as essential for transactivation by ligand-activated LXRα/RXRα heterodimers. Silencing of endogenous FOXA2 in HepG2 cells by siRNAs or by treatment with insulin compromised the induction of the LPL gene by LXR agonists whereas mutations in the FOXA2 site abolished the synergistic transactivation of the LPL promoter by LXRα/RXRα and FOXA2. Physical and functional interactions between LXRα and FOXA2 were established in vitro and ex vivo. In summary, the present study revealed a novel mechanism of human LPL gene induction by oxysterols in the liver with is based on physical and functional interactions between transcription factors LXRα and FOXA2. This mechanism, which may not be restricted to the LPL gene, is critically important for a better understanding of the regulation of cholesterol and triglyceride metabolism in the liver under healthy or pathological states.

Graphical abstract

image


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Predicting fractures using trabecular patterns on panoramic radiographs

Abstract

Objectives

The observer score of the trabecular pattern on panoramic radiographs is known to be a strong predictor of bone fractures. The aim of this study was to enhance the predictive power of panoramic radiographs by means of texture analysis methods.

Material and methods

The study followed 304 postmenopausal women during 26 years. At the beginning of the study, panoramic radiographs were obtained. One observer assessed the trabecular pattern in the premolar region as dense, sparse, or alternating dense and sparse. In addition, on each radiograph, a region of interest was selected in the molar/premolar region and analyzed with texture analysis procedures. During 26 years of follow-up, 115 women suffered a fracture of the hip, spine, leg, or arm. Logistic regression was applied to test the predictive power of various variables with respect to fractures.

Results

Of all variables, the observer score of the trabecular pattern correlated strongest with the occurrence of fractures. By itself, the score yielded an ROC curve with an area of 0.80 under the curve. Combining the observer score with the texture analysis features increased the area under the ROC curve to 0.85.

Conclusions

The trabecular pattern on panoramic radiographs provides a strong predictor of fractures, at least for postmenopausal women. The assessment by an observer combined with texture analysis procedures yields a predictive power that parallels best known predictions in literature.

Clinical relevance

This study illustrates that panoramic radiographs are state of the art predictors of postcranial fractures.



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Predicting fractures using trabecular patterns on panoramic radiographs

Abstract

Objectives

The observer score of the trabecular pattern on panoramic radiographs is known to be a strong predictor of bone fractures. The aim of this study was to enhance the predictive power of panoramic radiographs by means of texture analysis methods.

Material and methods

The study followed 304 postmenopausal women during 26 years. At the beginning of the study, panoramic radiographs were obtained. One observer assessed the trabecular pattern in the premolar region as dense, sparse, or alternating dense and sparse. In addition, on each radiograph, a region of interest was selected in the molar/premolar region and analyzed with texture analysis procedures. During 26 years of follow-up, 115 women suffered a fracture of the hip, spine, leg, or arm. Logistic regression was applied to test the predictive power of various variables with respect to fractures.

Results

Of all variables, the observer score of the trabecular pattern correlated strongest with the occurrence of fractures. By itself, the score yielded an ROC curve with an area of 0.80 under the curve. Combining the observer score with the texture analysis features increased the area under the ROC curve to 0.85.

Conclusions

The trabecular pattern on panoramic radiographs provides a strong predictor of fractures, at least for postmenopausal women. The assessment by an observer combined with texture analysis procedures yields a predictive power that parallels best known predictions in literature.

Clinical relevance

This study illustrates that panoramic radiographs are state of the art predictors of postcranial fractures.



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Activation of ganglion cells and axon bundles using epiretinal electrical stimulation

Epiretinal prostheses for treating blindness activate axon bundles, causing large, arc-shaped visual percepts that limit the quality of artificial vision. Improving the function of epiretinal prostheses therefore requires understanding and avoiding axon bundle activation. This paper introduces a method to detect axon bundle activation based on its electrical signature, and uses the method to test whether epiretinal stimulation can directly elicit spikes in individual retinal ganglion cells without activating nearby axon bundles. Combined electrical stimulation and recording from isolated primate retina were performed using a custom multi-electrode system (512 electrodes, 10 μm diameter, 60 μm pitch). Axon bundle signals were identified by their bi-directional propagation, speed, and increasing amplitude as a function of stimulation current. The threshold for bundle activation varied across electrodes and retinas, and was in the same range as the threshold for activating retinal ganglion cells near their somas. In the peripheral retina, 45% of electrodes that activated individual ganglion cells (17% of all electrodes) did so without activating bundles. This permitted selective activation of 21% of recorded ganglion cells (7% of all ganglion cells) over the array. In the central retina, 75% of electrodes that activated individual ganglion cells (16% of all electrodes) did so without activating bundles. The ability to selectively activate a subset of retinal ganglion cells without axon bundles suggests a possible novel architecture for future epiretinal prostheses.



