bluuebunny/crossref_metadata_2025_split huggingface dataset:
The human coronary vasodilatory response to acute mental stress is mediated by neuronal nitric oxide synthase
Authors: Khan Sitara G. , Melikian Narbeh , Shabeeh Husain , Cabaco Ana R. , Martin Katherine , Khan Faisal , O’Gallagher Kevin , Chowienczyk Philip J. , Shah Ajay M. 
Published: June 2017

Mental stress-induced ischemia approximately doubles the risk of cardiac events in patients with coronary artery disease, yet the mechanisms underlying changes in coronary blood flow in response to mental stress are poorly characterized. Neuronal nitric oxide synthase (nNOS) regulates basal coronary blood flow in healthy humans and mediates mental stress-induced vasodilation in the forearm. However, its possible role in mental stress-induced increases in coronary blood flow is unknown. We studied 11 patients (6 men and 5 women, mean age: 58 ± 14 yr) undergoing elective diagnostic cardiac catheterization and assessed the vasodilator response to mental stress elicited by the Stroop color-word test. Intracoronary substance P (20 pmol/min) and isosorbide dinitrate (1 mg) were used to assess endothelium-dependent and -independent vasodilation, respectively. Coronary blood flow was estimated using intracoronary Doppler recordings and quantitative coronary angiography to measure coronary artery diameter. Mental stress increased coronary flow by 34 ± 7.0% over the preceding baseline during saline infusion ( P < 0.01), and this was reduced to 26 ± 7.0% in the presence of the selective nNOS inhibitor S-methyl-l-thiocitrulline (0.625 µmol/min, P < 0.001). Mental stress increased coronary artery diameter by 6.9 ± 3.7% ( P = 0.02) and 0.5 ± 2.8% ( P = 0.51) in the presence of S-methyl-l-thiocitrulline. The response to substance P did not predict the response to mental stress ( r2 = −0.22, P = 0.83). nNOS mediates the human coronary vasodilator response to mental stress, predominantly through actions at the level of coronary resistance vessels. NEW & NOTEWORTHY Acute mental stress induces vasodilation of the coronary microvasculature. Here, we show that this response involves neuronal nitric oxide synthase in the human coronary circulation. Listen to this article’s corresponding podcast at http://ajpheart.podbean.com/e/nnos-and-coronary-flow-during-mental-stress/ .
Frequency and magnitude of intermittent hypoxia modulate endothelial wound healing in a cell culture model of sleep apnea
Authors: Campillo Noelia , Falcones Bryan , Montserrat Josep M. , Gozal David , Obeso Ana , Gallego-Martin Teresa , Navajas Daniel , Almendros Isaac , Farré Ramon 
Published: June 2017

Intermittent hypoxia (IH) has been implicated in the cardiovascular consequences of obstructive sleep apnea (OSA). However, the lack of suitable experimental systems has precluded assessment as to whether IH is detrimental, protective, or both for the endothelium. The aim of the work was to determine the effects of frequency and amplitude of IH oxygenation swings on aortic endothelial wound healing. Monolayers of human primary endothelial cells were wounded and subjected to constant oxygenation (1%, 4%, 13%, or 20% O2) or IH at different frequencies (0.6, 6, or 60 cycles/h) and magnitude ranges (13–4% O2or 20–1% O2), using a novel well-controlled system, with wound healing being measured after 24 h. Cell monolayer repair was similar at 20% O2and 13% O2, but was considerably increased (approximately twofold) in constant hypoxia at 4% O2. The magnitude and frequency of IH considerably modulated wound healing. Cycles ranging 13–4% O2at the lowest frequency (0.6 cycles/h) accelerated endothelial wound healing by 102%. However, for IH exposures consisting of 20% to 1% O2oscillations, wound closure was reduced compared with oscillation in the 13–4% range (by 74% and 44% at 6 cycles/h and 0.6 cycles/h, respectively). High-frequency IH patterns simulating severe OSA (60 cycles/h) did not significantly modify endothelial wound closure, regardless of the oxygenation cycle amplitude. In conclusion, the frequency and magnitude of hypoxia cycling in IH markedly alter wound healing responses and emerge as key factors determining how cells will respond in OSA.NEW & NOTEWORTHY Intermittent hypoxia (IH) induces cardiovascular consequences in obstructive sleep apnea (OSA) patients. However, the vast array of frequencies and severities of IH previously employed in OSA-related experimental studies has led to controversial results on the effects of IH. By employing an optimized IH experimental system here, we provide evidence that the frequency and magnitude of IH markedly alter human aortic endothelial wound healing, emerging as key factors determining how cells respond in OSA.
Utility of Genomic Analysis In Circulating Tumor DNA from Patients with Carcinoma of Unknown Primary
Authors: Kato Shumei , Krishnamurthy Nithya , Banks Kimberly C. , De Pradip , Williams Kirstin , Williams Casey , Leyland-Jones Brian , Lippman Scott M. , Lanman Richard B. , Kurzrock Razelle 
Published: June 2017

