tbuckley/cabot-search huggingface dataset:
The Brugada Syndrome Susceptibility Gene <i>HEY2</i> Modulates Cardiac Transmural Ion Channel Patterning and Electrical Heterogeneity
Authors: Christiaan C. Veerman, Svitlana Podliesna, Rafik Tadros, Elisabeth M. Lodder, Isabella Mengarelli, Berend de Jonge, Leander Beekman, Julien Barc, Ronald Wilders, Arthur A.M. Wilde, Bastiaan J. Boukens, Ruben Coronel, Arie O. Verkerk, Carol Ann Remme, Connie R. Bezzina
Journal: Circulation Research (2017)

Genome-wide association studies previously identified an association of rs9388451 at chromosome 6q22.3 (near HEY2) with Brugada syndrome. The causal gene and underlying mechanism remain unresolved.We used an integrative approach entailing transcriptomic studies in human hearts and electrophysiological studies in Hey2+/- (Hey2 heterozygous knockout) mice to dissect the underpinnings of the 6q22.31 association with Brugada syndrome.We queried expression quantitative trait locus data acquired in 190 human left ventricular samples from the genotype-tissue expression consortium for cis-expression quantitative trait locus effects of rs9388451, which revealed an association between Brugada syndrome risk allele dosage and HEY2 expression (β=+0.159; P=0.0036). In the same transcriptomic data, we conducted genome-wide coexpression analysis for HEY2, which uncovered KCNIP2, encoding the β-subunit of the channel underlying the transient outward current (Ito), as the transcript most robustly correlating with HEY2 expression (β=+1.47; P=2×10-34). Transcript abundance of Hey2 and the Ito subunits Kcnip2 and Kcnd2, assessed by quantitative reverse transcription-polymerase chain reaction, was higher in subepicardium versus subendocardium in both left and right ventricles, with lower levels in Hey2+/- mice compared with wild type. Surface ECG measurements showed less prominent J waves in Hey2+/- mice compared with wild-type. In wild-type mice, patch-clamp electrophysiological studies on cardiomyocytes from right ventricle demonstrated a shorter action potential duration and a lower Vmax in subepicardium compared with subendocardium cardiomyocytes, which was paralleled by a higher Ito and a lower sodium current (INa) density in subepicardium versus subendocardium. These transmural differences were diminished in Hey2+/- mice because of changes in subepicardial cardiomyocytes.This study uncovers a role of HEY2 in the normal transmural electrophysiological gradient in the ventricle and provides compelling evidence that genetic variation at 6q22.31 (rs9388451) is associated with Brugada syndrome through a HEY2-dependent alteration of ion channel expression across the cardiac ventricular wall.
Traitement endoscopique de l'hypertension portale de l'enfant de moins de 24 mois par injection de colle
Authors: C Rivet, J Dumortier, C Le Gall, S Marotte, T Ponchon, A Lachaux
Journal: Endoscopy (2006)

Le traitement endoscopique de l'hypertension portale du nourrisson reste problématique en particulier du fait du manque de matériel adapté. Nous rapportons ici la faisabilité et l'efficacité de l'injection de N-Butyl-2- Cyanoacrylate chez 8 enfants présentant une hypertension portale compliquée d'hémorragie digestive par rupture de varices oesophagiennes (VO) ou sous cardiales (VSC).
Molecular mechanisms of tamoxifen-induced apoptosis in cholangiocarcinoma
Authors: Pritish Pawar, Liping Ma, Nirag Jhala, Hui Liu, Jay McDonald, Yabing Chen
Journal: Clinical Cancer Research (2007)

