tbuckley/cabot-search huggingface dataset:
Hexavalent TRAIL Fusion Protein Eftozanermin Alfa Optimally Clusters Apoptosis-Inducing TRAIL Receptors to Induce On-Target Antitumor Activity in Solid Tumors
Authors: Darren C. Phillips, Fritz G. Buchanan, Dong Cheng, Larry R. Solomon, Yu Xiao, John Xue, Stephen K. Tahir, Morey L. Smith, Haichao Zhang, Deborah Widomski, Vivek C. Abraham, Nan Xu, Zhihong Liu, Li Zhou, Enrico DiGiammarino, Xin Lu, Nandini Rudra-Ganguly, Bruce Trela, Susan E. Morgan-Lappe
Journal: Cancer Research (2021)

TRAIL can activate cell surface death receptors, resulting in potent tumor cell death via induction of the extrinsic apoptosis pathway. Eftozanermin alfa (ABBV-621) is a second generation TRAIL receptor agonist engineered as an IgG1-Fc mutant backbone linked to two sets of trimeric native single-chain TRAIL receptor binding domain monomers. This hexavalent agonistic fusion protein binds to the death-inducing DR4 and DR5 receptors with nanomolar affinity to drive on-target biological activity with enhanced caspase-8 aggregation and death-inducing signaling complex formation independent of FcγR-mediated cross-linking, and without clinical signs or pathologic evidence of toxicity in nonrodent species. ABBV-621 induced cell death in approximately 36% (45/126) of solid cancer cell lines in vitro at subnanomolar concentrations. An in vivo patient-derived xenograft (PDX) screen of ABBV-621 activity across 15 different tumor indications resulted in an overall response (OR) of 29% (47/162). Although DR4 (TNFSFR10A) and/or DR5 (TNFSFR10B) expression levels did not predict the level of response to ABBV-621 activity in vivo, KRAS mutations were associated with elevated TNFSFR10A and TNFSFR10B and were enriched in ABBV-621-responsive colorectal carcinoma PDX models. To build upon the OR of ABBV-621 monotherapy in colorectal cancer (45%; 10/22) and pancreatic cancer (35%; 7/20), we subsequently demonstrated that inherent resistance to ABBV-621 treatment could be overcome in combination with chemotherapeutics or with selective inhibitors of BCL-XL. In summary, these data provide a preclinical rationale for the ongoing phase 1 clinical trial (NCT03082209) evaluating the activity of ABBV-621 in patients with cancer. SIGNIFICANCE: This study describes the activity of a hexavalent TRAIL-receptor agonistic fusion protein in preclinical models of solid tumors that mechanistically distinguishes this molecular entity from other TRAIL-based therapeutics.
FDA Approval Summary: Selumetinib for Plexiform Neurofibroma
Authors: Denise Casey, Suzanne Demko, Arup Sinha, Pallavi S. Mishra-Kalyani, Yuan-li Shen, Sachia Khasar, M. Anwar Goheer, Whitney S. Helms, Lili Pan, Yuan Xu, Jianghong Fan, Ruby Leong, Jiang Liu, Yuching Yang, Katherine Windsor, Mei Ou, Olen Stephens, Byeongtaek Oh, Gregory H. Reaman, Abhilasha Nair, Stacy S. Shord, Vishal Bhatnagar, Selena R. Daniels, Sharon Sickafuse, Kirsten B. Goldberg, Marc R. Theoret, Richard Pazdur, Harpreet Singh
Journal: Clinical Cancer Research (2021)

Abstract On April 10, 2020, the FDA approved selumetinib (KOSELUGO, AstraZeneca) for the treatment of pediatric patients 2 years of age and older with neurofibromatosis type 1 who have symptomatic, inoperable plexiform neurofibromas. Approval was based on demonstration of a durable overall response rate per Response Evaluation in Neurofibromatosis and Schwannomatosis criteria and supported by observed clinical improvements in plexiform neurofibroma–related symptoms and functional impairments in 50 pediatric patients with inoperable plexiform neurofibromas in a single-arm, multicenter trial. The overall reponse rate per NCI investigator assessment was 66% (95% confidence interval, 51–79) with at least 12 months of follow-up. The median duration of response was not reached, and 82% of responding patients experienced duration of response ≥12 months. Clinical outcome assessment endpoints provided supportive efficacy data. Risks of selumetinib are consistent with MAPK (MEK) inhibitor class effects, including ocular, cardiac, musculoskeletal, gastrointestinal, and dermatologic toxicities. Safety was assessed across a pooled database of 74 pediatric patients with plexiform neurofibromas and supported by adult and pediatric selumetinib clinical trial data in cancer indications. The benefit–risk assessment for selumetinib in patients with inoperable plexiform neurofibromas was considered favorable.
Trauma Informed Ethics Consultation
Authors: Elizabeth Lanphier, Uchenna E. Anani
Journal: The American Journal of Bioethics (2021)

