tbuckley/cabot-search huggingface dataset:
Abstract 17487: S-Nitroso Human Serum Albumin (S-NO-HSA) Attenuates Pulmonary Hypertension, Improves Right Ventricular-Arterial Coupling and Reduces Oxidative Stress in a Chronic Right Ventricle Volume Overload Model
Authors: Alessio Rungatscher, Seth Hallström, Mohammed Morjan, Daniele Linardi, Harald Gasser, Bruno K Podesser, Giovanni Battista Luciani, Alessandro Mazzucco, Giuseppe Faggian
Journal: Circulation (2011)

BACKGROUND The study was aimed to examine the acute overall hemodynamic and oxidative stress effects to intravenous S-NO-HSA infusion in a model of chronic left-to-right shunt-induced pulmonary arterial hypertension and right ventricle failure. METHODS AND RESULTS Fifty male Wistar rats underwent surgical creation of aorto-caval fistula (Qp/Qs&gt; 2.0) After 10 weeks they were randomly treated with S-NO-HSA (0.5 υmol/kg/h) (n. 20) or human serum albumin (HSA) (n. 25) infusion for 60 minutes. Right ventricular contractility, right ventriculo-vascular coupling and ventricular interdependence were assessed in vivo ad different preloads by biventricular conductance catheters prior and after 60 minutes infusion. Heart and lung biopsies were obtained to determine oxidative stress by reduced to oxidized glutathione (GSH/GSSG) ratio and high energy phosphates content. S-NO-HSA compared to HSA infusion resulted in a significant reduction in right ventricular afterload expressed by effective pulmonary arterial elastance (Ea) (0.49 +/- 0.3 versus 1.2 +/- 0.2 mmHg/ml; P = 0.0005). S-NO-HSA significantly improve right ventricular diastolic function (slope of end-diastolic pressure-volume relations) but not contractility (slope of preload recruitable stroke work), whereas a significant increase in the efficiency of ventricular-vascular coupling (ratio of end-systolic to pulmonary arterial elastances: Ees/Ea) occurred after S-NO-HSA but not HSA infusion (from 0.35 +/- 0.17 to 0.94 +/- 0.21; P = 0.005 and from 0.37 +/- 0.11 to 0.43 +/- 0.19; P = 0.1 respectively) with significant increase in left ventricular stroke volume (56 +/- 4 vs 9 +/- 5 %; P = 0.0013). S-NO-HSA compared to HSA treatment significantly improved ATP and PCr right ventricle myocardial content (13.9 +/- 1.1 vs. 7.0 +/- 1.8 and 5.9 +/- 3.3 vs. 1.9 +/- 0.6 micromol/g protein; P = 0.01) and increase tissue GSH/GSSG ratio (P = 0.001). CONCLUSIONS: S-NO-HSA reduces pulmonary hypertension and improves right ventricular diastolic function and right ventricular-arterial coupling with a positive effect on ventricular interdependence. This results in an increased energetic reserve of the heart and reduction of oxidative stress.
MO28-4 Multi-disciplinary collaboration on gene panel testing and review of factors in cases of unsuitable for gene profiling
Authors: Takayuki Takahama, Noriko Ichimura, Takafumi Okabe, Yusaku Akashi, Takao Tamura, Miyako Shimoyoshi, Keisuke Kameda, Tomoko Wakasa, Yoshio Ohta, Hidekazu Yamada, Masao Yukawa
Journal: Annals of Oncology (2021)
Pulmonary Artery 18F-Fluorodeoxyglucose Uptake by PET/CMR as a Marker of Pulmonary Hypertension in Sarcoidosis
Authors: Alexander Maier, Steve Lin Liao, Thomas Lescure, Philip M. Robson, Naoki Hirata, Samantha Sartori, Navneet Narula, Vittoria Vergani, Georgios Soultanidis, Adam Morgenthau, Jason C. Kovacic, Maria Padilla, Jagat Narula, Adam Jacobi, Zahi A. Fayad, Maria G. Trivieri
Journal: JACC. Cardiovascular imaging (2021)
Effectiveness of an ocular adhesive polyhedral oligomeric silsesquioxane hybrid thermo-responsive FK506 hydrogel in a murine model of dry eye
Authors: Yi Han, Lu Jiang, Huihui Shi, Chenfang Xu, Minting Liu, Qingjian Li, Lan Zheng, Hong Chi, Mingyue Wang, Zuguo Liu, Mingliang You, Xian Jun Loh, Yun-Long Wu, Zibiao Li, Cheng Li
Journal: Bioactive Materials (2021)

