tbuckley/cabot-search huggingface dataset:
Abstract 16460: Insulin-Like Growth Factor Binding Protein-2: A Putative Agent for Therapeutic Angiogenesis Acting via Its Arginine-Glycine-Aspartic Acid (RGD) Domain
Authors: Pooja Shah, Paul Cordell, Nadira Yuldasheva, Anna Skromna, Jess Smith, Alex Bruns, Natalie Haywood, Hema Viswambharan, Kirti Kain, Stephen Wheatcroft
Journal: Circulation (2017)

Therapeutic angiogenesis is under investigation to restore tissue perfusion in ischaemic heart disease and peripheral arterial disease. Insulin-like growth factor binding protein-2 (IGFBP-2) has be...
International Consensus on Risk Management of Diabetic Ketoacidosis in Patients With Type 1 Diabetes Treated With Sodium–Glucose Cotransporter (SGLT) Inhibitors
Authors: Thomas Danne, Satish Garg, Anne L. Peters, John B. Buse, Chantal Mathieu, Jeremy H. Pettus, Charles M. Alexander, Tadej Battelino, F. Javier Ampudia-Blasco, Bruce W. Bode, Bertrand Cariou, Kelly L. Close, Paresh Dandona, Sanjoy Dutta, Ele Ferrannini, Spiros Fourlanos, George Grunberger, Simon R. Heller, Robert R. Henry, Martin J. Kurian, Jake A. Kushner, Tal Oron, Christopher G. Parkin, Thomas R. Pieber, Helena W. Rodbard, Desmond Schatz, Jay S. Skyler, William V. Tamborlane, Koutaro Yokote, Moshe Phillip
Journal: Diabetes Care (2019)

Sodium–glucose cotransporter (SGLT) inhibitors are new oral antidiabetes medications shown to effectively reduce glycated hemoglobin (A1C) and glycemic variability, blood pressure, and body weight without intrinsic properties to cause hypoglycemia in people with type 1 diabetes. However, recent studies, particularly in individuals with type 1 diabetes, have demonstrated increases in the absolute risk of diabetic ketoacidosis (DKA). Some cases presented with near-normal blood glucose levels or mild hyperglycemia, complicating the recognition/diagnosis of DKA and potentially delaying treatment. Several SGLT inhibitors are currently under review by the U.S. Food and Drug Administration and European regulatory agencies as adjuncts to insulin therapy in people with type 1 diabetes. Strategies must be developed and disseminated to the medical community to mitigate the associated DKA risk. This Consensus Report reviews current data regarding SGLT inhibitor use and provides recommendations to enhance the safety of SGLT inhibitors in people with type 1 diabetes.
The impact of CDKN2A mutations on overall survival in pancreatic adenocarcinoma.
Authors: Allison Doyle, Manfred M Kubler, Ashton C Harris, Alfredo López, Prateek Govindaraj, Petra Prins, Benjamin Adam Weinberg
Journal: Journal of Clinical Oncology (2019)

278 Background: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with a five-year survival rate of only 9%. Analyses based on tumor DNA mutations indicate the presence of specific molecular subtypes of PDAC. Tumor genomic profiling could result in better treatment selection and improved overall survival. We performed a single institution analysis of PDAC mutations and correlated them with clinical outcomes. Methods: PDAC samples from patients (pts) seen at the Lombardi Comprehensive Cancer Center between 2014 and 2018 were profiled using next generation sequencing including 592 whole-gene targets (Caris Life Sciences). Relevant clinical data was mined retrospectively and correlated with genomic data. Pt outcomes were correlated with the presence of mutations in KRAS, MSH2, MSH6, MLH1, PMS2, TP53, SMAD4, CDKN2A, BRCA1, and BRCA2. Results: Our cohort (N = 100) included 50% men and 50% women, 59% were Caucasian and 21% African-American. Thirty-two percent had stage II, 14% had stage III, and 38% had stage IV disease. Seventy-seven percent developed metastatic disease. Genetic mutations were found in KRAS 87% (N = 82), TP53 76% (N = 82), SMAD4 37% (N = 49), CDKN2A 29% (N = 66), and BRCA2 21% (N = 81). Sixty percent of pts with KRAS mutations also had TP53 mutations. Almost all pts with mutated SMAD4, CDKN2A, or BRCA2 also had mutated KRAS (89%, 84%, and 80%). Median overall survival (OS) for all pts from time of diagnosis was 31 months (m). Stratification of OS based on single gene mutations did not significantly impact OS except for CDKN2A. Patients with CDKN2A mutations had significantly reduced OS compared to wild type (22 m vs. 35 m; P = 0.018). OS based on presence of co-occurring mutations only showed a negative OS impact when CDKN2A mutations were present (14 m vs. 35 m; P = 0.021). Conclusions: Our data demonstrate that the presence of CDKN2A mutations is an independent negative prognostic OS indicator for patients with PDAC. This finding highlights the need to select PDAC pts for potential targeted therapies, including those that target the cell cycle pathway (e.g. cyclin-dependent kinase inhibitors).
In vivo ratiometric optical mapping enables high-resolution cardiac electrophysiology in pig models
Authors: Peter Lee, Jorge G Quintanilla, José M Alfonso-Almazán, Carlos Galán-Arriola, Ping Yan, Javier Sánchez-González, Nicasio Pérez-Castellano, Julián Pérez-Villacastín, Borja Ibañez, Leslie M Loew, David Filgueiras-Rama
Journal: Cardiovascular Research (2019)

