tbuckley/cabot-search huggingface dataset:
Can remdesivir and its parent nucleoside GS-441524 be potential oral drugs? An in vitro and in vivo DMPK assessment
Authors: Jiashu Xie, Zhengqiang Wang
Journal: Acta Pharmaceutica Sinica B (2021)

Remdesivir (RDV) is the only US Food and Drug Administration (FDA)-approved drug for treating COVID-19. However, RDV can only be given by intravenous route, and there is a pressing medical need for oral antivirals. Significant evidence suggests that the role of the parent nucleoside GS-441524 in the clinical outcomes of RDV could be largely underestimated. We performed an in vitro and in vivo drug metabolism and pharmacokinetics (DMPK) assessment to examine the potential of RDV, and particularly GS-441524, as oral drugs. In our in vitro assessments, RDV exhibited prohibitively low stability in human liver microsomes (HLMs, t1/2 = ∼1 min), with the primary CYP-mediated metabolism being the mono-oxidation likely on the phosphoramidate moiety. This observation is poorly aligned with any potential oral use of RDV, though in the presence of cobicistat, the microsomal stability was drastically boosted to the level observed without enzyme cofactor NADPH. Conversely, GS-441524 showed excellent metabolic stability in human plasma and HLMs. In further in vivo studies in CD-1 mice, GS-441524 displayed a favorable oral bioavailability of 57%. Importantly, GS-441524 produced adequate drug exposure in the mice plasma and lung, and was effectively converted to the active triphosphate, suggesting that it could be a promising oral antiviral drug for treating COVID-19.
P66.04 Real World Data: Immunotherapy in Lung Cancer Patients over 65 Years Old in Spain
Authors: B. Nunez-Garcia, M. Blanco Clemente, Y. Garitaonaindía, R. Aguado Noya, A. Morito Aguilar, C. Traseira, M. Martínez, G. Visedo, V. Calvo, F. Franco, M. Provencio
Journal: Journal of Thoracic Oncology (2021)
Diagnosis and Management of Transient Ischemic Attack and Acute Ischemic Stroke
Authors: Scott J. Mendelson, Shyam Prabhakaran
Journal: JAMA (2021)

<h3>Importance</h3> Stroke is the fifth leading cause of death and a leading cause of disability in the United States, affecting nearly 800 000 individuals annually. <h3>Observations</h3> Sudden neurologic dysfunction caused by focal brain ischemia with imaging evidence of acute infarction defines acute ischemic stroke (AIS), while an ischemic episode with neurologic deficits but without acute infarction defines transient ischemic attack (TIA). An estimated 7.5% to 17.4% of patients with TIA will have a stroke in the next 3 months. Patients presenting with nondisabling AIS or high-risk TIA (defined as a score ≥4 on the age, blood pressure, clinical symptoms, duration, diabetes [ABCD2] instrument; range, 0-7 [7 indicating worst stroke risk]), who do not have severe carotid stenosis or atrial fibrillation, should receive dual antiplatelet therapy with aspirin and clopidigrel within 24 hours of presentation. Subsequently, combined aspirin and clopidigrel for 3 weeks followed by single antiplatelet therapy reduces stroke risk from 7.8% to 5.2% (hazard ratio, 0.66 [95% CI, 0.56-0.77]). Patients with symptomatic carotid stenosis should receive carotid revascularization and single antiplatelet therapy, and those with atrial fibrillation should receive anticoagulation. In patients presenting with AIS and disabling deficits interfering with activities of daily living, intravenous alteplase improves the likelihood of minimal or no disability by 39% with intravenous recombinant tissue plasminogen activator (IV rtPA) vs 26% with placebo (odds ratio [OR], 1.6 [95% CI, 1.1-2.6]) when administered within 3 hours of presentation and by 35.3% with IV rtPA vs 30.1% with placebo (OR, 1.3 [95% CI, 1.1-1.5]) when administered within 3 to 4.5 hours of presentation. Patients with disabling AIS due to anterior circulation large-vessel occlusions are more likely to be functionally independent when treated with mechanical thrombectomy within 6 hours of presentation vs medical therapy alone (46.0% vs 26.5%; OR, 2.49 [95% CI, 1.76-3.53]) or when treated within 6 to 24 hours after symptom onset if they have a large ratio of ischemic to infarcted tissue on brain magnetic resonance diffusion or computed tomography perfusion imaging (modified Rankin Scale score 0-2: 53% vs 18%; OR, 4.92 [95% CI, 2.87-8.44]). <h3>Conclusions and Relevance</h3> Dual antiplatelet therapy initiated within 24 hours of symptom onset and continued for 3 weeks reduces stroke risk in select patients with high-risk TIA and minor stroke. For select patients with disabling AIS, thrombolysis within 4.5 hours and mechanical thrombectomy within 24 hours after symptom onset improves functional outcomes.
Gastric per-oral endoscopic myotomy (G-POEM) for refractory gastroparesis: results from an international prospective trial
Authors: Kia Vosoughi, Yervant Ichkhanian, Petros Benias, Larry Miller, A Aziz Aadam, Joseph R Triggs, Ryan Law, William Hasler, Nicole Bowers, Dalton Chaves, Alberto M Ponte-Neto, Peter Draganov, Dennis Yang, Maan El Halabi, Omid Sanaei, Olaya Isabella Brewer Gutierrez, Robert Stephen Bulat, John Pandolfino, Mouen Khashab
Journal: Gut (2021)

