tbuckley/cabot-search huggingface dataset:
AntimiR-21 Prevents Myocardial Dysfunction in a Pig Model of Ischemia/Reperfusion Injury
Authors: Rabea Hinkel, Deepak Ramanujam, Veronika Kaczmarek, Andrea Howe, Katharina Klett, Christina Beck, Anne Dueck, Thomas Thum, Karl-Ludwig Laugwitz, Lars Maegdefessel, Christian Weber, Christian Kupatt, Stefan Engelhardt
Journal: Journal of the American College of Cardiology (2020)

miR-21 is a central regulator of cardiac fibrosis, and its inhibition in small-animal models has been shown to be an effective antifibrotic strategy in various organs, including the heart. Effective delivery of therapeutic antisense micro–ribonucleic acid (antimiR) molecules to the myocardium in larger organisms is challenging, though, and remains to be established for models of chronic heart failure. The aims of this study were to test the applicability and therapeutic efficacy of local, catheter-based delivery of antimiR-21 in a pig model of heart failure and determine its effect on the cardiac transcriptomic signature and cellular composition. Pigs underwent transient percutaneous occlusion of the left coronary artery and were followed up for 33 days. AntimiR-21 (10 mg) was applied by intracoronary infusion at days 5 and 19 after the injury. Cardiac function was assessed in vivo, followed by histological analyses and deep ribonucleic acid sequencing (RNA-seq) of the myocardium and genetic deconvolution analysis. AntimiR-21 effectively suppressed the remodeling-associated increase of miR-21. At 33 days after ischemia/reperfusion injury, LNA-21-treated hearts exhibited reduced cardiac fibrosis and hypertrophy and improved cardiac function. Deep RNA-seq revealed a significant derepression of the miR-21 targetome in antimiR-21-treated myocardium and a suppression of the inflammatory response and mitogen-activated protein kinase signaling. A genetic deconvolution approach built on deep RNA-seq and single-cell RNA-seq data identified reductions in macrophage and fibroblast numbers as the key cell types affected by antimiR-21 treatment. This study provides the first evidence for the feasibility and therapeutic efficacy of miR-21 inhibition in a large animal model of heart failure.
Not Dying Alone — Modern Compassionate Care in the Covid-19 Pandemic
Authors: Glenn K. Wakam, John R. Montgomery, Ben E. Biesterveld, Craig S. Brown
Journal: New England Journal of Medicine (2020)

Not Dying Alone When the wife of a severely ill patient with Covid-19 is told she can’t visit him, her anger quickly gives way to pleading — “What if I only spent 5 minutes and left?” How can we ha...
Rationalization is a suboptimal defense mechanism associated with clinical and forensic problems
Authors: Stuart Brody, Rui Miguel Costa
Journal: Behavioral and Brain Sciences (2020)

Abstract Cushman argues that “rationalization is rational.” We show that there is reasonable empirical clinical and forensic psychological evidence to support viewing rationalization as a quite suboptimal defense mechanism. Rationalization has been found to be associated not only with poorer emotional development, but also with a broad range of antisocial behavior, including not only shoplifting, but also pedophilia and murder.
First in human dose calculation of a single-chain bispecific antibody targeting glioma using the MABEL approach
Authors: Teilo H Schaller, David J Snyder, Ivan Spasojevic, Patrick C Gedeon, Luis Sanchez-Perez, John H Sampson
Journal: Journal for ImmunoTherapy of Cancer (2020)