B38   Cholangiocarcinoma is a highly fatal tumor of biliary epithelium with very limited therapeutic options. So far no chemotherapy regimen has been found to be effective in advanced stage cholangiocarcinoma. We have found that tamoxifen (TMX) induced apoptosis in cholangiocarcinoma cells, probably via its calmodulin (CaM) antagonist effects. In the present studies, we determined the role of TMX as a potential therapy and the molecular mechanisms responsible for TMX-induced apoptosis in cholangiocarcinoma.  Cholangiocarcinoma tumorigenesis in a mouse xenograft model was inhibited by intratumoral injection of TMX (tumor volumes: control=696.9±123.1mm 3  and TMX=217.8±49.3mm 3 , n=7, p=0.004). Immunohistochemical analyses of the tumors identified the expression of phosphorylated-AKT (pAKT) in all non-treated tumors (pAKT-positive tumor cells=27.1±11.1%) but not in adjacent stromal cells. All sections from the TMX-treated tumors were negative for pAKT staining. TMX (10µM) induced a 1.9-fold increased apoptosis in cells isolated from mouse tumor xenografts (n=5, p 2+ -dependent direct binding of CaM and FLIP, which was increased upon Fas-stimulation. TMX inhibited Fas-induced increase in CaM-FLIP binding, suggesting that TMX may interfere with stabilization of FLIP by inhibiting CaM-FLIP binding after Fas stimulation to enhance sensitivity of cholangiocarcinoma cells to apoptosis.  In summary, we demonstrated that TMX regulates AKT and FLIP activation to induce apoptosis of cholangiocarcinoma cells and may represent an effective therapy for cholangiocarcinoma.
GLI1 Blockade Potentiates the Antitumor Activity of PI3K Antagonists in Lung Squamous Cell Carcinoma
Authors: Sahba Kasiri, Chunli Shao, Baozhi Chen, Alexandra N. Wilson, Paul Yenerall, Brenda C. Timmons, Luc Girard, Hui Tian, Carmen Behrens, Ignacio I. Wistuba, Adi F. Gazdar, James Kim
Journal: Cancer Research (2017)

Lung squamous cell carcinoma (SCC), strongly associated with smoking, is treated primarily with traditional cytotoxic chemotherapy due to a lack of FDA-approved targeted agents available. Here, we identify the Hedgehog pathway transcription factor GLI1 as a critical driver of lung SCC. Analysis of human lung cancer datasets showed that GLI1 mRNA was highly expressed in human lung SCC and portended a poor prognosis. Inhibition of GLI1 in human lung SCC cell lines suppressed tumor cell clonogenicity and proliferation in culture and in vivo Addition of SHH ligand, SMO antagonists, or other Hedgehog pathway agonists did not affect GLI1 expression in lung SCC cells. However, GLI1 expression was modulated by either inhibition or activation of the PI3K and MAPK pathways. Furthermore, in vivo growth of SCC harboring amplifications of the PI3K gene PIK3CA was attenuated by antagonizing GLI1 and PI3K. Thus, a combinatorial therapeutic strategy that targets the PI3K-mTOR pathway and GLI1 may lead to effective outcomes for PI3K pathway-dependent cancers, in contrast to recent results of human trials with single-agent PI3K antagonists. Cancer Res; 77(16); 4448-59. ©2017 AACR.
TAX-TORC: A phase I trial of vistusertib (AZD2014) in combination with weekly paclitaxel with integrated pharmacodynamic (PD) and molecular characterization (MC) studies.
Authors: Raghav Sundar, Bristi Basu, Richard H. Wilson, James F. Spicer, Robert Hugh Jones, Matthew Krebs, Michael Brada, Denis Charles Talbot, Nicola Steele, Emma Hall, Holly Tovey, Suzanne Carreira, Flavia M de Oliveira, Karen E Swales, Geetha Balarajah, Joanna C Dawes, Mona Parmar, Johann S. De Bono, Udai Banerji
Journal: Journal of Clinical Oncology (2017)

