tbuckley/cabot-search huggingface dataset:
Association of Proton Pump Inhibitor Use on Cardiovascular Outcomes With Clopidogrel and Ticagrelor
Authors: Shaun G. Goodman, Robert Clare, Karen S. Pieper, José C. Nicolau, Robert F. Storey, Warren J. Cantor, Kenneth W. Mahaffey, Dominick J. Angiolillo, Steen Husted, Christopher P. Cannon, Stefan K. James, Jan Kilhamn, P. Gabriel Steg, Robert A. Harrington, Lars Wallentin
Journal: Circulation (2012)

Background— The clinical significance of the interaction between clopidogrel and proton pump inhibitors (PPIs) remains unclear. Methods and Results— We examined the relationship between PPI use and 1-year cardiovascular events (cardiovascular death, myocardial infarction, or stroke) in patients with acute coronary syndrome randomized to clopidogrel or ticagrelor in a prespecified, nonrandomized subgroup analysis of the Platelet Inhibition and Patient Outcomes (PLATO) trial. The primary end point rates were higher for individuals on a PPI (n=6539) compared with those not on a PPI (n=12 060) at randomization in both the clopidogrel (13.0% versus 10.9%; adjusted hazard ratio [HR], 1.20; 95% confidence interval [CI], 1.04–1.38) and ticagrelor (11.0% versus 9.2%; HR, 1.24; 95% CI, 1.07–1.45) groups. Patients on non-PPI gastrointestinal drugs had similar primary end point rates compared with those on a PPI (PPI versus non-PPI gastrointestinal treatment: clopidogrel, HR, 0.98; 95% CI, 0.79–1.23; ticagrelor, HR, 0.89; 95% CI, 0.73–1.10). In contrast, patients on no gastric therapy had a significantly lower primary end point rate (PPI versus no gastrointestinal treatment: clopidogrel, HR, 1.29; 95% CI, 1.12–1.49; ticagrelor, HR, 1.30; 95% CI, 1.14–1.49). Conclusions— The use of a PPI was independently associated with a higher rate of cardiovascular events in patients with acute coronary syndrome receiving clopidogrel. However, a similar association was observed between cardiovascular events and PPI use during ticagrelor treatment and with other non-PPI gastrointestinal treatment. Therefore, in the PLATO trial, the association between PPI use and adverse events may be due to confounding, with PPI use more of a marker for, than a cause of, higher rates of cardiovascular events. Clinical Trial Registration— http://www.clinicaltrials.gov . Unique identifier: NCT00391872.
Identification and Expression of δ-Isoforms of the Multifunctional Ca2+/Calmodulin-Dependent Protein Kinase in Failing and Nonfailing Human Myocardium
Authors: BrigitteHoch, RudolfMeyer, RolandHetzer, Ernst-GeorgKrause, PeterKarczewski
Journal: Circulation Research (1999)

Abstract—Despite its importance for the regulation of heart function, little is known about the isoform expression of the multifunctional Ca2+/calmodulin-dependent protein kinase (CaMKII) in human myocardium. In this study, we investigated the spectrum of CaMKII isoforms δ2, δ3, δ4, δ8, and δ9 in human striated muscle tissue. Isoform δ3 is characteristically expressed in cardiac muscle. In skeletal muscle, specific expression of a new isoform termed δ11 is demonstrated. Complete sequencing of human δ2 cDNA, representing all common features of the investigated CaMKII subclass, revealed its high homology to the corresponding rat cDNA. Comparative semiquantitative reverse transcription–polymerase chain reaction analyses from left ventricular tissues of normal hearts and from patients suffering from dilated cardiomyopathy showed a significant increase in transcript levels of isoform δ3 relative to the expression of glyceraldehyde-3-phosphate dehydrogenase in diseased hearts (101.6±11.0% versus 64.9±9.9% in th...
Heterogeneous expression of cytokines accounts for clinical diversity and refines prognostication in CMML
Authors: Sandrine Niyongere, Nolwenn Lucas, Jun-Min Zhou, Samer Sansil, Anthony D. Pomicter, Maria E. Balasis, John Robinson, Jodi Kroeger, Qing Zhang, Yu Long Zhao, Markus Ball, Rami Komrokji, Alan List, Michael W. Deininger, Brooke L. Fridley, Valeria Santini, Eric Solary, Eric Padron
Journal: Leukemia (2018)
Endogenous Drp1 Mediates Mitochondrial Autophagy and Protects the Heart Against Energy Stress
Authors: YoshiyukiIkeda, AkihiroShirakabe, YasuhiroMaejima, PeiyongZhai, SebastianoSciarretta, JessicaToli, MasatoshiNomura, KatsuyoshiMihara, KensukeEgashira, MitsuruOhishi, MahaAbdellatif, JunichiSadoshima
Journal: Circulation Research (2015)