Objective Although gastric per-oral endoscopic myotomy (G-POEM) is considered a promising technique for the management of refractory gastroparesis, high-quality evidence is limited. We prospectively investigated the efficacy and safety of G-POEM in unselected patients with refractory gastroparesis. Design In five tertiary centres, patients with symptomatic gastroparesis refractory to standard medical therapy and confirmed by impaired gastric emptying were included. The primary endpoint was clinical success, defined as at least one score decrease in Gastroparesis Cardinal Symptom Index (GCSI) with ≥25% decrease in two subscales, at 12 months. GCSI Score and subscales, adverse events (AEs) and 36-Item Short Form questionnaire of quality of life were evaluated at baseline and 1, 3, 6 and 12 months after G-POEM. Gastric emptying study was performed before and 3 months after the procedure. Results Of 80 enrolled patients, 75 patients (94%) completed 12-month follow-up. Clinical success at 12 months was 56% (95% CI, 44.8 to 66.7). GCSI Score (including subscales) improved moderately after G-POEM (p&lt;0.05). In a regression model, a baseline GCSI Score &gt;2.6 (OR=3.23, p=0.04) and baseline gastric retention &gt;20% at 4 hours (OR=3.65, p=0.03) were independent predictors of clinical success at 12 months, as was early response to G-POEM at 1 month after therapy (OR 8.75, p&lt;0.001). Mild procedure-related AEs occurred in 5 (6%) patients. Conclusion G-POEM is a safe procedure, but showed only modest overall effectiveness in the treatment of refractory gastroparesis. Further studies are required to identify the best candidates for G-POEM; unselective use of this procedure should be discouraged. Trial registration number ClinicalTrials.gov Registry NCT02732821 .
Oncotherapeutic Protein Kinase Inhibitors Associated With Pro-Arrhythmic Liability
Authors: Johan Z. Ye, Finn B. Hansen, Robert W. Mills, Alicia Lundby
Journal: JACC CardioOncology (2021)

Ibrutinib is a protein kinase inhibitor that has been widely successful in treating multiple common variations of B-cell cancers. However, an unfortunate side effect of ibrutinib is that it predisposes patients to development of atrial fibrillation.
RNA-seq of human T cells after hematopoietic stem cell transplantation identifies <i>Linc00402</i> as a regulator of T cell alloimmunity
Authors: Daniel Peltier, Molly Radosevich, Visweswaran Ravikumar, Sethuramasundaram Pitchiaya, Thomas Decoville, Sherri C. Wood, Guoqing Hou, Cynthia Zajac, Katherine Oravecz-Wilson, David Sokol, Israel Henig, Julia Wu, Stephanie Kim, Austin Taylor, Hideaki Fujiwara, Yaping Sun, Arvind Rao, Arul M. Chinnaiyan, Daniel R. Goldstein, Pavan Reddy
Journal: Science Translational Medicine (2021)