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Neurophysiology and Neural Engineering: a Review

Neurophysiology is the branch of physiology concerned with understanding the function of neural systems. Neural engineering (also known as neuroengineering) is a discipline within biomedical engineering that uses engineering techniques to understand, repair, replace, enhance, or otherwise exploit the properties and functions of neural systems. In most cases neural engineering involves the development of an interface between electronic devices and living neural tissue. This review describes the origins of neural engineering, the explosive development of methods and devices commencing in the late 1950s and the present-day devices that have resulted. The barriers to interfacing electronic devices with living neural tissues are many and varied and consequently there have been numerous stops and starts along the way. Representative examples are discussed. None of this could have happened without a basic understanding of the relevant neurophysiology. We will also consider examples of how neural engineering is repaying the debt to basic neurophysiology with new knowledge and insight.



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Separable systems for recovery of finger strength and control after stroke

Impaired hand function after stroke is a major cause of long-term disability. We developed a novel paradigm that quantifies two critical aspects of hand function, strength and independent control of fingers (individuation), and also removes any obligate dependence between them. Hand recovery was tracked in 54 patients with hemiparesis over the first year after stroke. Most recovery of strength and individuation occurred within the first three months. A novel time-invariant recovery function was identified: recovery of strength and individuation were tightly correlated up to a strength level of approximately 60% of estimated premorbid strength; beyond this threshold, strength improvement was not accompanied by further improvement in individuation. Any additional improvement in individuation was attributable instead to a second process that superimposed on the recovery function. We conclude that two separate systems are responsible for post-stroke hand recovery: one contributes almost all of strength and some individuation; the other contributes additional individuation.



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Development and ageing of human spinal cord circuitries

The neural motor circuitries in the spinal cord receive information from our senses and the rest of the nervous system and translate it into purposeful movements, which allow us to interact with the rest of the world. In this review, we discuss how these circuitries are established during early development and to what extent they are shaped according to the demands of the body that they control and the environment that the body has to interact with. We also discuss how ageing processes and physiological changes in our body are reflected in adaptations of activity in the spinal cord motor circuitries. The complex, multi-facetted connectivity of the spinal cord motor circuitries allow that they can be used to generate vastly different movements and that their activity can be adapted to meet new challenges imposed by bodily changes or a changing environment. There are thus plenty of possibilities for adaptive changes in the spinal motor circuitries both early and late in life.



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Functional Connectivity Between Somatosensory and Motor Brain Areas Predicts Individual Differences in Motor Learning by Observing

Action observation can facilitate the acquisition of novel motor skills, however, there is considerable individual variability in the extent to which observation promotes motor learning. Here we tested the hypothesis that individual differences in brain function or structure can predict subsequent observation-related gains in motor learning. Subjects underwent an anatomical MRI scan and resting-state fMRI scans to assess pre-observation grey matter volume and pre-observation resting-state functional connectivity (FC), respectively. On the following day, subjects observed a video of a tutor adapting her reaches to a novel force field. After observation, subjects performed reaches in a force field as a behavioral assessment of gains in motor learning resulting from observation. We found that individual differences in resting-state FC, but not grey matter volume, predicted post-observation gains in motor learning. Pre-observation resting-state FC between left S1 and bilateral PMd, M1, S1 and left SPL was positively correlated with behavioral measures of post-observation motor learning. Sensory-motor resting-state FC can thus predict the extent to which observation will promote subsequent motor learning.



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Mesoscale-duration activated states gate spiking in response to fast rises in membrane voltage in the awake brain

Seconds-scale network states, affecting many neurons within a network, modulate neural activity by complementing fast integration of neuron-specific inputs that arrive in the milliseconds before spiking. Non-rhythmic subthreshold dynamics at intermediate timescales, however, are less well-characterized. We found, using automated whole cell patch clamping in vivo, that spikes recorded in CA1 and barrel cortex in awake mice are often preceded not only by monotonic voltage rises lasting milliseconds, but also by more gradual (lasting 10s-100s of ms) depolarizations. The latter exert a gating function on spiking, in a fashion that depends on the gradual rise duration: the probability of spiking was higher for longer gradual rises, even controlling for the amplitude of the gradual rises. Barrel cortex double-autopatch recordings show that gradual rises are shared across some but not all neurons. The gradual rises may represent a new kind of state, intermediate both in timescale and in proportion of neurons participating, which gates a neuron's ability to respond to subsequent inputs.