2571 Background: In ovarian cells isolated from ascites, p-S6K levels were found to correlate with resistance to chemotherapy. We hypothesised that inhibiting p-S6K signalling with dual m-TORC1/2 inhibitor vistusertib (V) in addition to paclitaxel (P) would improve outcomes of patients with high-grade serous ovarian cancer (HGSOC). Methods: In the dose escalation part, weekly P 80mg/m 2 IV (6/7 weeks) was evaluated in combination with two schedules of V; Schedule A: V (25, 50 or 75mg) BID PO on day(D) 1-3/week and Schedule B: V (75 or 100mg) BID PO D1-2/week. This was followed by an expansion cohort in 25 HGSOC patients. Results: Dose limiting toxicities in Schedule A were fatigue and mucositis and in Schedule B were diarrhoea, rash and fatigue. The AUC, Cmax and half-life of V in the 50mg-cohort were 2821ng.hr/ml, 926ng/ml and 3hrs, comparable to single agent studies. PD analysis (from six 50mg-cohort patients) in platelet-rich plasma showed increased phosphorylation of Ser473 AKT following P induction (1.4 fold, p = 0.1378). Following addition of V to P, phosphorylation levels 4hrs post-treatment with V fell significantly to 53% of pre-dose levels (p = 0.0495). This was 61% lower than the corresponding time point following P alone. Based on toxicity, pharmacokinetic and PD evaluation, recommended phase 2 dose was established as P 80mg/m 2 D1 and V 50mg BID D1-3 for 6/7 weeks. In the HGSOC expansion, 96% of patients had relapsed within 12 months of last platinum therapy and 100% had received previous paclitaxel, with a median of 3 previous lines of treatments. RECIST and GCIG CA125 response rates were 13/25 (52%) and 15/25 (60%) respectively, with median progression free survival of 5.5 months. MC was performed on archival tumor tissue of 24/25 HGSOC expansion cohort patients, with the most common mutations occurring in p53 (100%), BRCA (17%), and MUC16 (17%). ATM mutations occurred in 17% (n = 4), 3 of whom had a response. Conclusions: We report a highly active combination of paclitaxel with an intermittent schedule of vistusertib in patients with HGSOC. This combination is now being evaluated in a randomised controlled trial for this indication. Clinical trial information: NCT02193633.
Concordance of HER2 and its related molecules between primary and paired liver metastatic sites in gastric cancer.
Authors: Eiji Shinozaki, Noriko Yamamoto, Akio Saiura, Takeshi Sano, Keisho Chin, Mariko Ogura, Satoshi Matsusaka, Mitsukuni Suenaga, Masato Ozaka, Nobuyuki Mizunuma
Journal: Journal of Clinical Oncology (2013)

4108 Background: Trastuzumab is the 1 st molecular targeting drug in HER2-positive advanced gastric cancer that has been shown to confer overall survival benefit adding to chemotherapy. In breast cancer it has been already used long time, it is known that there are the discordance of its target; HER2 between primary and metastatic site. Although molecular targeting drugs as Trastuzumab are expected to control the metastatic disease, molecular status is usually evaluated in the primary site because metastatic sites are difficult to biopsy. In this study we attempted to compare HER2 and its related molecular status, which have interaction each together, between primary and paired liver metastatic sites in gastric cancer. Methods: Total 58 consecutive cases with gastric cancer who underwent surgical resection of primary site and synchronous or metachronous liver metastasis were examined. HER2, EGFR, c-MET and IGF-1R status were evaluated by immunohistochemistry(IHC) in primary and paired liver metastasis. HER2 expression by IHC using HercepTest (DAKO) were assessed according to Gastric Cancer Scoring System. On the other molecular expression by IHC, positive expression was defined as 25% or more staining with intensity 2 or 3+. We analyzed the concordance of their expression in both sites. Results: The patient cohort consists predominantly of male (78%), with Lauren’s diffuse (37%) and intestinal tumors (62%). Fifty three percent of cases were synchronous liver metastasis. The positive rate of primary and paired liver metastatic sites were 10.3%, 8.6% in HER2, 1.7%, 5.1% in EGFR, 44.8%, 31.0% in c-MET and 31.0%, 29.3% in IGF-1R. The concordance between primary and paired liver metastatic sites were 91.3%, 93.1%, 75.8%, and 70.6%, respectively. Conclusions: Our data suggested that in HER2 and EGFR the concordance between primary and metastatic site were high, other hands the concordance of c-MET and IGF-1R were relatively low. It might be necessary to rebiopsy to estimate the expression of c-MET and IGF-1R in gastric cancer.
Стан IgG4-позитивних плазматичних клітин у слизовій оболонці товстої кишки при хронічних запальних захворюваннях кишечника
Authors: Yu.А. Gaidar, G.Yu. Arzhanova, A.P. Galenko
Journal: GASTROENTEROLOGY (2017)