LncRNAs are differentially expressed by allogeneic antigen-stimulated T cells, and Linc00402 regulates allogeneic T cells.
Assessment of Lymph Node Metastasis in Patients With Gastric Cancer to Identify Those Suitable for Middle Segmental Gastrectomy
Authors: Harbi Khalayleh, Young-Woo Kim, Hong Man Yoon, Keun Won Ryu
Journal: JAMA Network Open (2021)

<h3>Importance</h3> Segmental gastrectomy, a type of function-preserving surgery, is not broadly studied but can improve postoperative function and quality of life among patients with gastric cancer (GC). <h3>Objective</h3> To establish an indication for middle segmental gastrectomy (MSG) as a treatment for middle-body (MB) and high-body (HB) GC. <h3>Design, Setting, and Participants</h3> This cohort study analyzed patients with GC undergoing surgery between January 2000 and December 2015 in the National Cancer Center, Goyang, Korea, a high-volume cancer center with a structured database and accurate long-term follow-up. Inclusion criteria were age 18 to 85 year, histologically proven adenocarcinoma located in the HB or MB, cT1 to cT3 category cancers, curative resection with negative margins performed, and follow-up for at least 3 years. Exclusion criteria were Borrmann type 4 GC, T4 category cancer, neoadjuvant chemotherapy, and a history of other cancers. Data analysis was performed from December 2018 to May 2020. <h3>Exposures</h3> Total or subtotal gastrectomy and LN dissection. <h3>Main Outcome and Measures</h3> The primary outcome was the rate of metastasis at LN stations 2, 4sa, 5, 6, and 11d, which cannot be dissected during MSG. <h3>Results</h3> Among 9952 patients who underwent surgery for GC, 8219 underwent either laparoscopic or open total or subtotal gastrectomy. Seven hundred seventy-three patients (mean [SD] age, 56.21 [12.16] years; 464 men [60.0%]) had GC in the MB or HB of the stomach. Among the 701 patients included in the final analysis after exclusion of the cN2/N3 carcinomas, the mean (SD) age was 56.35 (12.24) years, and 418 (59.6%) were men. The incidence of LN metastasis was 0% at station 5 for cT1-3N0/1M0 cancers, station 4sa for cT1-2N0/1M0 cancers, station 2 for cT1N0/1M0 cancers, station 6 for cT1N1M0 cancers, station 11d for cT1N1M0-cT2N0/1M0 cancers, and station 12a for cT1N0/1M0-T2N1M0 cancers, regardless of size and differentiation. The rates of LN metastasis for cT1N0M0 cancers were 0.3% (1 of 396 LNs) at station 6 and 0.8% (1 of 129 LNs) at station 11d. Tumors 4 cm or smaller were associated with a lower risk of LN metastasis compared with tumors 4.1 cm or larger (odds ratio, 2.10; 95% CI, 1.20-3.67;<i>P</i> = .009), and well-differentiated tumors were associated with lower risk of LN metastasis compared with poorly differentiated tumors (odds ratio, 2.88; 95% CI, 1.45-5.73;<i>P</i> = .002). <h3>Conclusions and Relevance</h3> These findings suggest that MSG with dissection of stations 1, 3, 4sb, 4d, 7, 8a, 9, 11p, and 12a could be done for HB and MB cT1N0/1M0 gastric cancers 4 cm or smaller and well-differentiated cT2N0/1M0 cancers.
P33.06 Utilizing Serum Proteome to Understand Response and Resistance to Immune Checkpoint Inhibitors in Advanced Non-Small Cell Lung Cancer
Authors: Y.K. Chae, J. Park, W. Iams, M. Oh, R. Lentz, H. Roder, J. Roder, S. Asmellash, W.K. Hur, J.Y. Hwang, N. Mohindra, V. Villaflor, A.A. Davis
Journal: Journal of Thoracic Oncology (2021)
Abstract 18572: A Comparison of Contemporary Revascularization Strategies in Diabetics With Multivessel Disease: Insights From the Alberta Provincial Project for Outcomes Assessment in Coronary Heart Disease (APPROACH) Registry
Authors: Jay Shavadia, Colleen Norris, Erik Youngson, Robert Welsh, Kevin R Bainey
Journal: Circulation (2017)