Rationale:Both fusion and fission contribute to mitochondrial quality control. How unopposed fusion affects survival of cardiomyocytes and left ventricular function in the heart is poorly understood. Objective:We investigated the role of dynamin-related protein 1 (Drp1), a GTPase that mediates mitochondrial fission, in mediating mitochondrial autophagy, ventricular function, and stress resistance in the heart. Methods and Results:Drp1 downregulation induced mitochondrial elongation, accumulation of damaged mitochondria, and increased apoptosis in cardiomyocytes at baseline. Drp1 downregulation also suppressed autophagosome formation and autophagic flux at baseline and in response to glucose deprivation in cardiomyocytes. The lack of lysosomal translocation of mitochondrially targeted Keima indicates that Drp1 downregulation suppressed mitochondrial autophagy. Mitochondrial elongation and accumulation of damaged mitochondria were also observed in tamoxifen-inducible cardiac-specific Drp1 knockout mice. Aft...
Contribution of obstructive sleep apnoea to arterial stiffness: a meta-analysis using individual patient data
Authors: Marie Joyeux-Faure, Renaud Tamisier, Jean-Christian Borel, Sandrine Millasseau, Louis-Marie Galerneau, Marie Destors, Sébastien Bailly, Jean Louis Pepin
Journal: Thorax (2018)

Background Arterial stiffness, measured by pulse wave velocity (PWV), is a strong independent predictor of late cardiovascular events and mortality. It is recognised that obstructive sleep apnoea (OSA) is associated with cardiovascular comorbidities and mortality. Although previous meta-analyses concluded that PWV is elevated in OSA, we feel that an individual patient data analysis from nine relatively homogeneous studies could help answer: to what extent does OSA drive arterial stiffness? Methods Individual data from well-characterised patients referred for suspicion of OSA, included in nine studies in which carotid–femoral PWV was measured using a Complior device, were merged for an individual patient data meta-analysis. Results 893 subjects were included (age: 56±11 (mean±SD), 72% men, 84% with confirmed OSA). Body Mass Index varied from 15 to 81 kg/m 2 (30±7 kg/m 2 ). PWV ranged from 5.3 to 20.5 m/s (10.4±2.3 m/s). In univariate analysis, log(PWV) was strongly related to age, gender, systolic blood pressure, presence of type 2 diabetes (all p&lt;0.01) as well as to dyslipidaemia (p=0.03) and an Epworth Sleepiness Scale score ≥9 (p=0.04), whereas it was not related to obesity (p=0.54), a severe Apnoea–Hypopnoea Index (p=0.14), mean nocturnal saturation (p=0.33) or sleep time with oxygen saturation below 90% (p=0.47). In multivariable analysis, PWV was independently associated with age, systolic blood pressure and diabetes (all p&lt;0.01), whereas severe OSA was not significantly associated with PWV. Conclusion Our individual patient meta-analysis showed that elevated arterial stiffness in patients with OSA is driven by conventional cardiovascular risk factors rather than apnoea parameters.
Geographic Variation in Postoperative Imaging for Low-Risk Breast Cancer
Authors: Benjamin L. Franc, Timothy P. Copeland, Robert Thombley, Miran Park, Ben Marafino, Mitzi L. Dean, W. John Boscardin, Hope S. Rugo, David Seidenwurm, Bhupinder Sharma, Stephen R. Johnston, R. Adams Dudley
Journal: Journal of the National Comprehensive Cancer Network (2018)