Мета роботи: вивчити стан IgG4-позитивних плазматичних клітин у слизовій оболонці товстої кишки в пацієнтів із встановленим морфологічним і ендоскопічним діагнозом неспецифічного виразкового коліту (НВК) та хвороби Крона (ХК). Матеріали та методи. У дослідженні був використаний біопсійний матеріал від 14 пацієнтів із встановленим морфологічним і ендоскопічним діагнозом НВК (8 хворих) і ХК (6 хворих) у стадії загострення, які проходили лікування в Інституті гастроентерології, у відділенні захворювань кишечника. Наявність автоімунного панкреатиту I і II типу була критерієм виключення. Гістологічні препарати виготовляли стандартним методом, забарвлювали гематоксиліном та еозином. Для імуногістохімічного дослідження використовували моноклональні IgG4-антитіла (Abcam, США). Результати. Отримані результати свідчать про те, що при НВК у 37,5 % випадків не були виявлені IgG4-позитивні плазматичні клітини в слизовій оболонці товстої кишки, у 25 % випадків визначені поодинокі IgG4-позитивні плазматичні клітини, у 37,5 % виявлено групи IgG4-позитивних плазматичних клітин, але не більше 5 клітин в одній групі. При ХК спостерігались групи IgG4-позитивних плазматичних клітин, що складаються з 10 або більше клітин. Висновки. При НВК IgG4-позитивні плазматичні клітини можуть бути відсутніми, а також можуть бути поодинокими або зібрані в невеликі групи до 5 клітин у кожній. При ХК спостерігаються групи, що складаються з 10 і більше IgG4-позитивних плазматичних клітин.
Abstract 18802: Short Periods of High-intensity Intermittent Exercise Decreases Arterial Stiffness via Upregulation of Endothelial Nitric Oxide Signalling
Authors: Natsuki Hasegawa, Shumpei Fujie, Naoki Horii, Izumi Tabata, Motoyuki Iemitsu
Journal: Circulation (2016)

Introduction:  Aerobic exercise and short periods of high-intensity intermittent exercise training (HIIT) induce improvement of arterial stiffness, whereas resistance training induces no change or deterioration of arterial stiffness. Release of endothelium-derived nitric oxide (NO) in response to aerobic exercise contributes to exercise-induced vasodilation, resulting in the reduction in arterial stiffness. However, the short periods of HIIT on endothelial NO production remain unclear.   Purpose:  This study aimed to clarify the effects of short periods of HIIT on arterial stiffness and endothelial NO production in rats.   Methods:  Forty male Sprague-Dawley rats were randomly divided into 4groups; CON: sedentary control, AT: aerobic exercise training (treadmill running for 60min at 30m/min, 5days/wk for 8weeks from 10-week-old), HIIT: short periods of high-intensity intermittent exercise training (fourteen 20sec swimming sessions with a weight equivalent to 14-16% of each body weight and 10 sec pause was allowed between exercise sessions, 4days/wk for 6weeks from 12-week-old), and RT: resistance training (ladder climbing, 8-10sets/day, 3days/wk for 8weeks from 10-week-old) groups (n=10 each group). After training session, we measured aortic pulse wave velocity (aortic PWV) as an index of arterial stiffness and plasma nitrite/nitrate (NOx) concentrations and phosphorylation of endothelial nitric oxide (eNOS) and protein kinase B (Akt) proteins in the aorta.   Results:  Aortic PWV was significantly reduced in both AT and HIIT groups as compared to CON and RT groups, whereas there was no difference between RT and CON groups. HIIT-induced reduction of aortic PWV was similar to AT. Additionally, phosphorylation of eNOS and Akt proteins and plasma NOx level were significantly elevated in both AT and HIIT groups as compared to CON and RT groups, whereas there was no difference between RT and CON groups. Moreover, HIIT-induced increase in phosphorylation of eNOS and Akt proteins and plasma NOx levels was similar to AT.   Conclusions:  These results suggest that short periods of HIIT-induced increase in aortic NO production via the Akt/eNOS signalling pathway may reduce arterial stiffness, as same degree of AT in rats.
Differential responses of HER2-positive breast cancer cells to anti-HER2 treatment.
Authors: Rong Yu, Kung Y. Chiu, Lili Shi, Peter Zhang, Chun-Xiao Duan, Sunny Lu
Journal: Journal of Clinical Oncology (2016)