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Diverse effects of stimulus history in waking mouse auditory cortex

Responses to auditory stimuli are often strongly influenced by recent stimulus history. For example, in a paradigm called forward suppression, brief sounds can suppress the perception of, and the neural responses to, a subsequent sound - the magnitude of this suppression depending on both the spectral and temporal distances between the sounds. As a step towards understanding the mechanisms that generate these adaptive representations in awake animals, we quantitatively characterize responses to two-tone sequences in the auditory cortex of waking mice. We find that cortical responses in a forward suppression paradigm are more diverse in waking mice than previously appreciated, that these responses vary between cells with different firing characteristics and waveform shapes, but that the variability in these responses is not substantially related to cortical depth or columnar location. Moreover, responses to the first tone in the sequence are often not linearly related to the suppression of the second tone response, suggesting that spike-frequency adaptation of cortical cells is not a large contributor to forward suppression or its variability. Instead, we use a simple multilayered model to show that cell-to-cell differences in the balance of intracortical inhibition and excitation will naturally produce such a diversity of forward interactions. We propose that diverse inhibitory connectivity allows the cortex to encode spectro-temporally fluctuating stimuli in multiple parallel ways.



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The Stochastic Nature of Action Potential Backpropagation in Apical Tuft Dendrites

In cortical pyramidal neurons, backpropagating action potentials (bAPs) supply Ca2+ to synaptic contacts on dendrites. To determine whether the efficacy of AP backpropagation into apical tuft dendrites is stable over time, we performed dendritic Ca2+ and voltage imaging in rat brain slices. We found that the amplitude of bAP-Ca2+ in apical tuft branches was unstable, as it varied from trial to trial (termed "bAP-Ca2+ flickering"). Small perturbations in dendritic physiology, such as spontaneous synaptic inputs, channel inactivation, or temperature-induced changes in channel kinetics, can cause bAP flickering. In the tuft branches, the density of Na+ and K+ channels was sufficient to support local initiation of fast spikelets by glutamate iontophoresis. We quantified the time delay between the somatic AP burst and the peak of dendritic Ca2+ transient in the apical tuft, because this delay is important for induction of spike-timing dependent plasticity (STDP). Depending on the frequency of the somatic AP triplets, Ca2+ signals peaked in the apical tuft 20 - 50 ms after the first AP in the soma. Interestingly, at low frequency (<20 Hz), the Ca2+ peaked sooner than at high frequency, because only the 1st AP invaded tuft. Activation of dendritic VGCCs is sensitive to the duration of the dendritic voltage transient. In apical-tuft branches, small changes in the duration of bAP voltage waveforms cause disproportionately large increases in dendritic Ca2+ influx (bAP-Ca2+ flickering). The stochastic nature of bAP-Ca2+ adds a new perspective on the mechanisms by which pyramidal neurons combine inputs arriving at different cortical layers.



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iSepsis- Clinical Features and Diagnosis

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iSepsis: Clinical features and diagnosis of Sepsis

EMCrit by Paul Marik.



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Activation of ganglion cells and axon bundles using epiretinal electrical stimulation

Epiretinal prostheses for treating blindness activate axon bundles, causing large, arc-shaped visual percepts that limit the quality of artificial vision. Improving the function of epiretinal prostheses therefore requires understanding and avoiding axon bundle activation. This paper introduces a method to detect axon bundle activation based on its electrical signature, and uses the method to test whether epiretinal stimulation can directly elicit spikes in individual retinal ganglion cells without activating nearby axon bundles. Combined electrical stimulation and recording from isolated primate retina were performed using a custom multi-electrode system (512 electrodes, 10 μm diameter, 60 μm pitch). Axon bundle signals were identified by their bi-directional propagation, speed, and increasing amplitude as a function of stimulation current. The threshold for bundle activation varied across electrodes and retinas, and was in the same range as the threshold for activating retinal ganglion cells near their somas. In the peripheral retina, 45% of electrodes that activated individual ganglion cells (17% of all electrodes) did so without activating bundles. This permitted selective activation of 21% of recorded ganglion cells (7% of all ganglion cells) over the array. In the central retina, 75% of electrodes that activated individual ganglion cells (16% of all electrodes) did so without activating bundles. The ability to selectively activate a subset of retinal ganglion cells without axon bundles suggests a possible novel architecture for future epiretinal prostheses.



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Neurophysiology and Neural Engineering: a Review

Neurophysiology is the branch of physiology concerned with understanding the function of neural systems. Neural engineering (also known as neuroengineering) is a discipline within biomedical engineering that uses engineering techniques to understand, repair, replace, enhance, or otherwise exploit the properties and functions of neural systems. In most cases neural engineering involves the development of an interface between electronic devices and living neural tissue. This review describes the origins of neural engineering, the explosive development of methods and devices commencing in the late 1950s and the present-day devices that have resulted. The barriers to interfacing electronic devices with living neural tissues are many and varied and consequently there have been numerous stops and starts along the way. Representative examples are discussed. None of this could have happened without a basic understanding of the relevant neurophysiology. We will also consider examples of how neural engineering is repaying the debt to basic neurophysiology with new knowledge and insight.