We argue for the addition of trauma informed awareness, training, and skill in clinical ethics consultation by proposing a novel framework for Trauma Informed Ethics Consultation (TIEC). This approach expands on the American Society for Bioethics and Humanities (ASBH) framework for, and key insights from feminist approaches to, ethics consultation, and the literature on trauma informed care (TIC). TIEC keeps ethics consultation in line with the provision of TIC in other clinical settings. Most crucially, TIEC (like TIC) is systematically sensitive to culture, history, difference, power, social exclusion, oppression, and marginalization. By engaging a neonatal intensive care ethics consult example, we define our TIEC approach and illustrate its application. Through TIEC we argue it is the role of ethics consultants to not only hold open moral spaces, but to furnish them in morally habitable ways for all stakeholders involved in the ethics consultation process, including patients, surrogates, and practitioners.
Abstract 10569: Prognostic Value of Periatrial Adipose Tissue and Cardiac Sympathetic Nervous System in Atrial Fibrillation Recurrence After Catheter Ablation
Authors: Masato Kawasaki, Takahisa Yamada, Takahisa Morita, Yoshio Furukawa, Shunsuke Tamaki, Yusuke Iwasaki, Atsushi Kikuchi, Tsutomu Kawai, Masahiro Seo, Makoto Abe, Jun Nakamura, Kyouko Yamamoto, Masatsugu Kawahira, Kiyomi Kayama, Kazuya Tanabe, Masatake Fukunami
Journal: Circulation (2018)

Background: Both the periatrial epicardial adipose tissue (EAT) and the disorder of cardiac nervous sympathetic system (CSNS) are known to play an important role in atrial fibrillation (AF) substra...
Annals Graphic Medicine - Time to Speak Up: A Graphical Depiction of Psychological Safety in Health Care Teams
Authors: Nour Houbby, Arwa Hagana, Ridhaa Remtulla, Anannya Menon, Kajal Ruparell, Santhosh Thavarajasingam, Nivaran Aojula
Journal: Annals of Internal Medicine (2021)

Web ExclusivesMarch 2021Annals Graphic Medicine - Time to Speak Up: A Graphical Depiction of Psychological Safety in Health Care TeamsFREENour Houbby, Arwa Hagana, Ridhaa Remtulla, Anannya Menon, Kajal Ruparell, BSc, Santhosh Thavarajasingam, and Nivaran AojulaNour HoubbyImperial College London, London, United Kingdom (N.H., A.H., A.M., K.R., S.T., N.A.)Search for more papers by this author, Arwa HaganaImperial College London, London, United Kingdom (N.H., A.H., A.M., K.R., S.T., N.A.)Search for more papers by this author, Ridhaa RemtullaUniversity of Birmingham, Birmingham, United Kingdom (R.R.)Search for more papers by this author, Anannya MenonImperial College London, London, United Kingdom (N.H., A.H., A.M., K.R., S.T., N.A.)Search for more papers by this author, Kajal Ruparell, BScImperial College London, London, United Kingdom (N.H., A.H., A.M., K.R., S.T., N.A.)Search for more papers by this author, Santhosh ThavarajasingamImperial College London, London, United Kingdom (N.H., A.H., A.M., K.R., S.T., N.A.)Search for more papers by this author, and Nivaran AojulaImperial College London, London, United Kingdom (N.H., A.H., A.M., K.R., S.T., N.A.)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/G20-0059 SectionsAboutVisual AbstractPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Download figure Download PowerPoint Download figure Download PowerPoint Download figure Download PowerPoint Comments0 CommentsSign In to Submit A Comment Author, Article, and Disclosure InformationAffiliations: Imperial College London, London, United Kingdom (N.H., A.H., A.M., K.R., S.T., N.A.)University of Birmingham, Birmingham, United Kingdom (R.R.)Disclosures: Authors have disclosed no conflicts of interest. Forms can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=G20-0059.Author/Illustrator Information: Nour Houbby (e-mail, [email protected]ac.uk); Arwa Hagana (e-mail, arwa.[email protected]ac.uk); Ridhaa Remtulla (e-mail, [email protected]bham.ac.uk); Anannya Menon (e-mail, anannya.[email protected]ac.uk); Kajal Ruparell, BSc (e-mail, kajal.[email protected]ac.uk); Santhosh Thavarajasingam (e-mail, santhosh.[email protected]ac.uk); Nivaran Aojula (e-mail, nivaran.[email protected]ac.uk).This article was published at Annals.org on 9 March 2021. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics March 2021Volume 174, Issue 3Page: W32-W34 ePublished: 9 March 2021 Issue Published: March 2021 Copyright & PermissionsCopyright © 2021 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
The 2021 US Preventive Services Task Force Recommendation on Lung Cancer Screening
Authors: Mayuko Ito Fukunaga, Renda Soylemez Wiener, Christopher G. Slatore
Journal: JAMA Oncology (2021)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Oncology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Oncology journal
Abstract 11689: Inhibition of Angiotensin-converting Enzyme Reduces Bactericidal Immunity of Neutrophils
Authors: Zakir Khan, Jorge Giani, Ellen Bernstein, Luciana C Veiras, Duo-Yao Cao, Suguru Saito, Zhenzi Peng, Derick Okwan, Kenneth E Bernstein
Journal: Circulation (2019)

