tbuckley/cabot-search huggingface dataset:
cGMP-Elevating Compounds and Ischemic Conditioning Provide Cardioprotection Against Ischemia and Reperfusion Injury via Cardiomyocyte-Specific BK Channels
Authors: Sandra Frankenreiter, Piotr Bednarczyk, Angelina Kniess, Nadja I. Bork, Julia Straubinger, Piotr Koprowski, Antoni Wrzosek, Eva Mohr, Angela Logan, Michael P. Murphy, Meinrad Gawaz, Thomas Krieg, Adam Szewczyk, Viacheslav O. Nikolaev, Peter Ruth, Robert Lukowski
Journal: Circulation (2017)

Background: The nitric oxide–sensitive guanylyl cyclase/cGMP-dependent protein kinase type I signaling pathway can afford protection against the ischemia/reperfusion injury that occurs during myocardial infarction. Reportedly, voltage and Ca 2+ -activated K + channels of the BK type are stimulated by cGMP/cGMP-dependent protein kinase type I, and recent ex vivo studies implicated that increased BK activity favors the survival of the myocardium at ischemia/reperfusion. It remains unclear, however, whether the molecular events downstream of cGMP involve BK channels present in cardiomyocytes or in other cardiac cell types. Methods: Gene-targeted mice with a cardiomyocyte- or smooth muscle cell–specific deletion of the BK (CMBK or SMBK knockouts) were subjected to the open-chest model of myocardial infarction. Infarct sizes of the conditional mutants were compared with litter-matched controls, global BK knockout, and wild-type mice. Cardiac damage was assessed after mechanical conditioning or pharmacological stimulation of the cGMP pathway and by using direct modulators of BK. Long-term outcome was studied with respect to heart functions and cardiac fibrosis in a chronic myocardial infarction model. Results: Global BK knockouts and CMBK knockouts, in contrast with SMBK knockouts, exhibited significantly larger infarct sizes compared with their respective controls. Ablation of CMBK resulted in higher serum levels of cardiac troponin I and elevated amounts of reactive oxygen species, lower phosphorylated extracellular receptor kinase and phosphorylated AKT levels and an increase in myocardial apoptosis. Moreover, CMBK was required to allow beneficial effects of both nitric oxide–sensitive guanylyl cyclase activation and inhibition of the cGMP-degrading phosphodiesterase-5, ischemic preconditioning, and postconditioning regimens. To this end, after 4 weeks of reperfusion, fibrotic tissue increased and myocardial strain echocardiography was significantly compromised in CMBK-deficient mice. Conclusions: Lack of CMBK channels renders the heart more susceptible to ischemia/reperfusion injury, whereas the pathological events elicited by ischemia/reperfusion do not involve BK in vascular smooth muscle cells. BK seems to permit the protective effects triggered by cinaciguat, riociguat, and different phosphodiesterase-5 inhibitors and beneficial actions of ischemic preconditioning and ischemic postconditioning by a mechanism stemming primarily from cardiomyocytes. This study establishes mitochondrial CMBK channels as a promising target for limiting acute cardiac damage and adverse long-term events that occur after myocardial infarction.
TCT-146 The impact of clinical frailty on one-year mortality post transcatheter aortic valve replacement
Authors: M. Chadi Alraies, Homam Moussa Pacha, Elizabeth Bond, Kyle Buchanan, Toby Rogers, Edward Koifman, Arie Steinvil, Petros Okubagzi, Linzhi Xu, Rebecca Torguson, Itsik Ben-Dor, Augusto Pichard, Lowell Satler, Ron Waksman
Journal: Journal of the American College of Cardiology (2017)
Intergenerational diabetes and obesity—A cycle to break?
Authors: Ronald C. W. Ma, Barry M. Popkin
Journal: PLoS Medicine (2017)