Dry eye is a common ocular disease that results in discomfort and impaired vision, impacting an individual's quality of life. A great number of drugs administered in eye drops to treat dry eye are poorly soluble in water and are rapidly eliminated from the ocular surface, which limits their therapeutic effects. Therefore, it is imperative to design a novel drug delivery system that not only improves the water solubility of the drug but also prolongs its retention time on the ocular surface. Herein, we develop a copolymer from mono-functional POSS, PEG, and PPG (MPOSS-PEG-PPG, MPEP) that exhibits temperature-sensitive sol-gel transition behavior. This thermo-responsive hydrogel improves the water solubility of FK506 and simultaneously provides a mucoadhesive, long-acting ocular delivery system. In addition, the FK506-loaded POSS hydrogel possesses good biocompatibility and significantly improves adhesion to the ocular surface. In comparison with other FK506 formulations and the PEG-PPG-FK506 (F127-FK506) hydrogel, this novel MPOSS-PEG-PPG-FK506 (MPEP-FK506) hydrogel is a more effective treatment of dry eye in the murine dry eye model. Therefore, delivery of FK506 in this POSS hydrogel has the potential to prolong drug retention time on the ocular surface, which will improve its therapeutic efficacy in the management of dry eye.
P-219 Real-life experience with chemotherapy plus biologics in first-line treatment of right-sided, RAS wild-type, metastatic colon cancer: A multicenter Onco-Colon Turkey study
Authors: None Ç. Arslan, U. Kefeli, E. Yildirim, A. Isıkdogan, N. Karadurmus, B. Karabulut, I. Cicin, E. Cubukcu, C. Bilir, M. Ozcelik, T. Cil, S. Celik, O. Bozkurt, H. Harputluoglu, B. Oven, C. Geredeli, D. Tural, A. Sakin, D. Çevik, M. Gumus, S. Yalcin
Journal: Annals of Oncology (2021)
Bacterial and fungal bloodstream infections in solid organ transplant recipients: results from a Danish cohort with nationwide follow-up
Authors: Dina Leth Møller, Søren Schwartz Sørensen, Michael Perch, Finn Gustafsson, Omid Rezahosseini, Andreas Dehlbæk Knudsen, Thomas Scheike, Jenny Dahl Knudsen, Jens Lundgren, Allan Rasmussen, Susanne Dam Nielsen
Journal: Clinical Microbiology and Infection (2021)
MO9-5 Clinical implementation of cancer genomic medicine using gene profiling test under national health insurance in Japan
Authors: Ippei Fukada, Naomi Hayashi, Masumi Yamazaki, Gyohi Oh, Mari Hosonaga, Takeshi Nakajima, Seiichi Mori, Kengo Takeuchi, Shunji Takahashi
Journal: Annals of Oncology (2021)
Public-sector Contributions to Novel Biologic Drugs
Authors: Rahul K. Nayak, ChangWon C. Lee, Jerry Avorn, Aaron S. Kesselheim
Journal: JAMA Internal Medicine (2021)

is the basis for permissible advertising or other promotional claims by the manufacturer.Labeling should be consistent in communicating what is or is not known at the time it is issued, so prescribers understand how well new drugs work and what important open questions remain. 6 Currently, relevant information on cancer drugs' OS benefits is variably reported in labeling text, tables, figures, or footnotes.The FDA should harmonize survival data reporting cancer drug labeling.For example, labeling should routinely contain clear, nontechnical statements of whether or not clinical trials show statistically significant OS benefit, and, if applicable, statements on the magnitude of OS benefit.The potential role of crossover in diluting drug effects on survival should be consistently mentioned when labeling reports with statistically nonsignificant trial findings.Limitations of this study include not evaluating the reporting of end points other than OS, not using an instrument to measure clarity of reporting, and not examining the magnitude of OS benefits for indications with such evidence.Notwithstanding these limitations, our findings reveal that labeling frequently fails to consistently communicate the survival benefits of cancer drugs, or lack thereof.
Insulin: A 100-Year-Old Discovery With a Fascinating History
Authors: William Rostène, Pierre De Meyts
Journal: Endocrine Reviews (2021)