Background: The objective of this study was to examine the presence and magnitude of US geographic variation in use rates of both recommended and high-cost imaging in young patients with early-stage breast cancer during the 18 month period after surgical treatment of their primary tumor. Methods: Using the Truven Health MarketScan Commercial Database, a descriptive analysis was conducted of geographic variation in annual rates of dedicated breast imaging and high-cost body imaging of 36,045 women aged 18 to 64 years treated with surgery for invasive unilateral breast cancer between 2010 and 2012. Multivariate hierarchical analysis examined the relationship between likelihood of imaging and patient characteristics, with metropolitan statistical area (MSA) serving as a random effect. Patient characteristics included age group, BRCA1/2 carrier status, family history of breast cancer, combination of breast surgery type and radiation therapy, drug therapy, and payer type. All MSAs in the United States were included, with areas outside MSAs within a given state aggregated into a single area for analytic purposes. Results: Descriptive analysis of rates of imaging use and intensity within MSA regions revealed wide geographic variation, irrespective of treatment cohort or age group. Increased probability of recommended postoperative dedicated breast imaging was primarily associated with age and treatment including both surgery and radiation therapy, followed by MSA region (odds ratio, 1.42). Increased probability of PET use—a high-cost imaging modality for which postoperative routine use is not recommended in the absence of specific clinical findings—was primarily associated with surgery type followed by MSA region (odds ratio, 1.82). Conclusions: In patients with breast cancer treated for low-risk disease, geography has effects on the rates of posttreatment imaging, suggesting that some patients are not receiving beneficial dedicated breast imaging, and high-cost nonbreast imaging may not be targeted to those groups most likely to benefit.
Antiprogrammed Cell Death‐1 Immunotherapy‐Related Secondary Sclerosing Cholangitis
Authors: Kohei Ogawa, Kenya Kamimura, Shuji Terai
Journal: Hepatology (2018)

1Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental SciencesNiigata University1‐757, Aasahimachi‐Dori, Chuo‐KuNiigataJapan * Address Correspondence and Reprint Requests to: Correspondence Kenya Kamimura, M.D. Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, 1‐757 Asahimachi‐dori, Chuo‐ku, Niigata, Niigata 9518510, Japan. E‐mail: [email protected] Tel: +81‐25‐227‐2207 Fax: +81‐25‐227‐0776 †These authors contributed equally to this work.
Circulating Testosterone as the Hormonal Basis of Sex Differences in Athletic Performance
Authors: David J Handelsman, Angelica L Hirschberg, Stephane Bermon
Journal: Endocrine Reviews (2018)

Elite athletic competitions have separate male and female events due to men’s physical advantages in strength, speed, and endurance so that a protected female category with objective entry criteria is required. Prior to puberty, there is no sex difference in circulating testosterone concentrations or athletic performance, but from puberty onward a clear sex difference in athletic performance emerges as circulating testosterone concentrations rise in men because testes produce 30 times more testosterone than before puberty with circulating testosterone exceeding 15-fold that of women at any age. There is a wide sex difference in circulating testosterone concentrations and a reproducible dose-response relationship between circulating testosterone and muscle mass and strength as well as circulating hemoglobin in both men and women. These dichotomies largely account for the sex differences in muscle mass and strength and circulating hemoglobin levels that result in at least an 8% to 12% ergogenic advantage in men. Suppression of elevated circulating testosterone of hyperandrogenic athletes results in negative effects on performance, which are reversed when suppression ceases. Based on the nonoverlapping, bimodal distribution of circulating testosterone concentration (measured by liquid chromatography–mass spectrometry)—and making an allowance for women with mild hyperandrogenism, notably women with polycystic ovary syndrome (who are overrepresented in elite athletics)—the appropriate eligibility criterion for female athletic events should be a circulating testosterone of <5.0 nmol/L. This would include all women other than those with untreated hyperandrogenic disorders of sexual development and noncompliant male-to-female transgender as well as testosterone-treated female-to-male transgender or androgen dopers.
Effects of Moderate Exercise Training on Thallium Uptake and Contractile Response to Low-Dose Dobutamine of Dysfunctional Myocardium in Patients With Ischemic Cardiomyopathy
Authors: RomualdoBelardinelli, DemetriosGeorgiou, LeonardGinzton, GiovanniCianci, AugustoPurcaro
Journal: Circulation (1998)