Abstract
Carcinoma of unknown primary (CUP) is a rare and difficult-to-treat malignancy, the management of which might be improved by the identification of actionable driver mutations. We interrogated 54 to 70 genes in 442 patients with CUP using targeted clinical-grade, next-generation sequencing of circulating tumor DNA (ctDNA). Overall, 80% of patients exhibited ctDNA alterations; 66% (290/442) ≥1 characterized alteration(s), excluding variants of unknown significance. TP53-associated genes were most commonly altered [37.8% (167/442)], followed by genes involved in the MAPK pathway [31.2% (138/442)], PI3K signaling [18.1% (80/442)], and the cell-cycle machinery [10.4% (46/442)]. Among 290 patients harboring characterized alterations, distinct genomic profiles were observed in 87.9% (255/290) of CUP cases, with 99.7% (289/290) exhibiting potentially targetable alterations. An illustrative patient with dynamic changes in ctDNA content during therapy and a responder given a checkpoint inhibitor–based regimen because of a mismatch repair gene anomaly are presented. Our results demonstrate that ctDNA evaluation is feasible in CUP and that most patients harbor a unique somatic profile with pharmacologically actionable alterations, justifying the inclusion of noninvasive liquid biopsies in next-generation clinical trials. Cancer Res; 77(16); 4238–46. ©2017 AACR.
Modulation of Endoplasmic Reticulum Stress Controls CD4+ T-cell Activation and Antitumor Function
Authors: Thaxton Jessica E. , Wallace Caroline , Riesenberg Brian , Zhang Yongliang , Paulos Chrystal M. , Beeson Craig C. , Liu Bei , Li Zihai 
Published: June 2017

Abstract
The endoplasmic reticulum (ER) is an energy-sensing organelle with intimate ties to programming cell activation and metabolic fate. T-cell receptor (TCR) activation represents a form of acute cell stress and induces mobilization of ER Ca2+ stores. The role of the ER in programming T-cell activation and metabolic fate remains largely undefined. Gp96 is an ER protein with functions as a molecular chaperone and Ca2+ buffering protein. We hypothesized that the ER stress response may be important for CD4+ T-cell activation and that gp96 may be integral to this process. To test our hypothesis, we utilized genetic deletion of the gp96 gene Hsp90b1 in a CD4+ T cell–specific manner. We show that gp96-deficient CD4+ T cells cannot undergo activation-induced glycolysis due to defective Ca2+ mobilization upon TCR engagement. We found that activating naïve CD4+ T cells while inhibiting ER Ca2+ exchange, through pharmacological blockade of the ER Ca2+ channel inositol trisphosphate receptor (IP3R), led to a reduction in cytosolic Ca2+ content and generated a pool of CD62Lhigh/CD44low CD4+ T cells compared with wild-type (WT) matched controls. In vivo IP3R-inhibited CD4+ T cells exhibited elevated tumor control above WT T cells. Together, these data show that ER-modulated cytosolic Ca2+ plays a role in defining CD4+ T-cell phenotype and function. Factors associated with the ER stress response are suitable targets for T cell–based immunotherapies. Cancer Immunol Res; 5(8); 666–75. ©2017 AACR.
Mediator 1 Is Atherosclerosis Protective by Regulating Macrophage Polarization
Authors: Bai Liang , Li Zhao , Li Qianwei , Guan Hua , Zhao Sihai , Liu Ruihan , Wang Rong , Zhang Jin , Jia Yuzhi , Fan Jianglin , Wang Nanping , Reddy Janardan K. , Shyy John Y.-J. , Liu Enqi 
Published: June 2017

Objective—
MED1 (mediator 1) interacts with transcription factors to regulate transcriptional machinery. The role of MED1 in macrophage biology and the relevant disease state remains to be investigated.

