tbuckley/cabot-search huggingface dataset:
Optimized Treatment of ST-Elevation Myocardial Infarction
Authors: Giampaolo Niccoli, Rocco A. Montone, Borja Ibanez, Holger Thiele, Filippo Crea, Gerd Heusch, Heerajnarain Bulluck, Derek J. Hausenloy, Colin Berry, Thomas Stiermaier, Paolo G. Camici, Ingo Eitel
Journal: Circulation Research (2019)

Primary percutaneous coronary intervention is nowadays the preferred reperfusion strategy for patients with acute ST-segment–elevation myocardial infarction, aiming at restoring epicardial infarct-related artery patency and achieving microvascular reperfusion as early as possible, thus limiting the extent of irreversibly injured myocardium. Yet, in a sizeable proportion of patients, primary percutaneous coronary intervention does not achieve effective myocardial reperfusion due to the occurrence of coronary microvascular obstruction (MVO). The amount of infarcted myocardium, the so-called infarct size, has long been known to be an independent predictor for major adverse cardiovascular events and adverse left ventricular remodeling after myocardial infarction. Previous cardioprotection studies were mainly aimed at protecting cardiomyocytes and reducing infarct size. However, several clinical and preclinical studies have reported that the presence and extent of MVO represent another important independent predictor of adverse left ventricular remodeling, and recent evidences support the notion that MVO may be more predictive of major adverse cardiovascular events than infarct size itself. Although timely and complete reperfusion is the most effective way of limiting myocardial injury and subsequent ventricular remodeling, the translation of effective therapeutic strategies into improved clinical outcomes has been largely disappointing. Of importance, despite the presence of a large number of studies focused on infarct size, only few cardioprotection studies addressed MVO as a therapeutic target. In this review, we provide a detailed summary of MVO including underlying causes, diagnostic techniques, and current therapeutic approaches. Furthermore, we discuss the hypothesis that simultaneously addressing infarct size and MVO may help to translate cardioprotective strategies into improved clinical outcome following ST-segment–elevation myocardial infarction.
Insights Into the Pathogenesis of Catecholaminergic Polymorphic Ventricular Tachycardia From Engineered Human Heart Tissue
Authors: Sung-Jin Park, Donghui Zhang, Yan Qi, Yifei Li, Keel Yong Lee, Vassilios J. Bezzerides, Pengcheng Yang, Shutao Xia, Sean L. Kim, Xujie Liu, Fujian Lu, Francesco S. Pasqualini, Patrick H. Campbell, Judith Geva, Amy E. Roberts, Andre G. Kleber, Dominic J. Abrams, William T. Pu, Kevin Kit Parker
Journal: Circulation (2019)

Background: Modeling of human arrhythmias with induced pluripotent stem cell–derived cardiomyocytes has focused on single-cell phenotypes. However, arrhythmias are the emergent properties of cells assembled into tissues, and the impact of inherited arrhythmia mutations on tissue-level properties of human heart tissue has not been reported. Methods: Here, we report an optogenetically based, human engineered tissue model of catecholaminergic polymorphic ventricular tachycardia (CPVT), an inherited arrhythmia caused by mutation of the cardiac ryanodine channel and triggered by exercise. We developed a human induced pluripotent stem cell–derived cardiomyocyte–based platform to study the tissue-level properties of engineered human myocardium. We investigated pathogenic mechanisms in CPVT by combining this novel platform with genome editing. Results: In our model, CPVT tissues were vulnerable to developing reentrant rhythms when stimulated by rapid pacing and catecholamine, recapitulating hallmark features of the disease. These conditions elevated diastolic Ca 2+ levels and increased temporal and spatial dispersion of Ca 2+ wave speed, creating a vulnerable arrhythmia substrate. Using Cas9 genome editing, we pinpointed a single catecholamine-driven phosphorylation event, ryanodine receptor–serine 2814 phosphorylation by Ca 2 + /calmodulin-dependent protein kinase II, that is required to unmask the arrhythmic potential of CPVT tissues. Conclusions: Our study illuminates the molecular and cellular pathogenesis of CPVT and reveals a critical role of calmodulin-dependent protein kinase II–dependent reentry in the tissue-scale mechanism of this disease. We anticipate that this approach will be useful for modeling other inherited and acquired cardiac arrhythmias.
Cardiac toxicity in breast cancer patients treated with dual HER2 blockade: A meta-analysis of randomized evidence.
Authors: Antonis Valachis, Andreas Demetrios Nearchou, Nikolaos P. Polyzos, Pehr Lind
Journal: Journal of Clinical Oncology (2013)