Background First-in-human (FIH) clinical trials require careful selection of a safe yet biologically relevant starting dose. Typically, such starting doses are selected based on toxicity studies in a pharmacologically relevant animal model. However, with the advent of target-specific and highly active immunotherapeutics, both the Food and Drug Administration and the European Medicines Agency have provided guidance that recommend determining a safe starting dose based on a minimum anticipated biological effect level (MABEL) approach. Methods We recently developed a T cell activating bispecific antibody that effectively treats orthotopic patient-derived malignant glioma and syngeneic glioblastoma in mice (hEGFRvIII:CD3 bi-scFv). hEGFRvIII:CD3 bi-scFv is comprized of two single chain antibody fragments (bi-scFvs) that bind mutant epidermal growth factor receptor variant III (EGFRvIII), a mutation frequently seen in malignant glioma, and human CD3ε on T cells, respectively. In order to establish a FIH dose, we used a MABEL approach to select a safe starting dose for hEGFRvIII:CD3 bi-scFv, based on a combination of in vitro data, in vivo animal studies, and theoretical human receptor occupancy modeling. Results Using the most conservative approach to the MABEL assessment, a dose of 57.4 ng hEGFRvIII:CD3 bi-scFv/kg body weight was selected as a safe starting dose for a FIH clinical study. Conclusions The comparison of our MABEL-based starting dose to our in vivo efficacious dose and the theoretical human receptor occupancy strongly supports that our human starting dose of 57.4 ng hEGFRvIII:CD3 bi-scFv/patient kg will be safe.
Abstract 16679: Plasma Omega-6 Fatty Acids and the Risk of Cardiovascular Events in Patients After an Acute Coronary Syndrome
Authors: Thomas A Zelniker, David A Morrow, Dariush Mozaffarian, Jianping Guo, KyungAh Im, Marc S Sabatine, Michelle L O’Donoghue
Journal: Circulation (2018)

Introduction: Prior studies have shown an inverse correlation between plasma omega-6 fatty acids (Ω6-PUFA) content and the risk of CV events in primary prevention populations. The prognostic value of Ω6-PUFA in patients after an acute coronary syndrome (ACS) is less clear. Methods: Baseline plasma Ω6-PUFA (7 species) was assessed through thin liquid chromatography in a case-control population (203 CV deaths, 271 VT, 325 MI, 161 AF and 1,612 controls) from MERLIN-TIMI 36, a randomized trial of ranolazine versus placebo in patients hospitalized with ACS. Logistic regression models were adjusted for age and sex, and then BMI, hypertension, prior MI, prior HF, diabetes mellitus, smoking, eGFR, LDL, HDL, TG, statin use, index diagnosis and treatment arm. Results: After age and sex adjustment, higher plasma gamma-linoleic acid (GLA) content was associated with a 22% lower odds of CV death (OR adj 0.78 per 1-SD, 95% CI 0.67-0.91). After further multivariable adjustment, higher plasma GLA remained significantly associated with lower odds of CV death (OR adj 0.84 per 1-SD, 0.71-0.99) [Figure] . Patients with higher plasma GLA content had significantly lower odds of AF (OR adj per 1-SD 0.79, 0.66 -0.94) and tended to have lower risk of VT (OR adj per 1-SD 0.90, 0.78-1.03; OR adj top quartile versus lowest quartile: 0.67, 0.45-1.00). GLA was not significantly associated with the risk of MI (OR adj 0.95, 0.83-1.08). Other Ω6-PUFA, including linoleic acid, were not consistently associated with CV events. Conclusions: Plasma gamma-linoleic acid content is significantly associated with the odds of CV death after ACS. Future research should examine whether dietary intake of GLA after ACS may help to attenuate CV risk.
A Phase 2 Dose-Confirmation Study of Oral ASTX727, a Combination of Oral Decitabine with a Cytidine Deaminase Inhibitor (CDAi) Cedazuridine (E7727), in Subjects with Myelodysplastic Syndromes (MDS)
Authors: Guillermo Garcia-Manero, Elizabeth A. Griffiths, Gail J. Roboz, Lambert Busque, Richard A. Wells, Olatoyosi Odenike, David P. Steensma, Karen W.L. Yee, Stefan Faderl, Philip C. Amrein, Laura C. Michaelis, Hagop M. Kantarjian, Aram Oganesian, James N. Lowder, Mohammad Azab, Michael R. Savona
Journal: Blood (2017)
ANCA associated vasculitis
Authors: Robert W Hunter, Nicola Welsh, Tariq E Farrah, Peter J Gallacher, Neeraj Dhaun
Journal: BMJ (2020)