Cardiac optical mapping is the gold standard for measuring complex electrophysiology in ex vivo heart preparations. However, new methods for optical mapping in vivo have been elusive. We aimed at developing and validating an experimental method for performing in vivo cardiac optical mapping in pig models.First, we characterized ex vivo the excitation-ratiometric properties during pacing and ventricular fibrillation (VF) of two near-infrared voltage-sensitive dyes (di-4-ANBDQBS/di-4-ANEQ(F)PTEA) optimized for imaging blood-perfused tissue (n = 7). Then, optical-fibre recordings in Langendorff-perfused hearts demonstrated that ratiometry permits the recording of optical action potentials (APs) with minimal motion artefacts during contraction (n = 7). Ratiometric optical mapping ex vivo also showed that optical AP duration (APD) and conduction velocity (CV) measurements can be accurately obtained to test drug effects. Secondly, we developed a percutaneous dye-loading protocol in vivo to perform high-resolution ratiometric optical mapping of VF dynamics (motion minimal) using a high-speed camera system positioned above the epicardial surface of the exposed heart (n = 11). During pacing (motion substantial) we recorded ratiometric optical signals and activation via a 2D fibre array in contact with the epicardial surface (n = 7). Optical APs in vivo under general anaesthesia showed significantly faster CV [120 (63-138) cm/s vs. 51 (41-64) cm/s; P = 0.032] and a statistical trend to longer APD90 [242 (217-254) ms vs. 192 (182-233) ms; P = 0.095] compared with ex vivo measurements in the contracting heart. The average rate of signal-to-noise ratio (SNR) decay of di-4-ANEQ(F)PTEA in vivo was 0.0671 ± 0.0090 min-1. However, reloading with di-4-ANEQ(F)PTEA fully recovered the initial SNR. Finally, toxicity studies (n = 12) showed that coronary dye injection did not generate systemic nor cardiac damage, although di-4-ANBDQBS injection induced transient hypotension, which was not observed with di-4-ANEQ(F)PTEA.In vivo optical mapping using voltage ratiometry of near-infrared dyes enables high-resolution cardiac electrophysiology in translational pig models.
Clinical outcomes in patients with chronic hepatitis C after direct-acting antiviral treatment: a prospective cohort study
Authors: Fabrice Carrat, Hélène Fontaine, Céline Dorival, Mélanie Simony, Alpha Diallo, Christophe Hezode, Victor De Ledinghen, Dominique Larrey, Georges Haour, Jean-Pierre Bronowicki, Fabien Zoulim, Tarik Asselah, Patrick Marcellin, Dominique Thabut, Vincent Leroy, Albert Tran, François Habersetzer, Didier Samuel, Dominique Guyader, Olivier Chazouilleres, Philippe Mathurin, Sophie Metivier, Laurent Alric, Ghassan Riachi, Jérôme Gournay, Armand Abergel, Paul Cales, Nathalie Ganne, Véronique Loustaud-Ratti, Louis D'Alteroche, Xavier Causse, Claire Geist, Anne Minello, Isabelle Rosa, Moana Gelu-Simeon, Isabelle Portal, François Raffi, Marc Bourliere, Stanislas Pol
Journal: The Lancet (2019)
Reply
Authors: Tao Li, Jiaye Liu, Li Zhang, Aiqiang Xu
Journal: Hepatology (2019)