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Separable systems for recovery of finger strength and control after stroke

Impaired hand function after stroke is a major cause of long-term disability. We developed a novel paradigm that quantifies two critical aspects of hand function, strength and independent control of fingers (individuation), and also removes any obligate dependence between them. Hand recovery was tracked in 54 patients with hemiparesis over the first year after stroke. Most recovery of strength and individuation occurred within the first three months. A novel time-invariant recovery function was identified: recovery of strength and individuation were tightly correlated up to a strength level of approximately 60% of estimated premorbid strength; beyond this threshold, strength improvement was not accompanied by further improvement in individuation. Any additional improvement in individuation was attributable instead to a second process that superimposed on the recovery function. We conclude that two separate systems are responsible for post-stroke hand recovery: one contributes almost all of strength and some individuation; the other contributes additional individuation.



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Development and ageing of human spinal cord circuitries

The neural motor circuitries in the spinal cord receive information from our senses and the rest of the nervous system and translate it into purposeful movements, which allow us to interact with the rest of the world. In this review, we discuss how these circuitries are established during early development and to what extent they are shaped according to the demands of the body that they control and the environment that the body has to interact with. We also discuss how ageing processes and physiological changes in our body are reflected in adaptations of activity in the spinal cord motor circuitries. The complex, multi-facetted connectivity of the spinal cord motor circuitries allow that they can be used to generate vastly different movements and that their activity can be adapted to meet new challenges imposed by bodily changes or a changing environment. There are thus plenty of possibilities for adaptive changes in the spinal motor circuitries both early and late in life.



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Functional Connectivity Between Somatosensory and Motor Brain Areas Predicts Individual Differences in Motor Learning by Observing

Action observation can facilitate the acquisition of novel motor skills, however, there is considerable individual variability in the extent to which observation promotes motor learning. Here we tested the hypothesis that individual differences in brain function or structure can predict subsequent observation-related gains in motor learning. Subjects underwent an anatomical MRI scan and resting-state fMRI scans to assess pre-observation grey matter volume and pre-observation resting-state functional connectivity (FC), respectively. On the following day, subjects observed a video of a tutor adapting her reaches to a novel force field. After observation, subjects performed reaches in a force field as a behavioral assessment of gains in motor learning resulting from observation. We found that individual differences in resting-state FC, but not grey matter volume, predicted post-observation gains in motor learning. Pre-observation resting-state FC between left S1 and bilateral PMd, M1, S1 and left SPL was positively correlated with behavioral measures of post-observation motor learning. Sensory-motor resting-state FC can thus predict the extent to which observation will promote subsequent motor learning.



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Mesoscale-duration activated states gate spiking in response to fast rises in membrane voltage in the awake brain

Seconds-scale network states, affecting many neurons within a network, modulate neural activity by complementing fast integration of neuron-specific inputs that arrive in the milliseconds before spiking. Non-rhythmic subthreshold dynamics at intermediate timescales, however, are less well-characterized. We found, using automated whole cell patch clamping in vivo, that spikes recorded in CA1 and barrel cortex in awake mice are often preceded not only by monotonic voltage rises lasting milliseconds, but also by more gradual (lasting 10s-100s of ms) depolarizations. The latter exert a gating function on spiking, in a fashion that depends on the gradual rise duration: the probability of spiking was higher for longer gradual rises, even controlling for the amplitude of the gradual rises. Barrel cortex double-autopatch recordings show that gradual rises are shared across some but not all neurons. The gradual rises may represent a new kind of state, intermediate both in timescale and in proportion of neurons participating, which gates a neuron's ability to respond to subsequent inputs.



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Diverse effects of stimulus history in waking mouse auditory cortex

Responses to auditory stimuli are often strongly influenced by recent stimulus history. For example, in a paradigm called forward suppression, brief sounds can suppress the perception of, and the neural responses to, a subsequent sound - the magnitude of this suppression depending on both the spectral and temporal distances between the sounds. As a step towards understanding the mechanisms that generate these adaptive representations in awake animals, we quantitatively characterize responses to two-tone sequences in the auditory cortex of waking mice. We find that cortical responses in a forward suppression paradigm are more diverse in waking mice than previously appreciated, that these responses vary between cells with different firing characteristics and waveform shapes, but that the variability in these responses is not substantially related to cortical depth or columnar location. Moreover, responses to the first tone in the sequence are often not linearly related to the suppression of the second tone response, suggesting that spike-frequency adaptation of cortical cells is not a large contributor to forward suppression or its variability. Instead, we use a simple multilayered model to show that cell-to-cell differences in the balance of intracortical inhibition and excitation will naturally produce such a diversity of forward interactions. We propose that diverse inhibitory connectivity allows the cortex to encode spectro-temporally fluctuating stimuli in multiple parallel ways.