What you need to know• Consider ANCA associated vasculitis (AAV) in people with chronic systemic symptoms and evidence of renal, pulmonary, ear, nose, and throat, ophthalmic, or peripheral nerve disease • Perform urinalysis in people presenting with persistent systemic symptoms and in those with specific features of vasculitis (scleritis, chronic dyspnoea, cough, haemoptysis, foot drop) because these individuals have a high probability of multi-system disease • Patients with haemoptysis plus other features of AAV warrant same day hospital assessment to evaluate for pulmonary haemorrhage Nicola, 44, goes to her general practitioner with a one month history of fatigue and night sweats.Physical examination is unremarkable.The duration of her symptoms prompts her GP to consider systemic inflammatory disease.Urinalysis is positive for blood and protein, and blood tests show new renal impairment (serum creatine 327 μmol/L, estimated glomerular filtration rate (eGFR) 13 mL/min/1.73m 2) and evidence of an inflammatory response (C-reactive protein 50 mg/L, haemoglobin 103 g/L, platelets 461×10 9 /L, albumin 33 g/L).Nicola is referred urgently to her local renal unit and undergoes kidney biopsy and testing for anti-neutrophil cytoplasmic antibodies (ANCA).She is diagnosed with ANCA-associated vasculitis.
Dapansutrile, an oral selective NLRP3 inflammasome inhibitor, for treatment of gout flares: an open-label, dose-adaptive, proof-of-concept, phase 2a trial
Authors: Viola Klück, Tim L Th A Jansen, Matthijs Janssen, Antoaneta Comarniceanu, Monique Efdé, Isak W Tengesdal, Kiki Schraa, Maartje C P Cleophas, Curtis L Scribner, Damaris B Skouras, Carlo Marchetti, Charles A Dinarello, Leo A B Joosten
Journal: The Lancet Rheumatology (2020)
Noninvasive Markers of Portal Hypertension Detect Decompensation in Overweight or Obese Patients With Compensated Advanced Chronic Liver Disease
Authors: Yuly Mendoza, Sila Cocciolillo, Giuseppe Murgia, Tianyan Chen, Cristina Margini, Giada Sebastiani, Annalisa Berzigotti
Journal: Clinical Gastroenterology and Hepatology (2020)
Real-time and multimodality image-guided intelligent HIFU therapy for uterine fibroid
Authors: Guochen Ning, Xinran Zhang, Qin Zhang, Zhibiao Wang, Hongen Liao
Journal: Theranostics (2020)