624 Background: The dual antiHER2 blockade has been shown promising results in patients with HER2-positive breast cancer. Whether this treatment strategy jeopardizes the risk for cardiac adverse events is unclear. We conducted a meta-analysis of randomized trials to investigate the risk of cardiac adverse events when a combination of anti-HER2 therapies is used. Methods: We searched Medline, the Cochrane library, as long as the electronic abstract databases of the major international congresses’ proceedings to identify randomized trials that evaluated the administration of anti-HER2 monotherapy (lapatinib or trastuzumab or pertuzumab) versus anti-HER2 combination therapy with or without chemotherapy in breast cancer. Study outcomes were the congestive heart failure (CHF) grade &gt;/= 3 and left ventricular ejection fraction (LVEF) decline &lt; 50% or more than 10% from baseline. We calculated pooled odds ratios (ORs) and 95% Confidence Intervals (CI) with the Peto method. Results: Six trials were considered eligible. Overall incidence results for CHF in the combined antiHER2 therapy and the antiHER2 monotherapy were 0.88 % (95% CI: 0.47% - 1.64%) and 1.49 % (95% CI: 0.98% - 2.23%). The incidence of LVEF decline was 3.1 % (95% CI: 2.2% – 4.4%) and 2.9% (95% CI: 2.1% - 4.1%) respectively. The OR of CHF was 0.58 (95% CI: 0.26-1.27, p-value= 0.17) while the OR of LVEF decline was 0.88 (95% CI: 0.53-1.48, p-value= 0.64). In subgroup analyses, there were no significant differences in CHF or LVEF decline among different treatment settings or types of antiHER2 therapy. Conclusions: This meta-analysis offers substantial randomized evidence from trials with well-defined cardiac evaluations that a dual anti-HER2 therapeutic approach does not increase the risk for cardiac toxicity.
Effects of Psychology and Extragastrointestinal Symptoms on Health Care Use by Subjects With and Without Irritable Bowel Syndrome
Authors: David T. McNaughton, Anna Andreasson, Brjánn Ljótsson, Alissa P. Beath, Julia M. Hush, Nicholas J. Talley, Gunnar Ljunggren, Peter T. Schmidt, Lars Agréus, Michael P. Jones
Journal: Clinical Gastroenterology and Hepatology (2019)
Development of the Intrahepatic and Extrahepatic Biliary Tract: A Framework for Understanding Congenital Diseases
Authors: Frédéric P. Lemaigre
Journal: Annual Review of Pathology Mechanisms of Disease (2019)

The involvement of the biliary tract in the pathophysiology of liver diseases and the increased attention paid to bile ducts in the bioconstruction of liver tissue for regenerative therapy have fueled intense research into the fundamental mechanisms of biliary development. Here, I review the molecular, cellular and tissular mechanisms driving differentiation and morphogenesis of the intrahepatic and extrahepatic bile ducts. This review focuses on the dynamics of the transcriptional and signaling modules that promote biliary development in human and mouse liver and discusses studies in which the use of zebrafish uncovered unexplored processes in mammalian biliary development. The review concludes by providing a framework for interpreting the mechanisms that may help us understand the origin of congenital biliary diseases.
Clinical and molecular characteristics of responders versus non-responders to immune checkpoint inhibitors (ICI) in NSCLC.
Authors: Arpeet Shah, Sukhmani K. Padda, Joel W. Neal
Journal: Journal of Clinical Oncology (2019)

114 Background: Evidence from randomized clinical trials and retrospective studies has shown that tumors with specific driver mutations may be less likely to respond to ICI; the optimal timing of ICI is unknown in this population. In this analysis, we evaluated the characteristics of responders to ICI compared to non-responders, with emphasis on the role of driver mutations. Methods: We retrospectively collected clinical characteristics and outcomes for patients who received ICI for NSCLC at Stanford University between April 2015 and August 2016. Patients were classified as responders if time on ICI was 180 days or more, and as non-responders if less than 180 days. Outcomes included radiographic improvement while on ICI, survival from diagnosis, and survival from ICI initiation. Results: Data were available for 84 patients, with median follow-up of 31 months. 18 patients were deemed responders (21%); 66 were deemed non-responders (79%). Of the patients who underwent genomic testing, 13% (2/15) of responders had mutations in EGFR/ALK/ROS1, compared to 32% (17/49) of non-responders (p = 0.195). Within the responders, 89% (16/18) had an associated radiographic improvement, compared to 11% (7/66) of non-responders (p &lt; 0.0001). Patients with mutations in EGFR/ALK/ROS1 had a median overall survival of 46 months from diagnosis, compared to 26 months in those without these mutations (p = 0.08). Patients with mutations in EGFR/ALK/ROS1 had a median survival of 4.9 months from ICI initiation, compared to 7.0 months in those without (p = 0.45). Conclusions: Patients receiving ICI for 180 days or more had a significantly higher rate of radiographic improvement, suggesting that time on therapy appears to be a surrogate endpoint of clinical benefit. While there was not a statistically significant smaller number of responders with EGFR/ALK/ROS1, there appeared to be clinically meaningful lower response rate in these patients. This was likely limited by sample size; expansion of the sample size is planned. There was a trend to overall survival benefit in patients with driver mutations, likely driven by targeted therapy as there were no statistical differences in survival from time of ICI initiation.
Epigenetic biomarkers for noninvasive detection of colorectal cancer.
Authors: Dhruvajyoti Roy, David Taggart, Lianghong Zheng, Dan Liu, Gen Li, Mingzhen Li, Kang Zhang, Richard A. Van Etten
Journal: Journal of Clinical Oncology (2019)