e12095 Background: HER2 is a membrane tyrosine kinase receptor which promotes cells growth by activating downstream kinase pathways: RAS/MEK/ERK and PI3K/AKT. Given the fact that HER2 gene is amplified in certain population of breast cancer patients, therapeutic strategy has evolved to target HER2 function. However, it has been long controversial as to which patients are truly benefited from such treatment. In this study, we evaluate impact of HER2 overexpression on response to anti-HER2 treatment using a panel of breast cancer cell lines, and compared FISH vs. RT-PCR for their accuracy in predicting drug responses. Methods: Human breast cancer lines were obtained from ATCC or from cell repository bank at MD Anderson Cancer Center. RhuMAB HER2 was provided by Genentech. Her2 gene amplification was evaluated by FISH method using the PathVysion HER2/NeuDNA probe kit form Abbott. HER2 mRNA expression was analyzed by RT-PCR method. Growth inhibitory and cytotoxic effects of anti-HER2 antibody were determined by MTS assay. Apoptotic cell death was visualized with DAPI staining and quantified by Annexin V-based flow cytometric detection. Results: A total of 12 cell lines are chosen for this study, 4 of them are HER2-negative and 8 are HER2-positive as determined by FISH testing. Anti-HER2 antibody treatment inhibits growth of all cell lines tested, among them, 3 HER2-positive cell lines are identified to undergo apoptotic cell death. Re-culture in fresh medium restores cell growth potential in those non-apoptotic cells, but not in the apoptotic cell lines. FISH score has poor correlation with apoptotic cell death; in contrast, cell lines those expressing more than 20,000 copies of HER2 mRNA, as measured in 1 ng of total RNA, all show apoptosis. More interestingly, apoptotic death appears more severe as HER2 mRNA number increases. Conclusions: Accurate measurement of HER2 expression is essential for improving the outcome of anti-HER2 treatment. Our study suggests that RT-PCR technique seems to better fulfill the aim, and warrants future clinical trials of using RT-PCT to predict a positive response to anti-HER2 therapies.
Brain-Type Natriuretic Peptide and Amino-Terminal Pro–Brain-Type Natriuretic Peptide Discharge Thresholds for Acute Decompensated Heart Failure
Authors: Neil J. Nusbaum
Journal: Annals of Internal Medicine (2017)