Rationale: High-intensity focused ultrasound (HIFU) therapy represents a noninvasive surgical approach to treat uterine fibroids. The operation of HIFU therapy relies on the information provided by medical images. In current HIFU therapy, all operations such as positioning of the lesion in magnetic resonance (MR) and ultrasound (US) images are manually performed by specifically trained doctors. Manual processing is an important limitation of the efficiency of HIFU therapy. In this paper, we aim to provide an automatic and accurate image guidance system, intelligent diagnosis, and treatment strategy for HIFU therapy by combining multimodality information. Methods: In intelligent HIFU therapy, medical information and treatment strategy are automatically processed and generated by a real-time image guidance system. The system comprises a novel multistage deep convolutional neural network for preoperative diagnosis and a nonrigid US lesion tracking procedure for HIFU intraoperative image-assisted treatment. In the process of intelligent therapy, the treatment area is determined from the autogenerated lesion area. Based on the autodetected treatment area, the HIFU foci are distributed automatically according to the treatment strategy. Moreover, an image-based unexpected movement warning and other physiological monitoring are used during the intelligent treatment procedure for safety assurance. Results: In the experiment, we integrated the intelligent treatment system on a commercial HIFU treatment device, and eight clinical experiments were performed. In the clinical validation, eight randomly selected clinical cases were used to verify the feasibility of the system. The results of the quantitative experiment indicated that our intelligent system met the HIFU clinical tracking accuracy and speed requirements. Moreover, the results of simulated repeated experiments confirmed that the autodistributed HIFU focus reached the level of intermediate clinical doctors. Operations performed by junior- or middle-level operators with the assistance of the proposed system can reach the level of operation performed by senior doctors. Various experiments prove that our proposed intelligent HIFU therapy process is feasible for treating common uterine fibroid cases. Conclusion: We propose an intelligent HIFU therapy for uterine fibroid which integrates multiple medical information processing procedures. The experiment results demonstrated that the proposed procedures and methods can achieve monitored and automatic HIFU diagnosis and treatment. This research provides a possibility for intelligent and automatic noninvasive therapy for uterine fibroid.
Pimozide Alleviates Hyperglycemia in Diet-Induced Obesity by Inhibiting Skeletal Muscle Ketone Oxidation
Authors: Rami Al Batran, Keshav Gopal, Megan E. Capozzi, Jadin J. Chahade, Bruno Saleme, S. Amirhossein Tabatabaei-Dakhili, Amanda A. Greenwell, Jingjing Niu, Malak Almutairi, Nikole J. Byrne, Grant Masson, Ryekjang Kim, Farah Eaton, Erin E. Mulvihill, Léa Garneau, Andrea R. Masters, Zeruesenay Desta, Carlos A. Velázquez-Martínez, Céline Aguer, Peter A. Crawford, Gopinath Sutendra, Jonathan E. Campbell, Jason R.B. Dyck, John R. Ussher
Journal: Cell Metabolism (2020)
Multiparametric MR-PET Imaging Predicts Pharmacokinetics and Clinical Response to GDC-0084 in Patients with Recurrent High-Grade Glioma
Authors: Benjamin M. Ellingson, Jingwen Yao, Catalina Raymond, David A. Nathanson, Ararat Chakhoyan, Jeremy Simpson, James S. Garner, Alan G. Olivero, Lars U. Mueller, Jordi Rodon, Elizabeth Gerstner, Timothy F. Cloughesy, Patrick Y. Wen
Journal: Clinical Cancer Research (2020)

Abstract Purpose: GDC-0084 is an oral, brain-penetrant small-molecule inhibitor of PI3K and mTOR. Because these two targets alter tumor vascularity and metabolism, respectively, we hypothesized multiparametric MR-PET could be used to quantify the response, estimate pharmacokinetic (PK) parameters, and predict progression-free survival (PFS) in patients with recurrent malignant gliomas. Patients and Methods: Multiparametric advanced MR-PET imaging was performed to evaluate physiologic response in a first-in-man, multicenter, phase I, dose-escalation study of GDC-0084 (NCT01547546) in 47 patients with recurrent malignant glioma. Results: Measured maximum concentration (Cmax) was associated with a decrease in enhancing tumor volume (P = 0.0287) and an increase in fractional anisotropy (FA; P = 0.0418). Posttreatment tumor volume, 18F-FDG uptake, Ktrans, and relative cerebral blood volume (rCBV) were all correlated with Cmax. A linear combination of change in 18F-FDG PET uptake, apparent diffusion coefficient (ADC), FA, Ktrans, vp, and rCBV was able to estimate both Cmax (R2 = 0.4113; P &amp;lt; 0.0001) and drug exposure (AUC; R2 = 0.3481; P &amp;lt; 0.0001). Using this composite multiparametric MR-PET imaging response biomarker to predict PK, patients with an estimated Cmax &amp;gt; 0.1 μmol/L and AUC &amp;gt; 1.25 μmol/L*hour demonstrated significantly longer PFS compared with patients with a lower estimated concentration and exposure (P = 0.0039 and P = 0.0296, respectively). Conclusions: Results from this study suggest composite biomarkers created from multiparametric MR-PET imaging targeting metabolic and/or physiologic processes specific to the drug mechanism of action may be useful for subsequent evaluation of treatment efficacy for larger phase II–III studies.
Oncogenic seRNA functional activation: a novel mechanism of tumorigenesis
Authors: Yuan Tan, Yuejin Li, Faqing Tang
Journal: Molecular Cancer (2020)