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The Stochastic Nature of Action Potential Backpropagation in Apical Tuft Dendrites

In cortical pyramidal neurons, backpropagating action potentials (bAPs) supply Ca2+ to synaptic contacts on dendrites. To determine whether the efficacy of AP backpropagation into apical tuft dendrites is stable over time, we performed dendritic Ca2+ and voltage imaging in rat brain slices. We found that the amplitude of bAP-Ca2+ in apical tuft branches was unstable, as it varied from trial to trial (termed "bAP-Ca2+ flickering"). Small perturbations in dendritic physiology, such as spontaneous synaptic inputs, channel inactivation, or temperature-induced changes in channel kinetics, can cause bAP flickering. In the tuft branches, the density of Na+ and K+ channels was sufficient to support local initiation of fast spikelets by glutamate iontophoresis. We quantified the time delay between the somatic AP burst and the peak of dendritic Ca2+ transient in the apical tuft, because this delay is important for induction of spike-timing dependent plasticity (STDP). Depending on the frequency of the somatic AP triplets, Ca2+ signals peaked in the apical tuft 20 - 50 ms after the first AP in the soma. Interestingly, at low frequency (<20 Hz), the Ca2+ peaked sooner than at high frequency, because only the 1st AP invaded tuft. Activation of dendritic VGCCs is sensitive to the duration of the dendritic voltage transient. In apical-tuft branches, small changes in the duration of bAP voltage waveforms cause disproportionately large increases in dendritic Ca2+ influx (bAP-Ca2+ flickering). The stochastic nature of bAP-Ca2+ adds a new perspective on the mechanisms by which pyramidal neurons combine inputs arriving at different cortical layers.



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Oral rehabilitation with implant-supported fixed dental prostheses of a patient with cleidocranial dysplasia

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Publication date: Available online 31 May 2017
Source:The Journal of Prosthetic Dentistry
Author(s): Fethi Atil, Ahmet Culhaoglu, Ismail Doruk Kocyigit, Zahit Adisen, Melda Misirlioglu, Burak Yilmaz
This clinical report describes the oral rehabilitation with implant-supported fixed dental prostheses in the maxilla and mandible of a patient with cleidocranial dysplasia. Cone-beam computed tomography and a tilted implant protocol in the mandible helped to establish a conservative approach for bone preservation, prevent surgical complications, enable proper implant positioning to avoid anatomic structures, and support the fixed dental prostheses.



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Circulating motilin, ghrelin and GLP-1 and their correlations with gastric slow waves in patients with chronic kidney disease

Background/Aims: Patients with chronic kidney disease (CKD) commonly complain upper gastrointestinal (GI) symptoms, especially anorexia. Hemodialysis (HD) has been noted to improve GI symptoms; however, underlying mechanisms are unclear. This study was designed 1) to study effects of HD on GI symptoms and gastric slow waves; 2) to investigate possible roles of ghrelin and glucagon-like peptide-1 (GLP-1). Methods: This study recruited 13 healthy controls, 20 CKD patients without HD (CKD group) and 18 CKD patients with HD (HD group). Dyspeptic symptoms, autonomic functions, gastric slow waves, and plasma level of ghrelin and GLP-1 were analyzed. Results: 1) The CKD patients with HD showed markedly lower scores of anorexia (0.6±0.2 vs. 3.2±0.4, P<0.001) compared to patients without HD. 2) The CKD group but not HD group showed a significant reduction (25.6%) in the percentage of normal gastric slow waves, compared to controls. 3)The CKD group exhibited a significantly lower ghrelin level compared to the HD group (26.8±0.9ng/L vs. 34.1±2.3ng/L, P<0.02) and a higher GLP-1 level(29.4±2.8 pmol/L vs. 20.0±2.1pmol/L, P<0.05) compared to controls. Moreover, the percentage of normal slow waves was positively correlated with ghrelin (r=0.385, P=0.019) but negatively correlated with GLP-1 (r=-0.558, P<0.001) in all CKD patients. Conclusions: Hemodialysis improves upper GI symptoms and gastric slow waves in CKD patients. An increase in ghrelin and a decrease in GLP-1 might be involved in the HD-induced improvement in gastric slow waves.



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Sustained increases in skin blood flow are not a pre-requisite to initiate sweating during passive heat exposure