Background—There is evidence that exercise training can induce myocardial and coronary adaptations in both animals and humans. However, the significance of these potentially important changes remains to be determined in patients with ischemic heart disease and left ventricular (LV) systolic dysfunction. Methods and Results—To investigate whether exercise training can improve thallium uptake and the contractile response to low-dose dobutamine of dysfunctional myocardium, 46 patients (42 men, 4 women; mean age, 57±9 years) with chronic coronary artery disease and impaired LV systolic function (ejection fraction <40%) were randomly assigned to two groups. The exercise group (n=26) underwent exercise training at 60% of peak oxygen uptake for 8 weeks. The control group (n=20) was not exercised. At baseline and after 8 weeks all patients underwent an exercise test with gas exchange analysis and stress echocardiography using low-dose dobutamine (5 to 10 μg/kg per minute) followed by thallium myocardial scintigra...
Judge voices concern over paediatrician’s 62 day fitness to practise hearing
Authors: Clare Dyer
Journal: BMJ (2018)

A High Court judge has called on the General Medical Council (GMC) to find a way to curtail lengthy hearings after a fitness to practise case took a medical practitioners’ tribunal 62 days to hear.1

Mr Justice Kerr was hearing an appeal from a tribunal decision to suspend a paediatrician, Ruth Hill, from the medical register for 12 months.

Kerr rejected arguments that the tribunal had erred, and he dismissed Hill’s appeal. But he highlighted shortcomings in the GMC’s processes and rules, including “the usually regrettably slow pace” of investigation and the length of hearings in some cases.

He concluded, “I very much hope that the GMC and the MPTS [Medical Practitioners Tribunal Service] will find a way in future to limit the length of tribunal hearings …
RASAL2 promotes tumor progression through LATS2/YAP1 axis of hippo signaling pathway in colorectal cancer
Authors: Yi Pan, Joanna Hung Man Tong, Raymond Wai Ming Lung, Wei Kang, Johnny Sheung Him Kwan, Wing Po Chak, Ka Yee Tin, Lau Ying Chung, Feng Wu, Simon Siu Man Ng, Tony Wing Chung Mak, Jun Yu, Kwok Wai Lo, Anthony Wing Hung Chan, Ka Fai To
Journal: Molecular Cancer (2018)