45 Background: Aberrant DNA hypermethylation is known to be a major mechanism for inactivation of cancer-associated genes, including tumor suppressor genes, in colorectal cancer (CRC) and in other human cancers. Cancer-specific DNA methylation patterns of cell-free DNA (cfDNA) isolated from blood samples is a non-invasive method to obtain representative epigenetic information from solid tumors. In the present study, we identified and validated colorectal cancer-specific methylation markers for diagnosis of the disease with high sensitivity and specificity. We also compared the relative amount of DNA methylation at these target sites in relation to colorectal cancer stage. Methods: For marker validation, a total of 154 samples drawn from 68 subjects diagnosed with colorectal cancer (Stage I to IV), 42 healthy donors, 14 subjects with benign colorectal diseases, and 30 subjects diagnosed with other cancer types (breast, liver and lung cancer: 10 cases each) were obtained for a randomized, blinded study. Cell-free DNA was then extracted from the samples, bisulfite converted, and DNA methylation was quantified by using the IvyGene Platform. Results: By quantifying DNA methylation at the target sites, colorectal cancer samples were differentiated from samples drawn from healthy subjects or subjects with benign disease with an overall sensitivity of 93% (95% CI: 86-99) and specificity of 100% (95% CI: 85-100). All stages (I to IV) of colorectal cancer were identified with sensitivities ranging from 67% to 100%. None of the 30 samples drawn from subjects diagnosed with breast, liver or lung cancers were incorrectly identified as a colorectal cancer by the assay, for a calculated analytical specificity of 100%. Conclusions: These results demonstrate the high diagnostic potential of cfDNA methylation markers isolated from blood for the detection of colorectal cancer. Taken together, these findings establish the utility of methylation biomarkers for the detection of colorectal cancers as early as Stage I. In addition, a quantitative analysis of cfDNA provides an opportunity for non-invasive detection and monitoring of disease.
Abstract 16922: Ranolazine Reduced Recurrent VT Events in High-Risk ICD Patients
Authors: Wojciech Zareba, David T Huang, Scott McNitt, Christopher A Beck, Valentina Kutyifa, Abrar Shah, Mark Haigney, Claudio Schuger, Jonathan P Piccini, Stephen Winters, James P Daubert, Arthur J Moss
Journal: Circulation (2017)

Introduction: Recurrent ventricular tachycardia and fibrillation (VT/VF) remain a challenging problem in patients with implantable cardioverter defibrillators (ICD). Ranolazine is a late sodium cur...
Brazil's unified health system: the first 30 years and prospects for the future
Authors: Marcia C Castro, Adriano Massuda, Gisele Almeida, Naercio Aquino Menezes-Filho, Monica Viegas Andrade, Kenya Valéria Micaela de Souza Noronha, Rudi Rocha, James Macinko, Thomas Hone, Renato Tasca, Ligia Giovanella, Ana Maria Malik, Heitor Werneck, Luiz Augusto Fachini, Rifat Atun
Journal: The Lancet (2019)
Association Between Subjective Well-being and Living Longer Without Disability or Illness
Authors: Paola Zaninotto, Andrew Steptoe
Journal: JAMA Network Open (2019)