Approach and Results—

To study the molecular mechanism by which MED1 regulates the M1/M2 phenotype switch of macrophage and the effect on atherosclerosis, we generated MED1/apolipoprotein E (ApoE) double-deficient (MED1
ΔMac
/ApoE
−
/−
) mice and found that atherosclerosis was greater in MED1
ΔMac
/ApoE
−/−
mice than in MED1
fl/fl
/ApoE
−/−
littermates. The gene expression of M1 markers was increased and that of M2 markers decreased in both aortic wall and peritoneal macrophages from MED1
ΔMac
/ApoE
−/−
mice, whereas MED1 overexpression rectified the changes in M1/M2 expression. Moreover, LDLR (low-density lipoprotein receptor)–deficient mice received bone marrow from MED1
ΔMac
mice showed greater atherosclerosis. Mechanistically, MED1 ablation decreased the binding of PPARγ (peroxisome proliferator–activated receptor γ) and enrichment of H3K4me1 and H3K27ac to upstream region of M2 marker genes. Furthermore, interleukin 4 induction of PPARγ and MED1 increased the binding of PPARγ or MED1 to the PPAR response elements of M2 marker genes.

Conclusions—
Our data suggest that MED1 is required for the PPARγ-mediated M2 phenotype switch, with M2 marker genes induced but M1 marker genes suppressed. MED1 in macrophages has an antiatherosclerotic role via PPARγ-regulated transactivation.
The Roadmap for Enhancing University–Industry Research Collaboration in India
Authors: Kumar Prateek , Gupta Roopali 
Published: June 2017

In this age of technology-led development and stiff international competition over Intellectual Property Rights (IPRs), developing countries, with their limited financial capabilities, face the challenge of creating appropriate environment that could facilitate the creation and commercialisation of technologies. The recognition of poor scientific outputs as a hindrance to the growth of domestic industry has brought research on the development agenda. This article focuses on university–industry research collaborations as one of the ways to kick-start innovation-led economic growth in India. It explores the evolution of relevant policy paradigm in India and presents the relevant highlights of National IPR Policy 2016. It identifies the impediments in the way of creative university–industry collaborations and offers solutions to attain optimum synergy between the academia and industry.
Nicotine and cigarette smoke modulate Nrf2-BDNF-dopaminergic signal and neurobehavioral disorders in adult rat cerebral cortex#
Authors: Naha Nibedita , Gandhi DN , Gautam AK , Prakash J Ravi 
Published: June 2017

Background: Nicotine and cigarette smoking (CS) are associated with addiction behavior, drug-seeking, and abuse. However, the mechanisms that mediate this association especially, the role of brain-derived neurotrophic factor (BDNF), dopamine (DA), and nuclear factor erythroid 2-related factor 2 (Nrf2) signaling in the cerebral cortex, are not fully known. Therefore, we hypothesized that overexpression of BDNF and DA, and suppression of Nrf2 contribute to several pathological and behavioral alterations in adult cerebral cortex. Methodology/Principal Observations: We treated Wistar rats with different doses of oral nicotine and passive CS for 4-week (short-term) and 12-week (long-term) duration, where doses closely mimic the human smoking scenario. Our result showed dose-dependent association of anxiogenic and depressive behavior, and cognitive interference with neurodegeneration and DNA damage in the cerebral cortex upon exposure to nicotine/CS as compared to the control. Further, the results are linked to upregulation of oxidative stress, overexpression of BDNF, DA, and DA marker, tyrosine hydroxylase (TH), with concomitant downregulation of ascorbate and Nrf2 expression in the exposed cerebral cortex when compared with the control. Conclusion/Significance: Overall, our data strongly suggest that the intervention of DA and BDNF, and depletion of antioxidants are important factors during nicotine/CS-induced cerebral cortex pathological changes leading to neurobehavioral impairments, which could underpin the novel therapeutic approaches targeted at tobacco smoking/nicotine’s neuropsychological disorders including cognition and drug addiction.
An Assessment of Database-Validated microRNA Target Genes in Normal Colonic Mucosa: Implications for Pathway Analysis
Authors: Slattery Martha L , Herrick Jennifer S , Stevens John R , Wolff Roger K , Mullany Lila E 
Published: June 2017