Patients with colorectal cancer (CRC) have a high incidence of regional and distant metastases. Although metastasis is the main cause of CRC-related death, its molecular mechanisms remain largely unknown. Using array-CGH and expression microarray analyses, changes in DNA copy number and mRNA expression levels were investigated in human CRC samples. The mRNA expression level of RASAL2 was validated by qRT-PCR, and the protein expression was evaluated by western blot as well as immunohistochemistry in CRC cell lines and primary tumors. The functional role of RASAL2 in CRC was determined by MTT proliferation assay, monolayer and soft agar colony formation assays, cell cycle analysis, cell invasion and migration and in vivo study through siRNA/shRNA mediated knockdown and overexpression assays. Identification of RASAL2 involved in hippo pathway was achieved by expression microarray screening, double immunofluorescence staining and co-immunoprecipitation assays. Integrated genomic analysis identified copy number gains and upregulation of RASAL2 in metastatic CRC. RASAL2 encodes a RAS-GTPase-activating protein (RAS-GAP) and showed increased expression in CRC cell lines and clinical specimens. Higher RASAL2 expression was significantly correlated with lymph node involvement and distant metastasis in CRC patients. Moreover, we found that RASAL2 serves as an independent prognostic marker of overall survival in CRC patients. In vitro and in vivo functional studies revealed that RASAL2 promoted tumor progression in both KRAS/NRAS mutant and wild-type CRC cells. Knockdown of RASAL2 promoted YAP1 phosphorylation, cytoplasm retention and ubiquitination, therefore activating the hippo pathway through the LATS2/YAP1 axis. Our findings demonstrated the roles of RASAL2 in CRC tumorigenesis as well as metastasis, and RASAL2 exerts its oncogenic property through LATS2/YAP1 axis of hippo signaling pathway in CRC.
CCR5 Governs DNA Damage Repair and Breast Cancer Stem Cell Expansion
Authors: Xuanmao Jiao, Marco A. Velasco-Velázquez, Min Wang, Zhiping Li, Hallgeir Rui, Amy R. Peck, James E. Korkola, Xuelian Chen, Shaohua Xu, James B. DuHadaway, Sandra Guerrero-Rodriguez, Sankar Addya, Daniela Sicoli, Zhaomei Mu, Gang Zhang, Andres Stucky, Xi Zhang, Massimo Cristofanilli, Alessandro Fatatis, Joe W. Gray, Jiang F. Zhong, George C. Prendergast, Richard G. Pestell
Journal: Cancer Research (2018)

The functional significance of the chemokine receptor CCR5 in human breast cancer epithelial cells is poorly understood. Here, we report that CCR5 expression in human breast cancer correlates with poor outcome. CCR5
Evaluation of a Completion Total Mesorectal Excision in Patients After Local Excision of Rectal Cancer: A Word of Caution
Authors: Julia T. van Groningen, Pieter van Hagen, Rob A.E.M. Tollenaar, Jurriaan B. Tuynman, Perla J. Marang-van de Mheen, Pascal G. Doornebosch, Pieter J. Tanis, Eelco J.R. de Graaf
Journal: Journal of the National Comprehensive Cancer Network (2018)

Background: According to Dutch guidelines, locally excised, low-risk, pT1 or ypT0–1 rectal cancer should not necessarily be followed by completion total mesorectal excision (cTME) in contrast to rectal cancers with higher T stages or unfavorable features. This study evaluated cTME after local excision at a national level with possible determinants for decision-making. Methods: All patients in the Dutch Colorectal Audit (DCRA) who underwent local excision of rectal cancer between 2012 and 2015 were included. Guideline adherence for performing cTME was determined with univariate and multivariate analyses to identify factors related to noncompliance. Results: According to the guidelines, of 530 included patients, cTME was indicated in 283 (53%), and among those, was performed in 82 (29%). Guideline adherence for performing cTME improved significantly (P<.001), from 10% in 2012 to 44% in 2015. Lower Charlson comorbidity index in patients with high-risk pT1 rectal cancer and younger patients (aged 61–70 years vs ≥80 years) with pT≥2 rectal cancer were associated with increased performance of cTME (odds ratio [OR], 13.50; 95% CI, 1.39–131.32, and OR, 6.25; 95% CI, 1.83–21.31, respectively). Conclusions: In this population-based study from the Netherlands, only a minority of patients underwent cTME after local excision of rectal cancer with pathologic features indicating the need for further treatment according to the guidelines. Although the percentage of patients undergoing cTME increased over time, the study indicated a tendency toward rectal-preserving treatment with potential oncologic risks.
Sulfonylureas as second line drugs in type 2 diabetes and the risk of cardiovascular and hypoglycaemic events: population based cohort study
Authors: Antonios Douros, Sophie Dell’Aniello, Oriana Hoi Yun Yu, Kristian B Filion, Laurent Azoulay, Samy Suissa
Journal: BMJ (2018)