Abstract seRNA is a noncoding RNA (ncRNA) transcribed from active super-enhancer (SE), through which SE exerts biological functions and participates in various physiological and pathological processes. seRNA recruits cofactor, RNA polymerase II and mediator to constitute and stabilize chromatin loop SE and promoter region, which regulates target genes transcription. In tumorigenesis, DNA insertion, deletion, translocation, focal amplification and carcinogen factor mediate oncogenic SE generation, meanwhile, oncogenic SE transcribes into tumor-related seRNA, termed as oncogenic seRNA. Oncogenic seRNA participates in tumorigenesis through activating various signal-pathways. The recent reports showed that oncogenic seRNA implicates in a widespread range of cytopathological processes in cancer progression including cell proliferation, apoptosis, autophagy, epithelial-mesenchymal transition, extracellular matrix stiffness and angiogenesis. In this article, we comprehensively summarized seRNA’s characteristics and functions, and emphatically introduced inducible formation of oncogenic seRNA and its functional mechanisms. Lastly, some research strategies on oncogenic seRNA were introduced, and the perspectives on cancer therapy that targets oncogenic seRNA were also discussed.
A change of climate for climate change: the environmental benefit of specialty outreach clinics
Authors: Cathal O’Connor, Lisa Kiely, Anthony O’Riordan, Garrett O’Connell, Mary Bennett, Sally O’Shea, Lesley Ann Murphy, John Bourke, Michelle Murphy
Journal: BMJ (2020)

Climate change is a devastating threat to global health.1 Gill and colleagues draw our attention to the need to think, act, and advocate for change.2

The main benefits of outreach clinics are thought to be patient convenience and resource efficiency.3 We assessed the environmental benefit of dermatology outreach clinics in the south of Ireland, from our regional centre of …
Transmission of COVID-19 to Health Care Personnel During Exposures to a Hospitalized Patient — Solano County, California, February 2020
Authors: Amy Heinzerling, Matthew J. Stuckey, Tara Scheuer, Kerui Xu, Kiran M. Perkins, Heather Resseger, Shelley Magill, Jennifer R. Verani, Seema Jain, Meileen Acosta, Erin Epson
Journal: MMWR Morbidity and Mortality Weekly Report (2020)

On February 26, 2020, the first U.S. case of community-acquired coronavirus disease 2019 (COVID-19) was confirmed in a patient hospitalized in Solano County, California (1). The patient was initially evaluated at hospital A on February 15; at that time, COVID-19 was not suspected, as the patient denied travel or contact with symptomatic persons. During a 4-day hospitalization, the patient was managed with standard precautions and underwent multiple aerosol-generating procedures (AGPs), including nebulizer treatments, bilevel positive airway pressure (BiPAP) ventilation, endotracheal intubation, and bronchoscopy. Several days after the patient's transfer to hospital B, a real-time reverse transcription-polymerase chain reaction (real-time RT-PCR) test for SARS-CoV-2 returned positive. Among 121 hospital A health care personnel (HCP) who were exposed to the patient, 43 (35.5%) developed symptoms during the 14 days after exposure and were tested for SARS-CoV-2; three had positive test results and were among the first known cases of probable occupational transmission of SARS-CoV-2 to HCP in the United States. Little is known about specific risk factors for SARS-CoV-2 transmission in health care settings. To better characterize and compare exposures among HCP who did and did not develop COVID-19, standardized interviews were conducted with 37 hospital A HCP who were tested for SARS-CoV-2, including the three who had positive test results. Performing physical examinations and exposure to the patient during nebulizer treatments were more common among HCP with laboratory-confirmed COVID-19 than among those without COVID-19; HCP with COVID-19 also had exposures of longer duration to the patient. Because transmission-based precautions were not in use, no HCP wore personal protective equipment (PPE) recommended for COVID-19 patient care during contact with the index patient. Health care facilities should emphasize early recognition and isolation of patients with possible COVID-19 and use of recommended PPE to minimize unprotected, high-risk HCP exposures and protect the health care workforce.
Management of cytomegalovirus infection in pregnancy: is it time for valacyclovir?
Authors: L. Zammarchi, T. Lazzarotto, M. Andreoni, I. Campolmi, L. Pasquini, M. Di Tommaso, G. Simonazzi, L.R. Tomasoni, F. Castelli, L. Galli, B. Borchi, P. Clerici, A. Bartoloni, M. Tavio, M. Trotta
Journal: Clinical Microbiology and Infection (2020)
Studies on Congestive Circulatory Failure
Authors: HENRY A. SCHROEDER
Journal: Circulation (1950)