Potential conflict of interest: Nothing to report. We appreciate the comments from Wang et al. and their efforts to explore the value of hepatitis B surface antigen (HBsAg) at the end of treatment (EOT) in nucleos(t)ide analogues (NAs) cessation. Although we did not include the article1 for unavailable clinical relapse data in the setting of different HBsAg levels at EOT, a cumulative incidence of 9.3%1 for clinical relapse in chronic hepatitis B (CHB) patients with HBsAg <100 IU/mL at EOT should be a strong support for conclusions in our review.2 Endpoints of NAs treatment were still debatable. Taking account of current evidences and the unrealistic characteristic of HBsAg loss or seroconversion, we recommended HBsAg level <100 IU/mL at EOT as an important addition for cessation criteria of current guidelines.2 Although the risk of relapse could decrease in CHB patients with HBsAg level <100 IU/mL at EOT, cautions of probable adverse outcomes should still be reminded in clinical practice. Thus, regular monitoring is required to identify adverse events after NA cessation. We further analyzed the 11 studies included in our systematic review2 and found seven studies referring to adverse outcomes after NA cessation. Two of the seven studies did not observe any adverse outcome in 201 CHB or patients with cirrhosis. In the remaining five studies, 37 hepatocellular carcinomas (HCCs) in 1087 CHB patients or patients with cirrhosis, 12 hepatic decompensations in 561 patients with cirrhosis, and two hepatic decompensations in 526 CHB patients were documented during off‐therapy follow‐up. However, all adverse outcomes were not identified in the setting of different HBsAg levels at EOT. Furthermore, our previous cohort3 prospectively included 223 CHB patients who met cessation criteria (no requirement for HBsAg level at EOT) and discontinued NAs; 87 patients relapsed and underwent salvage treatment. No hepatic decompensation was observed, and 1 patient was diagnosed as HCC. We also could not evaluate the role of HBsAg levels at EOT because of the low incidence of adverse events. Further studies on the risk and benefit of NA cessation in the setting of HBsAg level <100 IU/mL at EOT are still required in future. In conclusion, HBsAg level <100 IU/mL at EOT could be an important addition for current guidelines in NA cessation of CHB patients. Regular monitoring after cessation is still required to explore the risk of adverse outcomes.
Knowledge Gaps On Asthma Diagnosis Among General Physicians And Specialists In Contrast With Evidence-Based Clinical Guideline Recommendations: Results From A National Survey
Authors: Jorge A. Luna-Pech, Monica Rodriguez Gonzalez, Margarita Fernandez-Vega, Blanca Estela Del Rio-Navarro, Maria del Carmen Cano-Salas, José Antonio Ortega-Martell, Jade Romero-Lombard, Erika Del Carmen Lopez-Estrada, Desiree E.S. Larenas Linnemann
Journal: Journal of Allergy and Clinical Immunology (2019)
Transgenic Expression of a Novel Secreted and Active Form of IL-33 Promotes Tissue Eosinophilia in a Mouse Model of Eosinophilic Esophagitis
Authors: Alfred D. Doyle, Kelly P. Shim, Huijun Luo, William E. LeSuer, James J. Lee, Hirohito Kita, Elizabeth A. Jacobsen, Matthew A. Rank, Benjamin L. Wright
Journal: Journal of Allergy and Clinical Immunology (2019)
Efficacy and Toxicity Profile of Elotuzumab for Multiple Myeloma: A Systematic Review and Meta-Analysis
Authors: Faiza Jamil, Madeeha Shafqat, Sharoon Samuel, Zunairah Shah, Ceren Durer, Seren Durer, Maryam Sadiq, Muhammad Junaid Tariq, Jemin Aby Jose, Warda Faridi, Mohamed Mokhtar Bakr, Umar Zahid, Ali McBride, Ahmad Safdar, Faiz Anwer
Journal: Blood (2018)
Glutamine Metabolism Regulates Proliferation and Lineage Allocation in Skeletal Stem Cells
Authors: Yilin Yu, Hunter Newman, Leyao Shen, Deepika Sharma, Guoli Hu, Anthony J. Mirando, Hongyuan Zhang, Everett Knudsen, Guo-Fang Zhang, Matthew J. Hilton, Courtney M. Karner
Journal: Cell Metabolism (2019)
Gene Set Enrichment Analysis Suggests That Increased Rituximab-Mediated NK Cell Cytotoxicity after Vitamin D Substitution Is Driven By Upregulation of Interferon Alpha (IFN-a) Isoforms
Authors: Konstantinos Christofyllakis, Frank Neumann, Stephan Stilgenbauer, Dominic Kaddu-Mulindwa, Evi Regitz, Moritz Bewarder, Andreas Keller, Jörg Thomas Bittenbring
Journal: Blood (2018)
Dying for your group or for your faith? On the power of belief
Authors: Maarten Boudry
Journal: Behavioral and Brain Sciences (2018)