Abstract Diabetes has been known since antiquity. We present here a historical perspective on the concepts and ideas regarding the physiopathology of the disease, on the progressive focus on the pancreas, in particular on the islets discovered by Langerhans in 1869, leading to the iconic experiment of Minkowski and von Mering in 1889 showing that pancreatectomy in a dog induced polyuria and diabetes mellitus. Subsequently, multiple investigators searched for the active substance of the pancreas and some managed to produce extracts that lowered blood glucose and decreased polyuria in pancreatectomized dogs but were too toxic to be administered to patients. The breakthrough came 100 years ago, when the team of Frederick Banting, Charles Best, and James Collip working in the Department of Physiology headed by John Macleod at the University of Toronto managed to obtain pancreatic extracts that could be used to treat patients and rescue them from the edge of death by starvation, the only treatment then available. This achievement was quickly recognized by the Nobel Prize in Physiology or Medicine to Banting and Macleod in 1923. At 32, Banting remains the youngest awardee of this prize. Here we discuss the work that led to the discovery and its main breakthroughs, the human characters involved in an increasingly dysfunctional relationship, the controversies that followed the Nobel Prize, and the debate as to who actually “discovered” insulin. We also discuss the early commercial development and progress in insulin crystallization in the decade or so following the Nobel Prize.
Nicotine promotes vascular calcification via intracellular Ca2+-mediated, Nox5-induced oxidative stress, and extracellular vesicle release in vascular smooth muscle cells
Authors: Ploingarm Petsophonsakul, Mathias Burgmaier, Brecht Willems, Sylvia Heeneman, Nadina Stadler, Felix Gremse, Sebastian Reith, Kathrin Burgmaier, Florian Kahles, Nikolaus Marx, Ehsan Natour, Elham Bidar, Michael Jacobs, Barend Mees, Chris Reutelingsperger, Malgorzata Furmanik, Leon Schurgers
Journal: Cardiovascular Research (2021)

Smokers are at increased risk of cardiovascular events. However, the exact mechanisms through which smoking influences cardiovascular disease resulting in accelerated atherosclerosis and vascular calcification are unknown. The aim of this study was to investigate effects of nicotine on initiation of vascular smooth muscle cell (VSMC) calcification and to elucidate underlying mechanisms.We assessed vascular calcification of 62 carotid lesions of both smoking and non-smoking patients using ex vivo micro-computed tomography (µCT) scanning. Calcification was present more often in carotid plaques of smokers (n = 22 of 30, 73.3%) compared to non-smokers (n = 11 of 32, 34.3%; P < 0.001), confirming higher atherosclerotic burden. The difference was particularly profound for microcalcifications, which was 17-fold higher in smokers compared to non-smokers. In vitro, nicotine-induced human primary VSMC calcification, and increased osteogenic gene expression (Runx2, Osx, BSP, and OPN) and extracellular vesicle (EV) secretion. The pro-calcifying effects of nicotine were mediated by Ca2+-dependent Nox5. SiRNA knock-down of Nox5 inhibited nicotine-induced EV release and calcification. Moreover, pre-treatment of hVSMCs with vitamin K2 ameliorated nicotine-induced intracellular oxidative stress, EV secretion, and calcification. Using nicotinic acetylcholine receptor (nAChR) blockers α-bungarotoxin and hexamethonium bromide, we found that the effects of nicotine on intracellular Ca2+ and oxidative stress were mediated by α7 and α3 nAChR. Finally, we showed that Nox5 expression was higher in carotid arteries of smokers and correlated with calcification levels in these vessels.In this study, we provide evidence that nicotine induces Nox5-mediated pro-calcific processes as novel mechanism of increased atherosclerotic calcification. We identified that activation of α7 and α3 nAChR by nicotine increases intracellular Ca2+ and initiates calcification of hVSMCs through increased Nox5 activity, leading to oxidative stress-mediated EV release. Identifying the role of Nox5-induced oxidative stress opens novel avenues for diagnosis and treatment of smoking-induced cardiovascular disease.
Using Consistently Low Performance to Identify Low-Quality Physician Groups
Authors: Christina A. Nguyen, Lauren G. Gilstrap, Michael E. Chernew, J. Michael McWilliams, Bruce E. Landon, Mary Beth Landrum
Journal: JAMA Network Open (2021)