The diabetes apocalypse?Globally, efforts to prevent diabetes and obesity have attained mixed success.Although prevalence of adult-onset diabetes is declining in some countries, the prevalence of childhood obesity and young-onset diabetes, with risk of associated complications, continues to increase in many high-and lower-income countries [1].More than 1. 9 billion children and adults are overweight and obese, and prevalence is rapidly rising, with the greatest increase found among children [2][3,4].Ongoing efforts to promote lifestyle intervention have had limited impact on the obesity and diabetes epidemic because of several critical factors.One factor comprises early life effects, a new field that has emerged surrounding developmental origins of many noncommunicable diseases (NCDs).This is the impact of nutritional and other insults during pregnancy and the first 2 years of life on the long-term risk of diabetes.Beginning with pathbreaking work by Barker on the relationship between low birth weight infants and subsequent risk of many adverse cardiometabolic outcomes [5,6], this field expanded to include multigenerational studies in animals and humans to highlight some of the potential mechanisms that may mediate the effect of fetal and infant undernutrition and related insults, including, for example, epigenetic changes affecting pancreatic islets, adipose tissue, and vasculature [7].A large number of human cohort studies have followed those exposed to nutritional and infection insults in the fetus and infancy through early adulthood and are even exploring intergenerational factors, all showing that early exposures, when interacting with obesogenic dietary and related factors, lead to much greater risks of NCDs [8][9][10].Most importantly, the increased risk of obesity and diabetes in individuals exposed in utero to undernutrition appears to be most exacerbated in those whose metabolic capacities are "mismatched" when exposed to metabolic challenges posed by overnutrition later in life [11,12].This pathway may be particularly relevant to lowand middle-income countries, including India and China, which have undergone rapid socioeconomic and nutritional transition, with both countries witnessing a dramatic increase in the prevalence of diabetes over recent decades [13].A second critical factor involves risks affecting populations of non-European origin, including Hispanic, African, Middle Eastern, or Asian groups [14][15][16][17][18].These populations appear to have greater adiposity in the visceral area; yet, at the same body mass index (BMI) as European origin adults, they have a greater likelihood of being susceptible to diabetes, which even led to many Asian countries proposing lower cutoffs for overweight and obesity [19].There is no clear explanation of the causes for these differences, although they are the subject of much
Most cost effective treatments for lung disease identified
Authors: Anne Gulland
Journal: BMJ (2017)

Lung specialists are urging the government to come up with a national strategy on lung disease as a new report identifies the most cost effective interventions for a range of respiratory illnesses.1

A literature review commissioned by the British Lung Foundation and British Thoracic Society has found that the most cost effective treatments are: patient education and self management for asthma; stop smoking support for chronic obstructive pulmonary disease (COPD); vaccination programmes for pneumonia; and awareness campaigns for lung cancer.

However, the report also outlined “real deficiencies” in current UK data and …
Brains, Genes, and Primates
Authors: Juan Carlos Izpisua Belmonte, Edward M. Callaway, Sarah J. Caddick, Patricia Churchland, Guoping Feng, Gregg E. Homanics, Kuo-Fen Lee, David A. Leopold, Cory T. Miller, Jude F. Mitchell, Shoukhrat Mitalipov, Alysson R. Moutri, J. Anthony Movshon, Hideyuki Okano, John H. Reynolds, Dario L. Ringach, Terrence J. Sejnowski, Afonso C. Silva, Peter L. Strick, Jun Wu, Feng Zhang
Journal: Neuron (2015)
Formação em epidemiologia de intervenção: uma perspectiva europeia
Authors: F van Loock, Mike Rowland, T Grein, A Moren
Journal: Eurosurveillance (2001)

Dentro da Uniao Europeia (UE) alargada, os movimentos de pessoas, animais e produtos alimentares em larga escala contribuiram de forma exponencial para a possibilidade da disseminacao de doencas transmissiveis. A UE obteve um mandato para accoes a nivel da saude publica apenas em 1992, sob o Tratado da Uniao Europeia (Tratado de Maastricht), o qual foi alargado em 1997 com o Tratado de Amesterdao.
Benign Traumatic Rib Fracture
Authors: Mads Ryø Jochumsen, André H. Dias, Kirsten Bouchelouche
Journal: Clinical Nuclear Medicine (2017)