Background: Improved percutaneous coronary intervention (PCI) outcomes have been observed with second-generation drug eluting stents (DES). Limited evaluation of their role in comparison to coronar...
P59.08 THOR: Multi-Ethnic, Open Access Thoracic Cancer Genomics Resource
Authors: J. Alvarez, K.P. Chua, N.L. Sim, M. Abedi, J. Chen, A. Tan, G. Lai, A. Takano, W. Lim, E. Tan, K.H.T. Lim, W. Zhai, D. Tan, A. Skanderup
Journal: Journal of Thoracic Oncology (2021)
JAK selectivity and the implications for clinical inhibition of pharmacodynamic cytokine signalling by filgotinib, upadacitinib, tofacitinib and baricitinib
Authors: Paqui G Traves, Bernard Murray, Federico Campigotto, René Galien, Amy Meng, Julie A Di Paolo
Journal: Annals of the Rheumatic Diseases (2021)

Objective Janus kinase inhibitors (JAKinibs) are efficacious in rheumatoid arthritis (RA) with variable reported rates of adverse events, potentially related to differential JAK family member selectivity. Filgotinib was compared with baricitinib, tofacitinib and upadacitinib to elucidate the pharmacological basis underlying its clinical efficacy and safety. Methods In vitro JAKinib inhibition of signal transducer and activator of transcription phosphorylation (pSTAT) was measured by flow cytometry in peripheral blood mononuclear cells and whole blood from healthy donors and patients with RA following cytokine stimulation of distinct JAK/STAT pathways. The average daily pSTAT and time above 50% inhibition were calculated at clinical plasma drug exposures in immune cells. The translation of these measures was evaluated in ex vivo-stimulated assays in phase 1 healthy volunteers. Results JAKinib potencies depended on cytokine stimulus, pSTAT readout and cell type. JAK1-dependent pathways (interferon (IFN)α/pSTAT5, interleukin (IL)-6/pSTAT1) were among the most potently inhibited by all JAKinibs in healthy and RA blood, with filgotinib exhibiting the greatest selectivity for JAK1 pathways. Filgotinib (200 mg once daily) had calculated average daily target inhibition for IFNα/pSTAT5 and IL-6/pSTAT1 that was equivalent to tofacitinib (5 mg two times per day), upadacitinib (15 mg once daily) and baricitinib (4 mg once daily), with the least average daily inhibition for the JAK2-dependent and JAK3-dependent pathways including IL-2, IL-15, IL-4 (JAK1/JAK3), IFNγ (JAK1/JAK2), granulocyte colony stimulating factor, IL-12, IL-23 (JAK2/tyrosine kinase 2) and granulocyte-macrophage colony-stimulating factor (JAK2/JAK2). Ex vivo pharmacodynamic data from phase 1 healthy volunteers clinically confirmed JAK1 selectivity of filgotinib. Conclusion Filgotinib inhibited JAK1-mediated signalling similarly to other JAKinibs, but with less inhibition of JAK2-dependent and JAK3-dependent pathways, providing a mechanistic rationale for its apparently differentiated efficacy:safety profile.
Extrahepatic Manifestations of Chronic HCV Infection
Authors: Patrice Cacoub, David Saadoun
Journal: New England Journal of Medicine (2021)