Some studies have observed a functional relationship between sweating and skin blood flow. However, the implications of this relationship during physiologically-relevant conditions remain unclear. We manipulated sudomotor activity through changes in sweating efficiency to determine if parallel changes in vasomotor activity are observed. Eight young males completed two trials at 36°C and two trials at 42°C. During these trials, air temperature remained constant while ambient vapor pressure increased from 1.6 to 5.6 kPa over 2 hours. Forced airflow across the skin was used to create conditions of high (HiSeff) or low (LoSeff) sweating efficiency. Local sweat rate (LSR), local skin blood flow (SkBF), as well as mean skin and esophageal temperatures were measured continuously. It took longer for LSR to increase during HiSeff at 36°C (HiSeff: 99 ± 11 vs. LoSeff: 77 ± 11 min, P<0.01) and 42°C (HiSeff: 72 ± 16 vs. LoSeff: 51 ± 15 min, P<0.01). In general, an increase in LSR preceded the increase in SkBF when expressed as ambient vapor pressure and time for all conditions (P<0.05). However, both responses were activated at a similar change in mean body temperature (average across all trials, LSR: 0.26 ± 0.15 vs. SkBF: 0.30 ± 0.18°C, P=0.26). These results demonstrate that altering the point at which local sweat rate is initiated during heat exposure is paralleled by similar shifts for the increase in SkBF. However, local sweat production occurs before an increase in SkBF, suggesting that SkBF is not necessarily a pre-requisite for sweating.



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Tissue-specific seasonal changes in mitochondrial function of a mammalian hibernator

Mammalian hibernators, such as golden-mantled ground squirrels (Callospermophilus lateralis; GMGS), cease to feed while reducing metabolic rate and body temperature during winter months, surviving exclusively on endogenous fuels stored prior to hibernation. We hypothesized that mitochondria, the cellular sites of oxidative metabolism, undergo tissue-specific seasonal adjustments in carbohydrate and fatty acid utilization to facilitate or compliment this remarkable phenotype. To address this, we performed high-resolution respirometry of mitochondria isolated from GMGS liver, heart, skeletal muscle, and brown adipose tissue (BAT) sampled during summer (active), fall (prehibernation), and winter (hibernation) seasons using multi-substrate titration protocols. Mitochondrial phospholipid composition was examined as a postulated intrinsic modulator of respiratory function across tissues and seasons. Respirometry revealed seasonal variations in mitochondrial oxidative phosphorylation capacity, substrate utilization, and coupling efficiency that reflected the distinct functions and metabolic demands of the tissues they support. A consistent finding across tissues was a greater influence of fatty acids (palmitoylcarnitine) on respiratory parameters during the prehibernation and hibernation seasons. In particular, fatty acids had a greater suppressive effect on pyruvate-supported oxidative phosphorylation in heart, muscle and liver mitochondria, and enhanced uncoupled respiration in BAT and muscle mitochondria in the colder seasons. Seasonal variations in the mitochondrial membrane composition reflected changes in the supply and utilization of polyunsaturated fatty acids, but were generally mild and inconsistent with functional variations. In conclusion, mitochondria respond to seasonal variations in physical activity, temperature and nutrient availability in a tissue-specific manner that compliment circannual shifts in the bioenergetic and thermoregulatory demands of mammalian hibernators.



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Combining lead isotopes and cluster analysis to distinguish the Guarani and Serra Geral Aquifer Systems and contaminated waters in a highly industrialized area in Southern Brazil

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Publication date: October 2017
Source:Journal of Environmental Radioactivity, Volume 177
Author(s): Isadora Aumond Kuhn, Ari Roisenberg
The Rio dos Sinos Watershed area is located at the Middle-West region of the Rio Grande do Sul State, Southern Brazil, along thirty two municipalities and affecting 1.5 million inhabitants and many important industrial centers. Three main aquifers are recognized in the study area: the unconfined-fractured Serra Geral Aquifer System, the porous Guarani Aquifer System, and the Permian Aquitard. This study aims to understand groundwater, surface water and human activity interactions in the Rio dos Sinos Watershed, evaluating the application of stable lead isotopic ratios analyzed for this propose. Thirty six groundwater samples, 8 surface water samples and 5 liquid effluents of tanneries and landfills samples were measured using a Thermal Ionization Mass Spectrometer Thermo-Finnigan and a Neptune Multi-Collector Inductively Coupled Plasma Mass Spectrometer. Groundwater isotopic ratios have a wider range compared to the surface water, with less radiogenic averages 208Pb/204Pb = 38.1837 vs 38.4050 (standard deviation = 0.2921 vs 0.1343) and 206Pb/204Pb = 18.2947 vs 18.4766 (standard deviation = 0.2215 vs 0.1059), respectively. Industrial liquid effluents (tanneries and industrial landfill) have averages 208Pb/204Pb = 38.1956 and 206Pb/204Pb = 18.3169, distinct from effluent samples of domestic sanitary landfill (averages 208Pb/204Pb = 38.2353 and 206Pb/204Pb = 18.6607). Hierarchical cluster analysis led to distinguish six groups of groundwater, representing the three aquifers that occur in the area, two clusters suggesting groundwater mixtures and one demonstrating a highly contaminated groundwater. By analyzing the cluster results and wells' stratigraphic profiles it was possible to distinguish the different aquifers in the area. The Serra Geral Aquifer System has 206Pb/204Pb ratios between 18.4718 and 18.7089; 207Pb/204Pb between 15.6692 and 15.6777; 208Pb/204Pb between 38.6826 and 38.7616; 207Pb/206Pb between 0.8372 and 0.8623; 208Pb/206Pb between 2.0671 and 2.0964 and the Guarani Aquifer System has a wider range (208Pb/204Pb ranged from 37.9393 to 38.1279 and 206Pb/204Pb ranged from 18.0892 to 18.3217). Water mixing of these two aquifer systems is reflected by transitional results. The results confirm that the hierarchical cluster analysis of lead isotopes is a useful tool to discriminate different aquifer conditions, reflecting mostly the influence of the natural lead isotopic composition of the aquifers instead of the anthropogenic activities (urban and industrial), except when the groundwater is highly contaminated by human activity.