Two, respectively, 72- and 76-year-old men with recently diagnosed high-risk prostate cancer were referred for primary staging with Ga-prostate-specific membrane antigen (PSMA) PET/CT. In both patients, the PET scans revealed increased Ga-PSMA uptake in, respectively, 3 and 4 rib fractures, characteristically placed as "pearls on a string." These cases illustrate important pitfalls when reporting PSMA PET.
PS04.07 Afatinib in Combination with Pembrolizumab in Patients with Qquamous Cell Carcinoma of the Lung: a Phase II Study (LUX-Lung IO/KEYNOTE 497)
Authors: B. Levy, J. Bennouna, L. Paz-Ares, M.J. Chisamore, C.L. Lind, B. Sadrolhefazi, J.W. Riess
Journal: Journal of Thoracic Oncology (2017)
TCT-147 Short and long term transcatheter aortic valve replacement outcome using clinical frailty status
Authors: M. Chadi Alraies, Homam Moussa Pacha, Elizabeth Bond, Kyle Buchanan, Toby Rogers, Edward Koifman, Arie Steinvil, Fahed Darmoch, Petros Okubagzi, Rebecca Torguson, Linzhi Xu, Itsik Ben-Dor, Augusto Pichard, Lowell Satler, Ron Waksman
Journal: Journal of the American College of Cardiology (2017)
PP2A Inactivation Mediated by <i>PPP2R4</i> Haploinsufficiency Promotes Cancer Development
Authors: Ward Sents, Bob Meeusen, Petar Kalev, Enrico Radaelli, Xavier Sagaert, Eline Miermans, Dorien Haesen, Caroline Lambrecht, Mieke Dewerchin, Peter Carmeliet, Jukka Westermarck, Anna Sablina, Veerle Janssens
Journal: Cancer Research (2017)

Protein phosphatase 2A (PP2A) complexes counteract many oncogenic kinase pathways. In cancer cells, PP2A function can be compromised by several mechanisms, including sporadic mutations in its scaffolding A and regulatory B subunits or more frequently through overexpression of cellular PP2A inhibitors. Here, we identify a novel genetic mechanism by which PP2A function is recurrently affected in human cancer, involving haploinsufficiency of PPP2R4, a gene encoding the cellular PP2A activator PTPA. Notably, up to 70% of cancer patients showed a heterozygous deletion or missense mutations in PPP2R4 Cancer-associated PTPA mutants exhibited decreased abilities to bind the PP2A-C subunit or activate PP2A and failed to reverse the tumorigenic phenotype induced by PTPA suppression, indicating they function as null alleles. In Ppp2r4 gene-trapped (gt) mice showing residual PTPA expression, total PP2A activity and methylation were reduced, selectively affecting specific PP2A holoenzymes. Both PTPAgt/gt and PTPA+/gt mice showed higher rates of spontaneous tumors, mainly hematologic malignancies and hepatocellular adenomas and carcinomas. These tumors exhibited increased c-Myc phosphorylation and increased Wnt or Hedgehog signaling. We observed a significant reduction in lifespan in PTPA+/gt mice compared with wild-type mice. In addition, chemical-induced skin carcinogenesis was accelerated in PTPA+/gt compared with wild-type mice. Our results provide evidence for PPP2R4 as a haploinsufficient tumor suppressor gene, defining a high-penetrance genetic mechanism for PP2A inhibition in human cancer. Cancer Res; 77(24); 6825-37. ©2017 AACR.
Factors Affecting the Association of Proton Pump Inhibitors and Capecitabine Efficacy in Advanced Gastroesophageal Cancer
Authors: Koen G. A. M. Hussaarts, Roelof W. F. van Leeuwen, Ron H. J. Mathijssen
Journal: JAMA Oncology (2017)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Oncology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Oncology journal
Prognostic Value of Combined Clinical and Myocardial Perfusion Imaging Data Using Machine Learning
Authors: Julian Betancur, Yuka Otaki, Manish Motwani, Mathews B. Fish, Mark Lemley, Damini Dey, Heidi Gransar, Balaji Tamarappoo, Guido Germano, Tali Sharir, Daniel S. Berman, Piotr J. Slomka
Journal: JACC. Cardiovascular imaging (2017)
Subcutaneous Sarcomas in Mice Implanted with Hydrocarbon-Cholesterol Pellets
Authors: Michael B. Shimkin, Rose S. Wyman
Journal: JNCI Journal of the National Cancer Institute (1947)