Subjective well-being is associated with reduced mortality, but it is not clear whether additional time is spent in good health or with chronic disease and disability.To evaluate the associations between affective well-being, total life expectancy, and life expectancy free of disability and chronic disease.This survey study used data on 9761 participants from the English Longitudinal Study of Ageing who were followed up for a maximum of 10 years (mean [SD] follow-up, 6 [3.7] years). Discrete-time multistate life table models were used to estimate total life expectancy and life expectancy free of disability or chronic disease. Data were collected between March 2002 and March 2013 and analyzed from December 2018 to April 2019. Analyses were adjusted for wealth and cohabiting status.The main outcome was life expectancy free of disability and chronic disease. Affective well-being was assessed at baseline as a combination of enjoyment of life and the lack of significant depressive symptoms. Disability was measured in terms of impaired activities of daily living and instrumental activities of daily living, and chronic disease as the occurrence of 6 serious illnesses.Data were analyzed from 9761 participants (5297 [54%] female; mean [SD] age at baseline, 64 [9.9] years). High affective well-being was associated with longer life expectancy and with longer disability-free and chronic disease-free life expectancies. For example, a woman aged 50 years who reported high affective well-being could expect to live 6 years longer than a woman of similar age with low well-being; 31.4 of her remaining years (95% CI, 30.5-31.9 years) would be likely to be free of disability, compared with 20.8 years (95% CI, 20.1-22.1 years) for a woman with low affective well-being. A man aged 50 years with high affective well-being could expect to live 20.8 years (95% CI, 18.7-22.4 years) without chronic disease, compared with 11.4 years (95% CI, 8.5-14.6 years) for a man reporting low well-being. Similar patterns were observed at the ages of 60, 70, and 80 years.This study suggests that people who report high levels of subjective well-being live longer and also healthier lives than those with lower well-being. These findings add weight to endeavors to promote the subjective well-being of older people.
Pharmacokinetics, pharmacodynamics, safety, and tolerability of BION-1301 in adults with relapsed or refractory multiple myeloma.
Authors: Jeroen Elassaiss-Schaap, Peter van Zandvoort, Jeannette Lo, Nitya Nair, Jackie Walling, Parameswaran Hari, William Bensinger
Journal: Journal of Clinical Oncology (2019)

8022 Background: APRIL (“a proliferation-inducing ligand”) levels are elevated in the serum of patients diagnosed with multiple myeloma (MM) and is correlated to promotion of malignancy, chemo- and immune-resistance. BION-1301 (BION) is a recombinant, humanized monoclonal antibody against APRIL. We report on the initial pharmacokinetic/ pharmacodynamic (PK-PD) profile, safety, and tolerability of BION in adults with relapsed or refractory MM. Methods: Adults with MM and disease progression after ≥3 systemic therapies were recruited for the study. BION was administered every 14 days through intravenous infusion. This ongoing Phase 1/2, open-label, multicenter study is evaluating 6 cohorts with increasing BION dose levels of 50, 150, 450, 1350, and 2700 mg administered Q2W intravenously (cohort 6 - 1350 mg dose given QW and Q2W). Serum was analyzed for BION, anti-drug antibodies (ADA), and free APRIL (fAPRIL) at baseline and upon treatment, and evaluated by PK-PD modeling. Results: As of 7Dec2018 reporting through the first 4 cohorts, 15 patients were enrolled in the study (N = 3-4 per cohort). BION has been well-tolerated to date. While exposure increased dose-proportionally from 50 to 1350 mg, half-life and clearance did not significantly differ between 50 and 1350 mg. APRIL serum levels decreased with increasing BION doses. To date no DLT was observed. Non-neutralizing ADA were detected in 1 of the 15 patients. BION transiently reduced fAPRIL levels starting at a dose of 50 mg. A prolonged reduction was seen at higher doses, and at 450 mg, reduction was maintained in 2 patients on treatment for 6 cycles (5.5 months). The area under the normalized fAPRIL curve (Days 1-15) decreased 5-fold from 50 to 1350 mg. Data fit well in an exploratory PK-PD model, with kinetic binding of BION and fAPRIL according to in vitro parameters, and peripheral compartments for both entities. While at 450 mg, 95% target engagement (TG) was achieved around peak exposure levels, at 1350 mg this 95% TG was maintained throughout the dosing interval of 3 doses. Conclusions: BION dose-dependently inhibits serum levels of fAPRIL between 50 to 1350 mg dose levels. Exposure was approximately dose-linear over the dose range evaluated, with a low incidence of ADA. Promising TG was obtained at prolonged dosing of 450 mg Q2W. A favorable safety profile supports continued dose escalation and more frequent dosing regimens based on PK-PD modeling. The study is ongoing with subjects exposed to higher and/or more frequent doses anticipated to result in accelerated and sustained APRIL TG. Clinical trial information: NCT03340883.
Abstract #1244: Monotherapeutic and combination antitumor activities of TAK-701, a humanized anti-hepatocyte growth factor neutralizing antibody, against multiple types of cancer
Authors: Akira Hori, Osamu Kitahara, Yuki Ito, Satoru Nishizawa, Yuko Misumi, Tetsuya Inaoka
Journal: Cancer Research (2009)