Background:Determination of functional pathways regulated by microRNAs (miRNAs), while an essential step in developing therapeutics, is challenging. Some miRNAs have been studied extensively; others have limited information. In this study, we focus on 254 miRNAs previously identified as being associated with colorectal cancer and their database-identified validated target genes.Methods:We use RNA-Seq data to evaluate messenger RNA (mRNA) expression for 157 subjects who also had miRNA expression data. In the replication phase of the study, we replicated associations between 254 miRNAs associated with colorectal cancer and mRNA expression of database-identified target genes in normal colonic mucosa. In the discovery phase of the study, we evaluated expression of 18 miRNAs (those with 20 or fewer database-identified target genes along with miR-21-5p, miR-215-5p, and miR-124-3p which have more than 500 database-identified target genes) with expression of 17 434 mRNAs to identify new targets in colon tissue. Seed region matches between miRNA and newly identified targeted mRNA were used to help determine direct miRNA-mRNA associations.Results:From the replication of the 121 miRNAs that had at least 1 database-identified target gene using mRNA expression methods, 97.9% were expressed in normal colonic mucosa. Of the 8622 target miRNA-mRNA associations identified in the database, 2658 (30.2%) were associated with gene expression in normal colonic mucosa after adjusting for multiple comparisons. Of the 133 miRNAs with database-identified target genes by non-mRNA expression methods, 97.2% were expressed in normal colonic mucosa. After adjustment for multiple comparisons, 2416 miRNA-mRNA associations remained significant (19.8%). Results from the discovery phase based on detailed examination of 18 miRNAs identified more than 80 000 miRNA-mRNA associations that had not previously linked to the miRNA. Of these miRNA-mRNA associations, 15.6% and 14.8% had seed matches for CRCh38 and CRCh37, respectively.Conclusions:Our data suggest that miRNA target gene databases are incomplete; pathways derived from these databases have similar deficiencies. Although we know a lot about several miRNAs, little is known about other miRNAs in terms of their targeted genes. We encourage others to use their data to continue to further identify and validate miRNA-targeted genes.
New insights into the burden and costs of multiple sclerosis in Europe: Results for Hungary
Authors: Péntek Márta , Kobelt Gisela , Berg Jenny , Capsa Daniela , Dalén Johan , Bíró Zita , Mátyás Klotild , Komoly Sámuel ,   The European Multiple Sclerosis Platform
Published: June 2017

Introduction: To estimate the value of interventions in multiple sclerosis (MS) – where lifetime costs and outcomes cannot be observed – outcome data have to be combined with costs. This requires that cost data be regularly updated. Objectives and methods: This study is part of a cross-sectional retrospective study in 16 countries collecting data on resource consumption, work capacity, health-related quality of life (HRQoL) and prevalent symptoms for patients with MS. Descriptive analyses are presented by level of disability, from the societal perspective, in HUF 2015. Results: A total of 521 patients (mean age 47 years) participated; 85% were below retirement age, and of these, 47% were employed. Employment was related to disability and MS affected productivity at work for 82% of those working. Overall, 94% and 66% of patients experienced fatigue and cognitive difficulties as a problem, respectively. The mean utility and annual costs were 0.691 and 3,432,000HUF at Expanded Disability Status Scale (EDSS) 0–3, 0.491 and 5,262,000HUF at EDSS 4–6.5 and 0.076 and 6,235,000HUF at EDSS 7–9, respectively. The average cost of a relapse was estimated at 240,500HUF. Conclusion: This study illustrates the burden of MS on Hungarian patients and provides current data that are important for the development of health policies.
Eye Injuries in High School and Collegiate Athletes
Authors: Boden Barry P. , Pierpoint Lauren A. , Boden Rebecca G. , Comstock R. Dawn , Kerr Zachary Y. 
Published: June 2017