Subcutaneous Sarcomas in Mice Implanted with Hydrocarbon-Cholesterol Pellets Get access Michael B. Shimkin, Michael B. Shimkin surgeon Search for other works by this author on: Oxford Academic PubMed Google Scholar Rose S. Wyman Rose S. Wyman laboratory technician National Cancer Institute, National Institute of Health, United States Public Health Service Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 8, Issue 2, October 1947, Pages 49–52, https://doi.org/10.1093/jnci/8.2.49 Published: 01 October 1947 Article history Received: 14 July 1947 Published: 01 October 1947
Systemic regulation of bilirubin homeostasis
Authors: Ryoichi Fujiwara, Mathias Haag, Elke Schaeffeler, Anne T. Nies, Ulrich M. Zanger, Matthias Schwab
Journal: Hepatology (2017)

Neurotoxic bilirubin is the end product of heme catabolism in mammals. Bilirubin is solely conjugated by uridine diphospho‐glucuronosyltransferase 1A1, which is a membrane‐bound enzyme that catalyzes the transfer of glucuronic acid. Due to low function of hepatic and intestinal uridine diphospho‐glucuronosyltransferase 1A1 during the neonatal period, human neonates develop mild to severe physiological hyperbilirubinemia. Accumulation of bilirubin in the brain leads to the onset of irreversible brain damage, termed kernicterus. Breastfeeding is one of the most significant factors that increase the risk of developing kernicterus in infants. Why does this most natural way of feeding increase the risk of brain damage or even death? This question leads to the hypothesis that breast milk–induced hyperbilirubinemia might bring certain benefits that outweigh those risks. While bilirubin is neurotoxic and cytotoxic, this compound is also a potent antioxidant. There are studies showing improved clinical conditions in patients with hyperbilirubinemia. Accumulating evidence also shows that genetic polymorphisms linked to hyperbilirubinemia are beneficial against various diseases. In this review article, we first introduce the production, metabolism, and transport of bilirubin. We then discuss the potential benefits of neonatal and adult hyperbilirubinemia. Finally, epigenetic factors as well as metabolomic information associated with hyperbilirubinemia are described. This review article advances the understanding of the physiological importance of the paradoxical compound bilirubin. (Hepatology 2018;67:1609‐1619)
Safety and efficacy of <i>nab</i>-paclitaxel (<i>nab</i>-P)–based therapy in patients (pts) with non-small cell lung cancer (NSCLC) and performance status (PS) 2: Results from ABOUND.PS2.
Authors: Ajeet Gajra, Nagla Abdel Karim, Deborah A. Mulford, Liza Cosca Villaruz, Marc Ryan Matrana, Haythem Y. Ali, Edgardo S. Santos, Teng Jin Ong, Alexandra Sanford, Katayoun Amiri, David R. Spigel
Journal: Journal of Clinical Oncology (2017)