Angiotensin-converting enzyme (ACE) activity is an important facilitator of the immune response. Here, we study if ACE is important for neutrophil immunity. To examine the effect of ACE inhibition,...
Abstract MP083: Autonomic Imbalance at the Level of Atrioventricular Node, but Not at the Level of Sinus Node, is Associated With Sudden Cardiac Death: The Atherosclerosis Risk in Community Study
Authors: Srini V Mukundan, Muammar M Kabir, Jason Thomas, Golriz Sedaghat, Jonathan W Waks, Nona Sotoodehnia, Wendy S Post, Charles Henrikson, Tor Biering-Sørensen, Scott S Solomon, Elsayed Z Soliman, David S Siscovick, Alfred Buxton, Mark E Josephson, Larisa Tereshchenko
Journal: Circulation (2017)

Introduction: Autonomic imbalance, quantified by decreased heart rate variability (HRV), is associated with increased cardiovascular mortality. It is unknown if autonomic influences on sinus and atrioventricular (AV) nodes are equally important for the risk of sudden cardiac death (SCD). Hypothesis: Autonomic influences on sinus and AV node are equally strongly associated with increased SCD, non-sudden cardiac death (non-SCD), and non-cardiac death. Methods: Baseline visit 10-second ECGs (n=14,250) of the Atherosclerosis Risk in Communities (ARIC) cohort were analyzed. Normalized variance of P-onset to P-onset intervals (PPVN) and QRS-onset to QRS-onset intervals (QQVN) was calculated to assess autonomic influence on sinus and AV node respectively. Normalized variance of Rpeak - Rpeak intervals was determined as HRV measure. Values were log-transformed to normalize distribution. SCD served as primary outcome. Secondary outcomes were non-SCD and non-cardiac death. Three Cox regression models were constructed for dichotomized at 20 th percentile predictor variables. Results: Over median follow-up of 24.4 years, there were 497 SCDs (incidence 1.66 [95%CI 1.52-1.82], 742 non-SCDs (incidence 2.48 [95%CI 2.31-2.67], and 3,753 non-cardiac deaths (incidence 12.6 [95%CI 12.1-13.0]) per 1,000 person-years. In paired analysis, LogPPVN was significantly larger than LogQQVN (-7.28±1.06 vs. -7.72±1.24; P&lt;0.0001). There was no difference between LogQQVN and Log RRVN (-7.72±1.24 vs -7.72±1.23; P=0.364). After full adjustment, LogRRVN and LogQQVN were significantly associated with non-SCD and SCD. Association with non-SCD was stronger. LogPPVN was independently associated with non-SCD but not SCD. No value was associated with non-cardiac death. Conclusion: Autonomic imbalance at the AV node, with likely summary effect at the bundle of His, is associated with SCD and non-SCD. Autonomic imbalance at the SA node is associated with non-SCD only. Autonomic input to SA and AV node should be further studied.
Addiction Screening—The <i>A Star Is Born</i> Movie Series and Destigmatization of Substance Use Disorders
Authors: Benjamin J. Oldfield, Jeanette M. Tetrault, Gretchen Berland
Journal: JAMA (2021)

This Arts and Medicine feature uses the A Star is Born movie series to chart trends in popular cultural representations of addiction and to argue for more authentic Hollywood depictions of substance use disorder.
In high-risk adults, the Moderna vaccine had 94% efficacy against COVID-19 ≥14 d after the 2nd dose
Authors: Zain Chagla
Journal: Annals of Internal Medicine (2021)

Source CitationBaden LR, El Sahly HM, Essink B, et al. Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine. N Engl J Med. 2021;384:403-16. https://pubmed.ncbi.nlm.nih.gov/33378609/AbstractClinical Impact RatingsGIM/FP/GP: Hospitalists: Infectious Disease: Critical Care: Pulmonology:
Covid-19: Female doctors felt compelled to step up during the pandemic, says BMA
Authors: Abi Rimmer
Journal: BMJ (2021)