<h3>Importance</h3> There has been a growth in the use of performance-based payment models in the past decade, but inherently noisy and stochastic quality measures complicate the assessment of the quality of physician groups. Examining consistently low performance across multiple measures or multiple years could potentially identify a subset of low-quality physician groups. <h3>Objective</h3> To identify low-performing physician groups based on consistently low performance after adjusting for patient characteristics across multiple measures or multiple years for 10 commonly used quality measures for diabetes and cardiovascular disease (CVD). <h3>Design, Setting, and Participants</h3> This cross-sectional study used medical and pharmacy claims and laboratory data for enrollees ages 18 to 65 years with diabetes or CVD in an Aetna health insurance plan between 2016 and 2019. Each physician group’s risk-adjusted performance for a given year was estimated using mixed-effects linear probability regression models. Performance was correlated across measures and time, and the proportion of physician groups that performed in the bottom quartile was examined across multiple measures or multiple years. Data analysis was conducted between September 2020 and May 2021. <h3>Exposures</h3> Primary care physician groups. <h3>Main Outcomes and Measures</h3> Performance scores of 6 quality measures for diabetes and 4 for CVD, including hemoglobin A<sub>1c</sub>(HbA<sub>1c</sub>) testing, low-density lipoprotein testing, statin use, HbA<sub>1c</sub>control, low-density lipoprotein control, and hospital-based utilization. <h3>Results</h3> A total of 786 641 unique enrollees treated by 890 physician groups were included; 414 655 (52.7%) of the enrollees were men and the mean (SD) age was 53 (9.5) years. After adjusting for age, sex, and clinical and social risk variables, correlations among individual measures were weak (eg, performance-adjusted correlation between any statin use and LDL testing for patients with diabetes,<i>r</i> = −0.10) to moderate (correlation between LDL testing for diabetes and LDL testing for CVD,<i>r</i> = .43), but year-to-year correlations for all measures were moderate to strong. One percent or fewer of physician groups performed in the bottom quartile for all 6 diabetes measures or all 4 cardiovascular disease measures in any given year, while 14 (4.0%) to 39 groups (11.1%) were in the bottom quartile in all 4 years for any given measure other than hospital-based utilization for CVD (1.1%). <h3>Conclusions and Relevance</h3> A subset of physician groups that was consistently low performing could be identified by considering performance measures across multiple years. Considering the consistency of group performance could contribute a novel method to identify physician groups most likely to benefit from limited resources.
Charities, patients, and researchers are working together to find the cause and effective treatments for ME/CFS
Authors: Charles B Shepherd
Journal: BMJ (2021)

As a charity that funds biomedical research into myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), we are not aware of any researchers who hold negative views about the patient community.1 Patients, charities, and researchers are all working together on research initiatives such as Decode ME (https://www.decodeme.org.uk), the ME Biobank (https://cureme.lshtm.ac.uk/the-uk-mecfs-biobank), and cardiorespiratory exercise testing.2

People with ME/CFS feel let down by the medical establishment because almost all biomedical research until recently has been funded by the …
Progressive multifocal leukoencephalopathy in patients treated with rituximab: a 20-year review from the Southern Network on Adverse Reactions
Authors: Charles L Bennett, Daniele Focosi, Mariana P Socal, Julia C Bian, Chadi Nabhan, William J Hrushesky, Andrew C Bennett, Martin W Schoen, Joseph R Berger, James O Armitage
Journal: The Lancet Haematology (2021)
Targeting ATF4-dependent pro-survival autophagy to synergize glutaminolysis inhibition
Authors: Shuting Han, Liyuan Zhu, Yiran Zhu, Yuan Meng, Jiaqiu Li, Ping Song, Neelum Aziz Yousafzai, Lifeng Feng, Miaoqin Chen, Yanmei Wang, Hongchuan Jin, Xian Wang
Journal: Theranostics (2021)

As glutamine plays a central role in cancer metabolism, inhibition of glutaminolysis has become an ideal anticancer therapeutic target.However, glutaminolysis inhibition leads to activation of autophagy, which compromises its antitumor effect.Hence, we investigated the mechanism underlying glutaminolysis inhibition-induced pro-survival autophagy.Methods: High-throughput sequencing was performed on colorectal cancer (CRC) cells before and after glutaminolysis inhibition to identify differentially expressed genes.Activating transcription factor 4 (ATF4) pathway enrichment in glutaminolysis inhibited cells was identified through gene set enrichment analysis.ATF4 expression was assessed by quantitative real-time PCR (qRT-PCR) and western blotting.The function of ATF4 on mechanistic target of rapamycin (mTOR) regulation was assessed by western blotting.Luciferase reporter assays and chromatin immunoprecipitation were used to confirm the regulation of DNA damage inducible transcript 4 (DDIT4) by ATF4.mRNA half-life assays, RNA immunoprecipitation, qRT-PCR and western blotting were performed to determine the relationship between FTO alpha-ketoglutarate dependent dioxygenase (FTO), YTH N 6 -methyladenosine RNA binding protein 2 (YTHDF2), and ATF4.ATF4 regulation of pro-survival autophagy was measured by tandem monomeric red fluorescent protein-green fluorescent protein fluorescence microscopy.Finally, the synergistic effect of autophagy and glutaminolysis inhibition was analyzed in an azoxymethane/dextran sodium sulfate mouse model.Results: The ATF4 pathway was activated in CRC cells upon glutaminolysis inhibition.Functionally, ATF4 transcriptionally upregulated DDIT4 to suppress mTOR, which induced pro-survival autophagy during glutaminolysis inhibition.Interestingly, glutaminolysis inhibition promoted ATF4 mRNA expression by abrogating N 6 -methyladenosine (m 6 A) modification and YTHDF2-mediated RNA decay.Finally, inhibition of ATF4-induced autophagy enhanced the antitumor efficacy of glutaminolysis inhibition.Conclusion: Glutaminolysis inhibition upregulated ATF4 expression in an m 6 A-dependent manner to activate pro-survival autophagy through transcriptional activation of the mTOR inhibitor DDIT4.Targeting ATF4-induced autophagy is a new strategy to synergize glutaminolysis-targeting therapies for cancer treatment.
A combination of fecal calprotectin and human beta-defensin 2 facilitates diagnosis and monitoring of inflammatory bowel disease
Authors: R. Gacesa, A. Vich Vila, V. Collij, Z. Mujagic, A. Kurilshikov, M.D. Voskuil, E.A.M. Festen, C. Wijmenga, D.M.A.E. Jonkers, G. Dijkstra, J. Fu, A. Zhernakova, F. Imhann, R.K. Weersma
Journal: Gut Microbes (2021)

Inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS) show a large overlap in clinical presentation, which presents diagnostic challenges. As a consequence, invasive and burdensome endoscopies are often used to distinguish between IBD and IBS. Here, we aimed to develop a noninvasive fecal test that can distinguish between IBD and IBS and reduce the number of endoscopies.We used shotgun metagenomic sequencing to analyze the composition and function of gut microbiota of 169 IBS patients, 447 IBD patients and 1044 population controls and measured fecal Calprotectin (FCal), human beta defensin 2 (HBD2), and chromogranin A (CgA) in these samples. These measurements were used to construct training sets (75% of data) for logistic regression and machine learning models to differentiate IBS from IBD and inactive from active IBD. The results were replicated on test sets (remaining 25% of the data) and microbiome data obtained using 16S sequencing.Fecal HBD2 showed high sensitivity and specificity for differentiating between IBD and IBS (sensitivity = 0.89, specificity = 0.76), while the inclusion of microbiome data with biomarkers (HBD2 and FCal) showed a potential for improvement in predictive power (optimal sensitivity = 0.87, specificity = 0.93). Shotgun sequencing–based models produced comparable results using 16S-sequencing data. HBD2 and FCal were found to have predictive power for IBD disease activity (AUC ≈ 0.7).HBD2 is a novel biomarker for IBD in patients with gastro-intestinal complaints, especially when used in combination with FCal and potentially in combination with gut microbiome data.
Safety of maximal cardiopulmonary exercise testing in individuals with sickle cell disease: a systematic review
Authors: Kellsey N Smith, Tracy Baynard, Peter S Fischbach, Jane S Hankins, Lewis L Hsu, Peggy M Murphy, Kiri K Ness, Shlomit Radom-Aizik, Amy Tang, Robert I Liem
Journal: British Journal of Sports Medicine (2021)

Objective We evaluated the safety of maximal cardiopulmonary exercise testing (CPET) in individuals with sickle cell disease (SCD). Maximal CPET using gas exchange analysis is the gold standard for measuring cardiopulmonary fitness in the laboratory, yet its safety in the SCD population is unclear. Design Systematic review. Data sources Systematic search of Medline (PubMed), EMBASE, Cochrane, ClinicalTrials.gov and professional society websites for all published studies and abstracts through December 2020. Eligibility criteria for selecting studies Two reviewers independently extracted data of interest from studies that assessed safety outcomes of maximal CPET in children and adults with SCD. A modified version of the Newcastle-Ottawa Scale was used to assess for risk of bias in studies included. Results In total, 24 studies met inclusion/exclusion criteria. Adverse events were reported separately or as part of study results in 36 (3.8%) of 939 participants with SCD undergoing maximal CPET in studies included. Most adverse events were related to transient ischaemic changes on ECG monitoring or oxygen desaturation during testing, which did not result in arrhythmias or other complications. Only 4 (0.43%) of 939 participants experienced pain events due to maximal CPET. Conclusion Maximal CPET appears to be a safe testing modality in children and adults with SCD and can be used to better understand the physiological basis of reduced exercise capacity and guide exercise prescription in this population. Some studies did not focus on reporting adverse events related to exercise testing or failed to mention safety monitoring, which contributed to risk of bias.