Abstract Whitehouse's theory offers one plausible pathway toward extreme self-sacrifice, but it fails to explain sacrificial acts that are inspired by heartfelt ideological beliefs, including jihadi terrorism and mass suicide in cults. If he wants to offer a “single overarching theory” of self-sacrifice, he will need to take seriously the power of belief.
Idiopathic interstitial pneumonia or idiopathic interstitial pneumonitis: what's in a name?
Authors: Lykourgos Kolilekas, Ulrich Costabel, Argyris Tzouvelekis, Vassilios Tzilas, Demosthenes Bouros
Journal: European Respiratory Journal (2019)

We read with interest the recently published perspective in the European Respiratory Journal by Wells et al. [1], "What's in a name? That which we call IPF, by any other name would act the same." Although there is also concern regarding the term "idiopathic" for idiopathic pulmonary fibrosis [2], there is more concern regarding the term "pneumonia" for the family of idiopathic interstitial pneumonias. The term "idiopathic interstitial pneumonitis" should be preferred to "idiopathic interstitial pneumonia" <http://ow.ly/xiu030kOyIb>
Poor Overall Survival in Hyperhaploid Multiple Myeloma Is Defined By Double-Hit Bi-Allelic Inactivation of TP53
Authors: Cody Ashby, Yan Wang, Ruslana G. Tytarenko, Carolina D. Schinke, Sharmilan Thanendrarajan, Maurizio Zangari, Frits van Rhee, Faith E. Davies, Jeffery R. Sawyer, Gareth Morgan, Brian A Walker
Journal: Blood (2018)
Although optimal models are useful, optimality claims are not that common
Authors: Claire Chambers, Konrad Paul Kording
Journal: Behavioral and Brain Sciences (2018)

Abstract Rahnev &amp; Denison (R&amp;D) argue that human behavior is often described as “optimal,” despite many previous findings of suboptimality. We address how the literature handles these concepts and discuss our own findings on suboptimality. Although we agree that the field should embrace the “systematic weirdness of human behavior” (sect. 6, para. 1), this does not detract from the value of the Bayesian approach.
Tislelizumab in combination with chemotherapy for the treatment of Chinese patients (pts) with esophageal squamous cell carcinoma (ESCC): Results from one cohort of an ongoing phase 2 study.
Authors: Nong Xu, Xianglin Yuan, Buhai Wang, Yu-Xian Bai, En Xiao Li, Yanyan Li, Huanli Wang, Jianming Xu
Journal: Journal of Clinical Oncology (2019)