Letters20 June 2017Brain-Type Natriuretic Peptide and Amino-Terminal Pro–Brain-Type Natriuretic Peptide Discharge Thresholds for Acute Decompensated Heart FailureNeil J. Nusbaum, JD, MDNeil J. Nusbaum, JD, MDFrom West Texas VA Health Care System, Big Spring, Texas.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/L17-0193 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail TO THE EDITOR:McQuade and colleagues (1) suggest that achieving predischarge natriuretic peptide (NP) thresholds is associated with reduced heart failure mortality and readmissions. Although this proposed association has biological plausibility, it should be evaluated with caution. One suspects that clinicians would hesitate to discharge patients who seem clinically unstable even if their NP level had decreased. As a result, patients would tend to remain hospitalized longer if their discharge was contingent on achieving both the clinical appearance of stability and a decreasing NP level rather than solely the former. A longer hospital stay in turn would mean that an ...Reference1. McQuade CN, Mizus M, Wald JW, Goldberg L, Jessup M, Umscheid CA. Brain-type natriuretic peptide and amino-terminal pro–brain-type natriuretic peptide discharge thresholds for acute decompensated heart failure: a systematic review. Ann Intern Med. 2017;166:180-90. [PMID: 27894126]. doi:10.7326/M16-1468 LinkGoogle Scholar Author, Article, and Disclosure InformationAffiliations: From West Texas VA Health Care System, Big Spring, Texas.Disclaimer: The views expressed here are those of the author and are not necessarily those of the Department of Veterans Affairs.Disclosures: Authors have disclosed no conflicts of interest. Forms can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=L17-0193. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetailsSee AlsoBrain-Type Natriuretic Peptide and Amino-Terminal Pro–Brain-Type Natriuretic Peptide Discharge Thresholds for Acute Decompensated Heart Failure Casey N. McQuade , Marisa Mizus , Joyce W. Wald , Lee Goldberg , Mariell Jessup , and Craig A. Umscheid Brain-Type Natriuretic Peptide and Amino-Terminal Pro–Brain-Type Natriuretic Peptide Discharge Thresholds for Acute Decompensated Heart Failure Casey N. McQuade and Craig A. Umscheid Metrics 20 June 2017Volume 166, Issue 12Page: 915KeywordsConflicts of interestDisclosureHeart failureHospitalizationsLength of stayMortalityNatriuretic peptidesOutpatient clinicsOutpatients ePublished: 20 June 2017 Issue Published: 20 June 2017 Copyright & PermissionsCopyright © 2017 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Genetics in the development of endometrial cancer: How does it affect East Asians?
Authors: Lindsay Gubernick, Jessica Lee, Jing-Yi Chern, Deanna Gerber, Leslie R. Boyd, John Patrick Curtin, Douglas A. Levine, Bhavana Pothuri
Journal: Journal of Clinical Oncology (2017)

e13022 Background: Obesity and Lynch syndrome are well-known risk factors for the development of endometrial cancer. However, there is a paucity of data comparing patients across multiple ethnicities. Methods: All patients diagnosed with endometrial cancer or complex atypical hyperplasia between 2012 and 2015 were retrospectively identified and evaluated. Comparative statistical analyses were performed and stratified by ethnicity with appropriate two-sided statistical tests. Results: A total of 506 patients were diagnosed with endometrial cancer (n = 447) or complex atypical hyperplasia (n = 59) and of these, 31 were East Asian (EA, 6.3%). The remaining 475 patients (93.9%) were of Caucasian, black, Latino, South Asian, Southeast Asian or other unspecified ethnicity. Compared to other patients, EA were diagnosed at a younger age (median age 53 vs 62, p = 0.0003) and had lower body mass indices (BMI) (median BMI 23.0 vs 30.7, p &lt; 0.0001). There were no differences in stage, tumor grade or histology. Differences in age and BMI remained significant despite controlling for these factors on multivariate analysis. Of the EA group, 10 of 31 patients (32.3%) underwent genetic testing and of these, three (30.0%) were found to have a germline mutation in a mismatch repair (MMR) gene. All three patients were of Chinese ancestry, and two had mutations in MLH1 and one in MSH2. In comparison, 69 (14.5%) of the remaining 475 had genetic testing, and six (8.7%) were diagnosed with Lynch syndrome. Chinese patients were more likely to have Lynch syndrome (42.9% vs 8.7%, p= 0.04). There were no differences found in family history of Lynch-related cancers between Chinese and other patients. There was no correlation between germline mutations and MMR testing on tumor immunohistochemistry. All three Chinese patients with Lynch syndrome had negative MMR tumor testing. Conclusions: EA patients with endometrial cancer are diagnosed at younger ages and with lower BMIs compared to patients of other ethnic backgrounds. Chinese patients have a high rate of germline Lynch mutations despite negative tumor MMR testing. EA, particularly Chinese patients, may represent a high-risk cohort, and referral for genetic counseling regardless of tumor MMR testing should be considered.