9058 Background: Chemotherapy can benefit pts with advanced NSCLC with poor Eastern Cooperative Oncology Group (ECOG) PS, despite an increased toxicity risk vs those with good PS. Safety and efficacy of nab-P/carboplatin ( nab-P/C) induction followed by nab-P monotherapy in pts with advanced NSCLC and ECOG PS 2 are reported. Methods: Chemotherapy-naive pts with histologically/cytologically confirmed stage IIIB/IV NSCLC and ECOG PS 2 received 4 cycles of nab-P 100 mg/m 2 d 1, 8 + C AUC 5 d 1 q3w. Pts without disease progression were eligible for monotherapy with nab-P 100 mg/m 2 d 1, 8 q3w until progression/unacceptable toxicity. Primary endpoint: percentage of pts discontinuing within the first 4 cycles due to treatment-emergent adverse events (TEAEs). Other endpoints: PFS, DCR, OS, ORR, and QoL. Results: Forty pts were treated during the first 4 cycles. Median age was 67.5 y, 60.0% were male, 92.5% were white, and 65.0% had nonsquamous histology. In the primary analysis, 9/40 pts (22.5%) discontinued due to TEAEs during induction. In total, 16/40 pts (40.0%) received nab-P as monotherapy. At the time of data cutoff, 4/40 pts remained on therapy beyond 11 cycles. In all treated pts, the median percentage of per-protocol dose of nab-P was 79.8% and the median nab-P dose intensity was 53.2 mg/m 2 /week (expected, 66.67 mg/m 2 /week). See table for other key safety and efficacy data. QoL by LCSS (global) was improved during the study, and similarly EQ-5D-5L dimensions were stable/improved at least once in the majority of pts. Conclusions: This nab-P–based regimen was well tolerated in PS 2 pts with advanced NSCLC. Efficacy outcomes are comparable with previous chemotherapy data with promising QoL. The results support the efficacy and tolerability of this regimen in these pts. NCT02289456. Clinical trial information: NCT02289456. [Table: see text]
Economic evaluation of HIV pre-exposure prophylaxis among men-who-have-sex-with-men in England in 2016
Authors: Koh Jun Ong, Sarika Desai, Nigel Field, Monica Desai, Anthony Nardone, Albert Jan van Hoek, Owen Noel Gill
Journal: Eurosurveillance (2017)

Clinical effectiveness of pre-exposure prophylaxis (PrEP) for preventing HIV acquisition in men who have sex with men (MSM) at high HIV risk is established. A static decision analytical model was constructed to inform policy prioritisation in England around cost-effectiveness and budgetary impact of a PrEP programme covering 5,000 MSM during an initial high-risk period. National genitourinary medicine clinic surveillance data informed key HIV risk assumptions. Pragmatic large-scale implementation scenarios were explored. At 86% effectiveness, PrEP given to 5,000 MSM at 3.3 per 100 person-years annual HIV incidence, assuming risk compensation (20% HIV incidence increase), averted 118 HIV infections over remaining lifetimes and was cost saving. Lower effectiveness (64%) gave an incremental cost-effectiveness ratio of + GBP 23,500 (EUR 32,000) per quality-adjusted life year (QALY) gained. Investment of GBP 26.9 million (EUR 36.6 million) in year-1 breaks even anywhere from year-23 (86% effectiveness) to year-33 (64% effectiveness). PrEP cost-effectiveness was highly sensitive to year-1 HIV incidence, PrEP adherence/effectiveness, and antiretroviral drug costs. There is much uncertainty around HIV incidence in those given PrEP and adherence/effectiveness, especially under programme scale-up. Substantially reduced PrEP drug costs are needed to give the necessary assurance of cost-effectiveness, and for an affordable public health programme of sufficient size.
Abstract 20036: Acute Carotid Plaque Rupture is Characterized by an Anti-Proliferative Serum miRNA Profile
Authors: Aaron M Brug, Sullivan Smith, Ashton J Brooks, Daniel J Lightell, Hernan A Bazan, Thomas C Woods
Journal: Circulation (2016)