14 Background: Tislelizumab, a humanized IgG4 mAb with high affinity and specificity for PD-1, is specifically engineered to minimize binding to FcγR on macrophages, thereby abrogating antibody-dependent phagocytosis, a potential mechanism of T-cell clearance and resistance to anti-PD-1 therapy. This phase 2 study assessed the safety and tolerability of tislelizumab combined with chemotherapy as first-line therapy in pts with gastric cancer and ESCC; the results of the ESCC cohort are presented here. Methods: Chinese pts with inoperable, locally advanced ESCC were treated with tislelizumab (200 mg IV Q3W), cisplatin (80 mg/m² IV Q3W for up to six cycles), and fluorouracil (800 mg/m²/d, days 1-5 IV Q3W for up to six cycles). Safety/tolerability of the combination regimen was assessed by monitoring adverse events (AEs) per NCI-CTCAE v4.03 criteria. Results: As of 13 June 2018, 15 pts (median age, 61 yrs; male/female, 14/1) were enrolled. The median treatment duration was 108 days (range 21-201). The mean (Q1, Q3) dose intensity was 0.92 (0.91, 0.97) for tislelizumab, 0.91 (0.90, 0.98) for cisplatin, and 0.78 (0.72, 0.97) for 5-FU. Among 15 pts, AEs occurring in &gt; 2 pts reported to be related to chemotherapy and/or tislelizumab are detailed in the table. One pt experienced grade 5 hepatic dysfunction (possibly from progressive disease and underlying hepatitis) which was possibly related to study treatment, according to the investigator. Four pts discontinued study treatment due to AEs (grade 3 tracheal fistula, grade 3 lung infection, grade 2 pneumonitis, and grade 3 increase in aspartate aminotransferase). The antitumor activity data remain unmatured and may be updated later. Conclusions: Tislelizumab combined with chemotherapy was generally well tolerated in pts with advanced ESCC. Clinical trial information: NCT03469557. [Table: see text]
Abstract 15371: Parathyroid Hormone-Related Peptide Protects Cardiomyocytes from Oxidative Stress: First Evidence of a Novel Endocrine-Cardiovascular Interaction
Authors: Sahiti Chukkapalli, Enbo Zhan, Robert Lasley, Nabanita S Datta
Journal: Circulation (2014)

There is growing interest in the molecular cross-talk between the endocrine and cardiovascular systems, including the effects of hormones on cardiomyocte viability in models of ischemic and oxidative stress. However, current attention has focused on reproductive and metabolic hormones; the cardiac effects of calcium-regulating hormones (i.e., parathyroid hormone-related peptide (PTHrP)) have not been explored. To address this, we interrogated the effect of PTHrP on the viability of isolated adult mouse cardiomyocytes subjected to H 2 O 2 -induced oxidative stress. In Aim 1 , myocytes from wild type (WT) C57 mice were incubated for 16 hrs with 100 nM PTHrP or vehicle and exposed to 100 μM H 2 O 2 for 15 min. Myocyte viability was significantly improved in PTHrP-treated cells vs vehicle control (70±12% vs 20±15%; mean ± SD, p&lt;0.01; Figure). Calcium sensing receptor and PTHrP signaling is purportedly associated with Mitogen-Activated Protein Kinases (MAPKs) and MAPK phosphatase-1 (MKP1). Accordingly, to achieve preliminary mechanistic insight into PTHrP-induced protection ( Aim 2 ), we: (i) incubated WT cardiomyocytes with PTHrP (100 nM) and probed for expression of MKP1; and (ii) repeated the viability assay as described above using myocytes from adult MKP1 knockout (KO) mice. Incubation of WT myocytes with PTHrP evoked a 55% decrease in MKP1 expression. Moreover, myocytes from MKP1 KO mice were resistant to oxidative injury: viability was maintained at 78±12% in vehicle controls (mean ± SD, p&lt;0.01 vs the value of 20±15% in vehicle-treated WT cells), with no added benefit of PTHrP treatment (Figure). Finally ( Aim 3 ), in both models (PTHrP treatment; MKP1 KO), the enhanced cell viability was accompanied by ~2-fold increases in Akt phosphorylation. These data provide novel evidence that: i) down-regulation of MKP1 affords profound protection against oxidative stress; and ii) PTHrP is cardioprotective, possibly via down-regulation of MKP1 and activation of Akt signaling.
Abstract 17900: Impact of Visceral Abdominal Adipose Tissue and Subcutaneous Abdominal Adipose Tissue on the Coronary Plaque Score Assessed by 320-Row CT Coronary Angiography in Japanese Population
Authors: Tetsu Tanaka, Satoru Kishi, Keita Koseki, Yu Sato, Taishi Okuno, Kazuyuki Yahagi, Kota Komiyama, Jiro Aoki, Kenji Ibukuro, Kengo Tanabe
Journal: Circulation (2017)