<h3>Abstract</h3> <h3>Objective</h3> To assess whether adding or switching to sulfonylureas is associated with an increased risk of myocardial infarction, ischaemic stroke, cardiovascular death, all cause mortality, and severe hypoglycaemia, compared with remaining on metformin monotherapy in patients with type 2 diabetes. <h3>Design</h3> Population based cohort study. <h3>Setting</h3> General practices contributing data to the UK Clinical Practice Research Datalink. <h3>Participants</h3> Patients with type 2 diabetes initiating metformin monotherapy between 1998 and 2013. <h3>Main outcome measures</h3> Using the prevalent new-user cohort design we matched 1:1 patients adding or switching to sulfonylureas with those remaining on metformin monotherapy on high-dimensional propensity score, haemoglobin A1c, and number of previous metformin prescriptions. The two groups were compared using Cox proportional hazards models to estimate adjusted hazard ratios and 95% confidence intervals for the study outcomes. <h3>Results</h3> Among 77 138 metformin initiators, 25 699 added or switched to sulfonylureas during the study period. During a mean follow-up of 1.1 years, sulfonylureas were associated with an increased risk of myocardial infarction (incidence rate 7.8 <i>v</i> 6.2 per 1000 person years, hazard ratio 1.26, 95% confidence interval 1.01 to 1.56), all cause mortality (27.3 <i>v</i> 21.5, 1.28, 1.15 to 1.44), and severe hypoglycaemia (5.5 <i>v</i> 0.7, 7.60, 4.64 to 12.44) compared with continuing metformin monotherapy. There was a trend towards increased risks of ischaemic stroke (6.7 <i>v</i> 5.5, 1.24, 0.99 to 1.56) and cardiovascular death (9.4 <i>v</i> 8.1, 1.18, 0.98 to 1.43). Compared with adding sulfonylureas, switching to sulfonylureas was associated with an increased risk of myocardial infarction (hazard ratio 1.51, 95% confidence interval, 1.03 to 2.24) and all-cause mortality (1.23, 1.00 to 1.50). No differences were observed for ischaemic stroke, cardiovascular death, or severe hypoglycaemia. <h3>Conclusions</h3> Sulfonylureas as second line drugs are associated with an increased risk of myocardial infarction, all cause mortality, and severe hypoglycaemia, compared with remaining on metformin monotherapy. Continuing metformin when introducing sulfonylureas appears to be safer than switching.
Transcriptome‐Wide Analysis Reveals the Landscape of Aberrant Alternative Splicing Events in Liver Cancer
Authors: Shengli Li, Zhixiang Hu, Yingjun Zhao, Shenglin Huang, Xianghuo He
Journal: Hepatology (2018)

Alternative splicing (AS) is assumed to be a pivotal determinant for the generation of diverse transcriptional variants in cancer. However, the comprehensive dysregulation of AS and the prospective biological and clinical relevance in hepatocellular carcinoma (HCC) remain obscure. Here, we identified and depicted the AS landscape in HCC by performing reference-based assembly of sequencing reads from over 600 RNA sequencing (RNA-seq) libraries. We detected various differentially spliced ASEs across patients covering not only protein-coding genes, but also considerable numbers of noncoding genes. Strikingly, alternative transcription initiation was found to frequently occur in HCC. These differential ASEs were highly related to "cancer hallmarks" and involved in metabolism-related pathways in particular. In addition, 243 differential ASEs were identified as risk predictors for HCC patient survival. The isoform switch of metabolism-related gene UGP2 (UDP-glucose pyrophosphorylase 2) might play an essential role in HCC. We further constructed regulatory networks between RNA-binding protein (RBP) genes and the corresponding ASEs. Further analysis demonstrated that the regulated networks were enriched in a variety of metabolism-related pathways. Conclusion: Differential ASEs are prevalent in HCC, where alternative transcription initiation was found to frequently occur. We found that genes having differential ASEs were significantly enriched in metabolism-related pathways. The expression variations, binding relations, and even mutations of RBP genes largely influenced differential ASEs in HCC.