Balance studies in chronic congestive circulatory failure showed marked depression of renal excretion of chloride and further depression when the intake of salt was elevated or when fluids were restricted. This defect may not be accompanied by diminished ability to excrete nitrogen. Although cardiac compensation was usually accompanied by chloride diuresis of proportionate degree, in over one-third of the cases there was evidence of excessive hydration without proportionate retention of salt. Although initiated by a cardiac disorder, congestive failure is mediated by disturbances in renal regulatory mechanisms of both salt and water balances suggesting that hormonal effects play a role.
Abstract 195: Stages of Bystander Intervention to Sudden Cardiac Arrest in a Virtual Reality Environment
Authors: David G Buckler, Alfredo Almodovar, Paul Snobelen, Audrey L Blewer, Marion Leary
Journal: Circulation (2018)

Introduction: Four stages of bystander intervention (BI) have been described in social behavioral research: noticing the situation as a problem, interpreting when it is appropriate to intervene, recognizing personal responsibly to intervene, and knowing how to intervene (i.e. having the skills to respond). Using virtual reality (VR), emergency events such as sudden cardiac arrest (SCA), can be used to observe the progression through these stages. Objective: We sought to compare bystander self-efficacy with action, based on each stage of BI before and after an unannounced simulated VR SCA scenario. Methods: In a secondary analysis of an observational cohort study, we analyzed self-efficacy with each stage of BI using a forced Likert scale survey before and after a simulated SCA. Each subject participated in a single-player, immersive, VR SCA scenario. Subjects interacted with avatars through voice commands such as “call 911” and “get an AED”. Actions taken in the scenario, such as performing CPR, were recorded. Scenario BI stage progression was compared based on dichotomized comfort/discomfort. Results: From 9/2016 to 6/2017, 119 subjects completed the study. Average age was 37±14 yrs, 44% were female and 58% had a bachelor’s degree or higher. During the scenario, 98% of subjects “noticed the event” and “interpreted it as a problem”, 78% “took responsibility”, and 54% “possessed the necessary skills” to act. Self-efficacy increased from pre- to post-scenario: noticing the event as a problem increased from 80% to 96%; interpreting it as a problem increased from 86% to 97%; taking responsibility increased from 56% to 93%; possessing necessary skills to intervene increased from 47% to 63% (p&lt;0.001, respectively). More subjects who reported pre-scenario comfort with responsibility to act, took responsibility for dealing with the SCA during the scenario (85% vs 71%, p=0.004). Conclusion: Bystanders who felt more comfortable taking responsibility for an emergency event pre-scenario were more likely to respond appropriately during the scenario. VR represents a potentially powerful tool to promote self-efficacy and understand how bystanders may respond during emergency situations.
<i>TMPRSS2</i> and COVID-19: Serendipity or Opportunity for Intervention?
Authors: Konrad H. Stopsack, Lorelei A. Mucci, Emmanuel S. Antonarakis, Peter S. Nelson, Philip W. Kantoff
Journal: Cancer Discovery (2020)

TMPRSS2 is both the most frequently altered gene in primary prostate cancer and a critical factor enabling cellular infection by coronaviruses, including SARS-CoV-2. The modulation of its expression by sex steroids could contribute to the male predominance of severe infections, and given that TMPRSS2 has no known indispensable functions, and inhibitors are available, it is an appealing target for prevention or treatment of respiratory viral infections.