Signaling of the hepatocyte growth factor (HGF)/c-Met pathway is strongly implicated in cancer progression and represents an important target for cancer treatment. TAK-701, a humanized anti-human HGF monoclonal antibody, inhibits the proliferation of cancer cells and endothelial cells in vitro and shows antitumor activity against the human glioblastoma cell line U-87 MG. Antitumor activities of TAK-701 against various cancer cells that show an autocrine dependence of HGF were investigated in subcutaneous xenograft models in athymic mice. Twice-weekly (BIW), intravenous (i.v.) administration of TAK-701 (1-10 mg/kg) inhibited the tumor growth of the U-118 MG human glioblastoma and human pancreatic cancer cell line KP-4 (MET positive, RAS mutant) xenografts in a dose dependant manner. After screening for HGF and c-Met expression in various cancer cell lines, the human gastric cancer cell line IM95m and human breast cancer cell line MC-10-JCK were chosen as representative tumors of HGF dependent autocrine cells. As expected, TAK-701 demonstrated antitumor activities against both IM95m and MC-10-JCK xenografts in vivo. TAK-701 demonstrated enhanced antitumor activity when combined with a cytotoxic small molecule (Temozolomide), anti-VEGF monoclonal antibody (Bevacizumab), and radiation therapy in the U-87 MG xenograft model. Co-treatment with TAK-701 was well tolerated in all studies. These results indicate that TAK-701 represents a novel therapeutic agent potentially useful for treating a wide variety of tumor types as a single agent or in combination with other approved therapies. A phase 1 clinical trial in patients is planned.  Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 1244.
NHS is urged to increase number of stroke specialists by a third to tackle “serious shortfall”
Authors: Gareth Iacobucci
Journal: BMJ (2019)

The number of full time stroke consultants in the NHS needs to increase by a third to meet UK patients’ current needs, a new report advises.1

The report, from the British Association of Stroke Physicians (BASP), identifies a “serious shortfall” of existing specialists, which has left services unable to keep pace with medical advances and thousands of patients missing out on lifesaving treatments. It recommends an additional 226 full time stroke consultants—an increase of 33% from current estimates of 676.

Having sufficient staff in place will ensure immediate patient access to procedures …
IL-1 receptor blockade skews inflammation towards Th2 in a mouse model of systemic sclerosis
Authors: Anna Birnhuber, Slaven Crnkovic, Valentina Biasin, Leigh M. Marsh, Balazs Odler, Anita Sahu-Osen, Elvira Stacher-Priehse, Luka Brcic, Frank Schneider, Nada Cikes, Bahil Ghanim, Walter Klepetko, Winfried Graninger, Yannick Allanore, Robert Eferl, Andrea Olschewski, Horst Olschewski, Grazyna Kwapiszewska
Journal: European Respiratory Journal (2019)

The interleukin (IL)-1 family of cytokines is strongly associated with systemic sclerosis (SSc) and pulmonary involvement, but the molecular mechanisms are poorly understood. The aim of this study was to assess the role of IL-1α and IL-1β in pulmonary vascular and interstitial remodelling in a mouse model of SSc. IL-1α and IL-1β were localised in lungs of SSc patients and in the fos-related antigen-2 (Fra-2) transgenic (TG) mouse model of SSc. Lung function, haemodynamic parameters and pulmonary inflammation were measured in Fra-2 TG mice with or without 8 weeks of treatment with the IL-1 receptor antagonist anakinra (25 mg·kg −1 ·day −1 ). Direct effects of IL-1 on pulmonary arterial smooth muscle cells (PASMCs) and parenchymal fibroblasts were investigated in vitro . Fra-2 TG mice exhibited increased collagen deposition in the lung, restrictive lung function and enhanced muscularisation of the vasculature with concomitant pulmonary hypertension reminiscent of the changes in SSc patients. Immunoreactivity of IL-1α and IL-1β was increased in Fra-2 TG mice and in patients with SSc. IL-1 stimulation reduced collagen expression in PASMCs and parenchymal fibroblasts via distinct signalling pathways. Blocking IL-1 signalling in Fra-2 TG worsened pulmonary fibrosis and restriction, enhanced T-helper cell type 2 (Th2) inflammation, and increased the number of pro-fibrotic, alternatively activated macrophages. Our data suggest that blocking IL-1 signalling as currently investigated in several clinical studies might aggravate pulmonary fibrosis in specific patient subsets due to Th2 skewing of immune responses and formation of alternatively activated pro-fibrogenic macrophages.