Introduction: Obesity is an important risk of coronary artery disease (CAD), while some studies recently addressed the protective effects of subcutaneous fat deposits. The association of distribution of adipose tissue, such as visceral fat and subcutaneous fat, and CAD remains to be clarified. Methods and Results: We examined a single-centered consecutive cohort of 4,327 patients without history of CAD who underwent 320-row multidetector coronary computed tomography angiography (CTA) from Jan 2009 to May 2017. Plaque was assessed in 3 ways, (1) modified Duke prognostic CAD index, (2) Segment Stenosis Score (SSS), (3) Segment Involvement Score (SIS). Using CT images, we evaluated visceral abdominal adipose tissue (VAT) area, subcutaneous abdominal adipose tissue (SAT) area, and VAT/SAT ratio. VAT/SAT ratio was categorized into 3 groups using tertile. Multivariable logistic regression analysis was used to quantify the association between VAT/SAT ratio and coronary plaque scores adjusting for CAD risk factor...
Gastroduodenal anastomotic insufficiency: pull-through technique for endoscopic negative pressure therapy with new types of open-pore drains
Authors: Frank Rucktaeschel, Marc Liedtke, Erik Schlöricke, Thomas Herrmann, Gunnar Loske
Journal: Endoscopy (2019)

A 61-year-old man underwent distal gastric resection with gastroduodenal anastomosis (Billroth I operation) because of perforated peptic ulcer and septic peritonitis. In addition, ischemic right colon was resected and ileostomy was performed. Anastomotic insufficiency was detected 2 days after the operation by duodenal secretions in the operative drainage tube. In two repeat laparotomies, operative closure of the leak could not be achieved. On postoperative Day 12, endoscopy showed a semicircular anastomotic leak ([Fig. 1]). The drain could be seen through the defect from the inside. Endoscopic negative pressure therapy (ENPT) was initiated immediately.
Abstract 410: Rhein Administration Prevents Cardiac Fibrosis by Interfering with the TGF-β Pathway
Authors: David Barbosa, Melanie Wehmöller, Maximilian R Spinner, Ulrich Rüther, Margriet Ouwens
Journal: Circulation Research (2017)

Fibrosis, which occurs in various heart diseases like acute myocardial ischemia and pressure overload, is triggered by the differentiation of fibroblasts into myofibroblasts. Dysregulation of this reparative mechanism results in excessive collagen accumulation leading to cardiac stiffness and impaired heart function. The aim of this study was to determine whether the rhubarb anthraquinone Rhein, a drug already used as treatment for chondroarthritis, prevents the transdifferentiation of cardiac fibroblasts. We observed that Rhein pre-treatment ameliorates the cardiac function and reduces adverse remodeling after acute myocardial infarction in mice, in vivo . In primary human cardiac fibroblasts, Rhein incubation dose-dependently inhibited the TGF-β-mediated upregulation of α-SMA, the master marker for myofibrolasts, and prevented the contraction of fibroblast-populated collagen gel lattices upon TGF-β stimulation. Further, Rhein reduced TGFβ-R1 expression in primary human cardiac fibroblast, resulting in decreased SMAD2 phosphorylation and blunting of the fibrogenic response. Furthermore, Rhein stabilized protein levels of SMAD7, a key inhibitor of TGF-β signaling. Collectively, these data show for the first time that Rhein administration prevents cardiac fibrosis in vivo and in vitro by blunting the TGF-β signaling pathway, and identify Rhein as potential therapeutic treatment to prevent excessive fibrosis and adverse remodeling in cardiac pathologies.
Abstract 15992: A Low-Frequency Coding Variant in Natriuretic Peptide Receptor 1 (NPR1) Increases Systolic Blood Pressure by Reducing Guanylate Cyclase Activity
Authors: Sara Vandenwijngaert, Clara D Ledsky, Lisa Corcoran, Toshiyuki Honda, John L Diener, Emmanuel S Buys, Donald B Bloch, Christopher Newton-Cheh
Journal: Circulation (2017)

Introduction: Hypertension is the leading modifiable risk factor for premature death and disability worldwide. We recently reported that an aggregation of rare and low-frequency (minor allele frequ...
CXCL1 regulates neutrophil homeostasis in pneumonia-derived sepsis caused by Streptococcus pneumoniae serotype 3
Authors: Sagar Paudel, Pankaj Baral, Laxman Ghimire, Scott Bergeron, Liliang Jin, Joseph A. DeCorte, John T. Le, Shanshan Cai, Samithamby Jeyaseelan
Journal: Blood (2019)