Hepatitis C virus infection is associated with nonhepatic diseases, including mixed cryoglobulinemic vasculitis, B-cell lymphoma, cardiovascular diseases, type 2 diabetes, and renal dysfunction. Direct-acting antiviral agents that cure the underlying infection are associated with a reduced incidence of most of these diseases.
Reporting guidelines for clinical trial reports for interventions involving artificial intelligence: the CONSORT-AI extension
Authors: Xiaoxuan Liu, Samantha Cruz Rivera, David Moher, Melanie J. Calvert, Alastair K. Denniston, An-Wen Chan, Ara Darzi, Christopher Holmes, Christopher Yau, Hutan Ashrafian, Jonathan J. Deeks, Lavinia Ferrante di Ruffano, Livia Faes, Pearse A. Keane, Sebastian J. Vollmer, Aaron Y. Lee, Adrian Jonas, Andre Esteva, Andrew L. Beam, An-Wen Chan, Maria Beatrice Panico, Cecilia S. Lee, Charlotte Haug, Christopher J. Kelly, Christopher Yau, Cynthia Mulrow, Cyrus Espinoza, John Fletcher, Dina Paltoo, Elaine Manna, Gary Price, Gary S. Collins, Hugh Harvey, James Matcham, Joao Monteiro, M. Khair ElZarrad, Lavinia Ferrante di Ruffano, Luke Oakden-Rayner, Melissa McCradden, Pearse A. Keane, Richard Savage, Robert Golub, Rupa Sarkar, Samuel Rowley
Journal: Nature Medicine (2020)

Abstract The CONSORT 2010 statement provides minimum guidelines for reporting randomized trials. Its widespread use has been instrumental in ensuring transparency in the evaluation of new interventions. More recently, there has been a growing recognition that interventions involving artificial intelligence (AI) need to undergo rigorous, prospective evaluation to demonstrate impact on health outcomes. The CONSORT-AI (Consolidated Standards of Reporting Trials–Artificial Intelligence) extension is a new reporting guideline for clinical trials evaluating interventions with an AI component. It was developed in parallel with its companion statement for clinical trial protocols: SPIRIT-AI (Standard Protocol Items: Recommendations for Interventional Trials–Artificial Intelligence). Both guidelines were developed through a staged consensus process involving literature review and expert consultation to generate 29 candidate items, which were assessed by an international multi-stakeholder group in a two-stage Delphi survey (103 stakeholders), agreed upon in a two-day consensus meeting (31 stakeholders) and refined through a checklist pilot (34 participants). The CONSORT-AI extension includes 14 new items that were considered sufficiently important for AI interventions that they should be routinely reported in addition to the core CONSORT 2010 items. CONSORT-AI recommends that investigators provide clear descriptions of the AI intervention, including instructions and skills required for use, the setting in which the AI intervention is integrated, the handling of inputs and outputs of the AI intervention, the human–AI interaction and provision of an analysis of error cases. CONSORT-AI will help promote transparency and completeness in reporting clinical trials for AI interventions. It will assist editors and peer reviewers, as well as the general readership, to understand, interpret and critically appraise the quality of clinical trial design and risk of bias in the reported outcomes.
Evaluation of Hospital Cesarean Delivery–Related Profits and Rates in the United States
Authors: Rie Sakai-Bizmark, Michael G. Ross, Dennys Estevez, Lauren E. M. Bedel, Emily H. Marr, Yusuke Tsugawa
Journal: JAMA Network Open (2021)