Background: Although eye injuries constitute a small percentage of high school and college sports injuries, they have the potential to be permanently debilitating. Hypothesis: Eye injury rates will vary by sport, sex, and between the high school and college age groups. Study Design: Descriptive epidemiology study. Level of Evidence: Level 3. Methods: Data from eye injury reports in high school and college athletes were obtained from the National High School Sports-Related Injury Surveillance System, High School Reporting Information Online (HS RIO) database over a 10-year span (2005-2006 through 2014-2015 school years) and the National Collegiate Athletic Association (NCAA) Injury Surveillance Program (ISP) over an 11-year span (2004-2005 through 2014-2015 school years). Injury rates per 100,000 athlete-exposures (AEs), injury rate ratios (RRs), and 95% CIs were calculated. Distributions of eye injuries by diagnosis, mechanism, time loss, and surgery needs were also examined. Results: A total of 237 and 273 eye injuries were reported in the HS RIO and the NCAA ISP databases, respectively. The sports with the highest eye injury rates (per 100,000 AEs) for combined high school and college athletes were women’s basketball (2.36), women’s field hockey (2.35), men’s basketball (2.31), and men’s wrestling (2.07). Overall eye injury rates at the high school and college levels were 0.68 and 1.84 per 100,000 AEs, respectively. Eye injury rates were higher in competition than practice in high school (RR, 3.47; 95% CI, 2.69-4.48) and college (RR, 3.13; 95% CI, 2.45-3.99). Most injuries were contusions (high school, 35.9%; college, 33.3%) and due to contact (high school, 89.9%; college, 86.4%). Only a small percentage of injuries resulted in time loss over 21 days (high school, 4.2%; college, 3.0%). Conclusion: Eye injury rates and patterns vary by sport, sex, and between the high school and college age groups. Although severe injuries do occur, most eye injuries sustained by high school and college athletes are minor, with limited time loss and full recovery. Clinical Relevance: Additional focus needs to be placed on preventing eye injuries at the collegiate level in women’s and men’s basketball, women’s field hockey, and men’s wrestling.
Combination targeted pulmonary hypertension therapy in the resolution of Dasatinib‐associated pulmonary arterial hypertension
Authors: Jose Arun , Rafei Hind , Ahari Jalil 
Published: June 2017

Dasatinib is a small‐molecule tyrosine kinase inhibitor used in the treatment of hematological malignancies. Pulmonary arterial hypertension (PAH) is a rare but known complication. The mainstay of treatment is cessation of Dasatinib, and while clinical improvement is rapid, complete hemodynamic resolution of pulmonary hypertension (PH) still remains exceedingly uncommon. We present a case of Dasatinib‐induced PAH in a woman with chronic myeloid leukemia, who demonstrated rapid and complete clinical and hemodynamic resolution following treatment with combination pulmonary vasodilator therapy using an endothelin receptor antagonist and a phosphodiesterase‐5 inhibitor. This case suggests there may be an association between the use of targeted PH medication in combination and the complete resolution of dasatinib‐associated PAH, but further investigation is required.
Prevalence and risk factors for colorectal adenomas in patients with ulcerative colitis
Authors: Gordillo Jordi , Zabana Yamile , Garcia‐Planella Esther , Mañosa Míriam , Llaó Jordina , Gich Ignasi , Marín Laura , Szafranska Justyna , Sáinz Sergio , Bessa Xavier , Cabré Eduard , Domènech Eugeni 
Published: June 2017

BackgroundPatients with ulcerative colitis (UC) have an increased risk of colorectal cancer. Scarce data regarding the development of adenomas in these patients are available both for normal and colitic mucosa.ObjectiveThe objective of this article is to evaluate the prevalence of adenomatous polyps and associated risk factors in patients with UC.MethodsPatients with UC were identified from the databases of two tertiary referral centers. Medical, endoscopic and histologic reports were reviewed.ResultsA total of 403 patients were included (53% male; 33% extensive colitis) and 1065 colonoscopies (median per patient, 2) were recorded and analyzed. Seventy‐four adenomas in 47 patients (11.7%) and three cases of colorectal cancer were found during a median follow‐up of 6.3 years. The cumulative risk of colorectal adenoma was 4.7%, 16.7%, 23.6% and 34.4% at 10, 20, 30 and 40 years from UC diagnosis, respectively. The cumulative risk of developing metachronous colorectal adenoma was 66.7%, 87.9%, and 90.9% at 5, 10, and 15 years from first adenoma detection. Older age at UC diagnosis and longer disease duration were independent risk factors for colorectal adenoma development.ConclusionsThe prevalence of colorectal adenomas among UC patients seems to be higher than previously reported, although lower than in the background population.