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Discriminative ability of commonly used indices to predict adverse outcomes after poster lumbar fusion: a comparison of demographics, ASA, the modified charlson comorbidity index, and the modified frailty index

As research tools, the American Society of Anesthesiologist physical classification system (ASA), the modified Charlson Comorbidity Index (mCCI), and the modified Frailty Index (mFI) have been associated with complications following spine procedures. However, with respect to clinical utility for various adverse outcomes, no known study has compared the predictive performance of these indices specifically following posterior lumbar fusion (PLF).

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Efficacy and safety of urinary catheters with silver alloy coating in spinal cord injured patients: a multicentric pragmatic randomized controlled trial. the ESCALE trial

Patients with spinal cord injury (SCI) that carry indwelling urinary catheters have an increased risk of urinary tract infection (UTIs). Antiseptic Silver Alloy-Coated silicone (SAC) urinary catheters prove to be a promising intervention to reduce UTIs; however, current evidence cannot be extrapolated to spinal cord injured patients.

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Patterns of regional recurrence in papillary thyroid cancer patients with lateral neck metastases undergoing neck dissection

Practice variability exists for the extent of neck dissection undertaken for papillary thyroid carcinoma (PTC) metastatic to the lateral neck nodes, with disagreement over routine level V dissection.

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Eosinophilic esophagitis induced by aeroallergen sublingual immunotherapy in an enteral feeding tube–dependent pediatric patient

Eosinophilic esophagitis (EoE) is an increasingly recognized eosinophilic gastrointestinal disorder that affects children and adults, with a prevalence of 5 per 10,000 inhabitants in Europe and the United States.1 Food antigens trigger more than 90% of cases; however, data suggest that aeroallergens may also play a pathogenic role.2,3 In addition, sublingual immunotherapy (SLIT) is being increasingly used for the treatment of allergic rhinitis and allergic asthma. In this report, we describe a 9-year-old enteral feeding tube–dependent boy who developed increased esophageal eosinophilia, suggesting EoE after initiating aeroallergen SLIT.

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Prospective evaluation of electronic medical record penicillin allergy documentation at a tertiary community teaching hospital

The global threat of increasing antibiotic resistance has driven regulatory organizations to advocate for the judicious and prudent use of antibiotics through robust antibiotic stewardship programs. Recently published antibiotic stewardship guidelines detail recommended strategies to optimize antibiotic use in a variety of health care settings.1 One such strategy includes a thorough penicillin allergy history assessment and, if indicated, subsequent penicillin skin testing in patients with a reported penicillin allergy.

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Evaluation of genetic variants in association with colorectal cancer risk and survival in Asians

Abstract

Genome-wide association studies (GWAS) have identified over 40 genetic loci associated with colorectal cancer (CRC) risk. The association of single nucleotide polymorphisms (SNPs) at these loci with CRC risk and survival has not been adequately evaluated in East Asians. GWAS-identified CRC risk variants were used to construct weighted genetic risk scores (GRSs). We evaluated these GRSs in association with CRC risk in 3,303 CRC cases and 3,553 controls using logistic regression models. Associations with overall and CRC-specific survival were assessed in 731 CRC patients using Cox regression models. The association between the GRSs (overall and Asian-specific) and CRC risk was approximately 2-fold (highest versus lowest quintile), and the shape of the dose-response was linear (Ptrend =1.24x10−13 and 3.02x10−14 for overall GRS and Asian-specific GRS, respectively). The association of the GRS with CRC risk was stronger among those with a family history of CRC (Pinteraction =0.007). Asian-specific GRS using previously reported survival SNPs increased risk for mortality and the shape of the dose-response was linear for CRC-specific and all-cause mortality (Ptrend =0.01 and 0.006, respectively). Furthermore, the minor alleles of rs6983267 and rs1957636 were associated with worse CRC-specific and overall survival. We show that GRSs constructed using GWAS-identified common variants are strongly associated with CRC risk in Asians. We confirm previous findings for the possible association between some SNPs with survival, and provide evidence for two additional CRC risk variants that may be related to CRC survival. This article is protected by copyright. All rights reserved.