Introduction:  Atherosclerotic plaque vulnerability is mediated by thinning of the plaque’s fibrous cap. miRNAs play an important role in this transition of an atherosclerotic plaque from a stable to a vulnerable state. Release of miRNAs from advanced atherosclerotic plaques into the circulation may provide a measurable miRNA profile to identify patients at greatest risk of plaque rupture and stroke.   Hypothesis:  Plaque destabilization and rupture are driven by anti-proliferative changes in microRNA expression within the plaque that can be detected in the sera of atherosclerosis patients.   Methods:  Using RNA-Seq methodology, serum and atherosclerotic plaque microRNA content was compared between patients undergoing carotid endarterectomy (CEA) for 2 distinct clinical phenotypes: (1) patients without previous neurological events but high-grade carotid stenosis (asymptomatic), and (2) patients with an acute neurological event within 5 days of the CEA (urgent).   Results:  A total of 695 miRNAs were detected in the sera with 22 miRNAs significantly decreased and 32 significantly increased in the sera of urgent compared to asymptomatic patients (adjusted p-value    Conclusions:  Carotid plaque rupture is associated with a unique serum miRNA profile that suggests an inhibition of proliferation. The majority of these miRNA changes are also exhibited within the atherosclerotic plaque. These circulating miRNAs are potential biomarkers for risk of carotid plaque rupture and stroke.
TCT-10 Mechanisms of Very Late Bioresorbable Scaffold Thrombosis Assessed by Optical Coherence Tomography: Insights from the international INVEST registry
Authors: Kyohei Yamaji, Yasushi Ueki, geraud souteyrand, Joost Daemen, Robert Byrne, Jens Wiebe, Petra Hoppmann, Holger Nef, Niklas Boeder, Tom Adriaenssens, Joshua Loh, Benoit Lattuca, Joanna Wykrzykowska, Josep Gomez Lara, Leo Timmers, Mohamed Abdel-Wahab, Felix Meincke, Benjamin Honton, Crochan O'Sullivan, Alfonso Ielasi, Günter Christ, Joe Lee, Michael Lee, Nicolas Amabile, Alexios Karagiannis, Stephan Windecker, Lorenz Raber
Journal: Journal of the American College of Cardiology (2017)
Tumor-penetrating Peptide Conjugated and Doxorubicin Loaded T<sub>1</sub>-T<sub>2</sub> Dual Mode MRI Contrast Agents Nanoparticles for Tumor Theranostics
Authors: Lipeng Gao, Jing Yu, Yang Liu, Jinge Zhou, Lei Sun, Jing Wang, Jianzhong Zhu, Hui Peng, Weiyue Lu, Lei Yu, Zhiqiang Yan, Yiting Wang
Journal: Theranostics (2017)

The conventional chemotherapeutics could not be traced in vivo and provide timely feedback on the clinical effectiveness of drugs.Methods: In this study, a tumor-penetrating peptide RGERPPR (RGE) modified, Gd-DTPA conjugated, and doxorubicin (DOX) loaded Fe3O4@SiO2@mSiO2 nanoparticle drug delivery system (Fe3O4@SiO2@mSiO2/DOX-(Gd-DTPA)-PEG-RGE NPs) was prepared for tumor theranostics.Results: The Fe3O4@SiO2@mSiO2/DOX-(Gd-DTPA)-PEG-RGE NPs showed a z-average hydrodynamic diameter of about 90 nm, and a pH-sensitive DOX release profile.The 3 T MRI results confirmed the relaxivity of the NPs (r1 = 6.13 mM -1 S -1 , r2 = 36.89mM -1 S -1 ).The in vitro cellular uptake and cytotoxicity assays on U87MG cells confirmed that the conjugation of RGERPPR played a significant role in increasing the cellular uptake and cytotoxicity of the NPs.The near-infrared fluorescence in vivo imaging results showed that the NPs could be significantly accumulated in the U87MG tumor tissue, which should result from the mediation of the tumor-penetrating peptide RGERPPR.The MRI results showed that the NPs offered a T1-T2 dual mode contrast imaging effect which would lead to a more precise diagnosis.Compared with unmodified NPs, the RGE-modified NPs showed significantly enhanced MR imaging signal in tumor tissue and antitumor effect, which should also be attributed to the tumor penetrating ability of RGERPPR peptide.Furthermore, the Hematoxylin and Eosin (H&E) staining and TUNEL assay proved that the NPs produced obvious cell apoptosis in tumor tissue.Conclusions: These results indicated that Fe3O4@SiO2@mSiO2/DOX-(Gd-DTPA)-PEG-RGE NPs are an effective targeted delivery system for tumor theranostics, and should have a potential value in the personalized treatment of tumor.