A high cesarean delivery rate in US hospitals indicates the potential overuse of this procedure; however, underlying causes of the excessive use of cesarean procedures in the US have not been fully understood.To investigate the association between the probability of cesarean delivery at the patient-level and profit per procedure from cesarean deliveries.This observational, cross-sectional study used a nationally representative sample of hospital discharge data from women at low risk for cesarean birth who delivered newborns between 2010 and 2014 in the US. Data were gathered from the Nationwide Readmissions Database from the Healthcare Cost and Utilization Project, compiled by the Agency for Healthcare Research and Quality. Data cleaning and analyses were conducted between August 2019 and May 2020.Hospital-level median value of profits from cesarean deliveries, defined as the difference between the charge and the cost for cesarean delivery calculated for each hospital.Our primary outcome was the individual-level probability of undergoing a cesarean delivery. We examined the association with the hospital-level median value of profits per procedure for cesarean delivery (defined as the difference between the charge and the cost for cesarean delivery) using hierarchical regression models adjusted for patient and hospital characteristics and year-fixed effects.A total of 13 215 853 deliveries were included in our analyses (mean [SE] age, 27.4 [0] years), of which 2 202 632 (16.7%) were cesarean deliveries. After adjusting for potential confounders, pregnant women were more likely to have a cesarean birth when they delivered at hospitals with higher profits per procedure from cesarean deliveries. Women cared for at hospitals with the highest (adjusted odds ratio, 1.08; 95% CI, 1.02-1.14; P = .005) and second-highest profit quartiles (adjusted odds ratio, 1.07; 95% CI, 1.02-1.13; P = .007) had higher probabilities of a cesarean delivery compared with those cared for at hospitals in the lowest profit quartile.In this cross-sectional study of US nationally representative hospital discharge data, hospitals with higher profits per cesarean procedure were associated with an increased probability of delivering newborns through cesarean birth. These findings highlight the potential influence financial incentives play in determining a high cesarean delivery rate in the US.
Chimeric antigen receptor engineered NK cellular immunotherapy overcomes the selection of T-cell escape variant cancer cells
Authors: Maxwell Y Lee, Yvette Robbins, Cem Sievers, Jay Friedman, Houssein Abdul Sater, Paul E Clavijo, Nancy Judd, Edward Tsong, Chris Silvin, Patrick Soon-Shiong, Michelle R Padget, Jeffrey Schlom, James Hodge, Christian Hinrichs, Clint Allen
Journal: Journal for ImmunoTherapy of Cancer (2021)

Background As heterogeneous tumors develop in the face of intact immunity, tumor cells harboring genomic or expression defects that favor evasion from T-cell detection or elimination are selected. For patients with such tumors, T cell-based immunotherapy alone infrequently results in durable tumor control. Methods Here, we developed experimental models to study mechanisms of T-cell escape and demonstrated that resistance to T-cell killing can be overcome by the addition of natural killer (NK) cells engineered to express a chimeric antigen receptor (CAR) targeting programmed death ligand-1 (PD-L1). Results In engineered models of tumor heterogeneity, PD-L1 CAR-engineered NK cells (PD-L1 t-haNKs) prevented the clonal selection of T cell-resistant tumor cells observed with T-cell treatment alone in multiple models. Treatment of heterogenous cancer cell populations with T cells resulted in interferon gamma (IFN-γ) release and subsequent upregulation of PD-L1 on tumor cells that escaped T-cell killing through defects in antigen processing and presentation, priming escape cell populations for PD-L1 dependent killing by PD-L1 t-haNKs in vitro and in vivo. Conclusions These results describe the underlying mechanisms governing synergistic antitumor activity between T cell-based immunotherapy that results in IFN-γ production, upregulation of PD-L1 on T-cell escape cells, and the use of PD-L1 CAR-engineered NK cells to target and eliminate resistant tumor cell populations.
Poly(Glycerol Sebacate) in Biomedical Applications—A Review of the Recent Literature
Authors: Lena Vogt, Florian Ruther, Sahar Salehi, Aldo R. Boccaccini
Journal: Advanced Healthcare Materials (2021)

Poly(glycerol sebacate) (PGS) continues to attract attention for biomedical applications owing to its favorable combination of properties. Conventionally polymerized by a two-step polycondensation of glycerol and sebacic acid, variations of synthesis parameters, reactant concentrations or by specific chemical modifications, PGS materials can be obtained exhibiting a wide range of physicochemical, mechanical, and morphological properties for a variety of applications. PGS has been extensively used in tissue engineering (TE) of cardiovascular, nerve, cartilage, bone and corneal tissues. Applications of PGS based materials in drug delivery systems and wound healing are also well documented. Research and development in the field of PGS continue to progress, involving mainly the synthesis of modified structures using copolymers, hybrid, and composite materials. Moreover, the production of self-healing and electroactive materials has been introduced recently. After almost 20 years of research on PGS, previous publications have outlined its synthesis, modification, properties, and biomedical applications, however, a review paper covering the most recent developments in the field is lacking. The present review thus covers comprehensively literature of the last five years on PGS-based biomaterials and devices focusing on advanced modifications of PGS for applications in medicine and highlighting notable advances of PGS based systems in TE and drug delivery.