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Oncolytic Maraba virus MG1 as a treatment for Sarcoma

Abstract

The poor prognosis of patients with advanced bone and soft-tissue sarcoma has not changed in the past several decades, highlighting the necessity for new therapeutic approaches. Immunotherapies, including oncolytic viral (OV) therapy, have shown great promise in a number of clinical trials for a variety of tumor types. However, the effective application of OV in treating sarcoma still remains to be demonstrated. Although few pre-clinical studies using distinct OVs have been performed and demonstrated therapeutic benefit in sarcoma models, a side-by-side comparison of clinically relevant OV platforms has not been performed.

Four clinically relevant OV platforms (Reovirus, Vaccinia virus, Herpes-simplex virus and Rhabdovirus) were screened for their ability to infect and kill human and canine sarcoma cell lines in vitro, and human sarcoma specimens ex vivo. In vivo treatment efficacy was tested in a murine model. The rhabdovirus MG1 demonstrated the highest potency in vitro. Ex vivo, MG-1 productively infected more than 80% of human sarcoma tissues tested, and treatment in vivo led to a significant increase in long-lasting cures in sarcoma-bearing mice. Importantly, MG1 treatment induced the generation of memory immune response that provided protection against a subsequent tumor challenge.

This study opens the door for the use of MG-1-based oncolytic immunotherapy strategies as treatment for sarcoma or as a component of a combined therapy. This article is protected by copyright. All rights reserved.



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Therapeutic targeting of chemoresistant and recurrent glioblastoma stem cells with a proapoptotic variant of oncolytic herpes simplex virus

Abstract

Temozolomide (TMZ) chemotherapy, in combination with maximal safe resection and radiotherapy, is the current standard of care for patients with glioblastoma (GBM). Despite this multimodal approach, GBM inevitably relapses primarily due to resistance to chemo-radiotherapy, and effective treatment is not available for recurrent disease. In this study we identified TMZ resistant patient-derived primary and previously treated recurrent GBM stem cells (GSC), and investigated the therapeutic activity of a pro-apoptotic variant of oHSV (oHSV-TRAIL) in vitro and in vivo. We show that oHSV-TRAIL modulates cell survival and MAP Kinase proliferation signaling pathways as well as DNA damage response pathways in both primary and recurrent TMZ-resistant GSC. Utilizing real time in vivo imaging and correlative immunohistochemistry, we show that oHSV-TRAIL potently inhibits tumor growth and extends survival of mice bearing TMZ-insensitive recurrent intracerebral GSC tumors via robust and selective induction of apoptosis-mediated death in tumor cells, resulting in cures in 40% of the treated mice. In comparison, the anti-tumor effects in a primary chemoresistant GSC GBM model exhibiting a highly invasive phenotype were significant but less prominent. This work thus demonstrates the ability of oHSV-TRAIL to overcome the therapeutic resistance and recurrence of GBM, and provides a basis for its testing in a GBM clinical trial. This article is protected by copyright. All rights reserved.



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Low Vitamin B12 Increases Risk of Gastric Cancer: A Prospective Study of One-Carbon Metabolism Nutrients and Risk of Upper Gastrointestinal Tract Cancer

Abstract

Previous studies have found associations between one-carbon metabolism nutrients and risk of several cancers, but little is known regarding upper gastrointestinal tract (UGI) cancer. We analyzed pre-diagnostic serum concentrations of several one-carbon metabolism nutrients (vitamin B12, folate, vitamin B6, riboflavin, and homocysteine) in a nested case-control study within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study of male smokers, which was undertaken in Finland between 1985 and 1988.

We conducted a nested case-control study including 127 non-cardia gastric adenocarcinoma (NCGA), 41 esophago-gastric junctional adenocarcinoma (EGJA), and 60 esophageal squamous cell carcinoma (ESCC) incident cases identified within ATBC. Controls were matched to cases on age, date of serum collection, and follow-up time. One-carbon nutrient concentrations were measured in fasting serum samples collected at baseline (up to 17 years prior to cancer diagnosis). Odds ratios (OR) and 95% confidence intervals (CI) were calculated using conditional logistic regression. Lower pre-diagnostic vitamin B12 concentrations at baseline were associated with a 5.8-fold increased risk of NCGA (95% CI = 2.7 to 12.6 for lowest compared to highest quartile, p-trend < 0.001). This association remained in participants who developed cancer more than 10 years after blood collection, and after restricting the analysis to participants with clinically normal serum vitamin B12 (>300 pmol/L). In contrast, pepsinogen I, a known serologic marker of gastric atrophy, was not associated with NCGA in this population.

As vitamin B12 absorption requires intact gastric mucosa to produce acid and intrinsic factor, our findings suggest vitamin B12 as a possible serologic marker for the atrophic gastritis that precedes NCGA, one more strongly associated with subsequent NCGA than pepsinogen. This article is protected by copyright. All rights reserved.



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