Apoptosis of tubular epithelial cells contributes to the tubular atrophy that accompanies diabetic nephropathy. Reactive oxygen species (ROS) promote tubular apoptosis, but the mechanisms by which this occurs are incompletely understood. Here, we sought proapoptotic genes that ROS differentially upregulate in renal proximal tubular cells of diabetic (db/db) mice. We performed microarray analysis using total RNA from freshly isolated renal proximal tubules of nondiabetic, diabetic, and diabetic transgenic mice overexpressing catalase in the proximal tubule (thereby attenuating ROS). We observed greater expression of caspase-12 in the proximal tubules of the diabetic mice compared with the nondiabetic and diabetic transgenic mice. Quantitative PCR and immunohistochemistry confirmed the enhanced expression of caspase-12, as well as members of the endoplasmic reticulum stress–induced apoptotic pathway. <i>Ex vivo</i>, albumin induced caspase-12 activity and expression (protein and mRNA) and mRNA expression of the CCAT/enhancer-binding protein homologous protein in freshly isolated wild-type proximal tubules but not in catalase-overexpressing proximal tubules. <i>In vitro</i>, albumin stimulated activity of both caspase-12 and caspase-3 as well as expression of caspase-12 and CCAT/enhancer-binding protein homologous protein in a human proximal tubule cell line (HK-2). The free radical scavenger tiron inhibited these effects. Furthermore, knockdown of caspase-12 with small interfering RNA reduced albumin-induced apoptosis in HK-2 cells. Taken together, these studies demonstrate that albuminuria may induce tubular apoptosis through generation of ROS and the subsequent expression and activation of endoplasmic reticulum stress genes in the diabetic kidney.
The early use of Antibiotics for at Risk CHildren with InfluEnza-like illness (ARCHIE): a double-blind randomised placebo-controlled trial
Authors: Kay Wang, Malcolm G. Semple, Michael Moore, Alastair D. Hay, Sharon Tonner, Ushma Galal, Jenna Grabey, Tricia Carver, Rafael Perera, Ly-Mee Yu, Jill Mollison, Paul Little, Andrew Farmer, Christopher C. Butler, Anthony Harnden
Journal: European Respiratory Journal (2021)

Introduction The UK government stockpiles co-amoxiclav to treat bacterial complications during influenza pandemics. This pragmatic trial examines whether early co-amoxiclav use reduces reconsultation due to clinical deterioration in “at risk” children presenting with influenza-like illness (ILI) in primary or ambulatory care. Methods “At risk” children aged from 6 months to 12 years presenting within 5 days of ILI onset were randomly assigned to oral co-amoxiclav 400/57 or a placebo twice daily for 5 days (dosing based on age±weight). “At risk” groups included children with respiratory, cardiac and neurological conditions. Randomisation was stratified by region and used a non-deterministic minimisation algorithm to balance age and current seasonal influenza vaccination status. Our target sample size was 650 children which would have allowed us to detect a reduction in the proportion of children reconsulting due to clinical deterioration from 40% to 26%, with 90% power and 5% two-tailed alpha error (including allowance for 25% loss to follow-up and an inflation factor of 1.041). Participants, caregivers and investigators were blinded to treatment allocation. Intention-to-treat analysis included all randomised participants with primary outcome data on reconsultation due to clinical deterioration within 28 days. Safety analysis included all randomised participants. Trial registration: ISRCTN 70714783 . EudraCT 2013-002822-21. Results We recruited 271 children between February 11, 2015 and April 20, 2018. Primary outcome data were available for 265 children. Only 61 out of 265 children (23.0%) reconsulted due to clinical deterioration. No evidence of a treatment effect was observed for reconsultation due to clinical deterioration (33 out of 133 for co-amoxiclav (24.8%) and 28 out of 132 (21.2%) for placebo; adjusted risk ratio (RR) 1.16, 95% confidence interval (CI) 0.75–1.80). There was also no evidence of a difference between groups in the proportion of children for whom one or more adverse events (AEs) were reported (32 out of 136 (23.5%) for co-amoxiclav and 22 out of 135 (16.3%) for placebo; adjusted RR 1.45, 95% CI 0.90–2.34). In total, 66 AEs were reported (co-amoxiclav, n=37; placebo, n=29). Nine serious AEs were reported per group, although none were considered related to study medication. Conclusion Our trial did not find evidence that treatment with co-amoxiclav reduces risk of reconsultation due to clinical deterioration in “at risk” children who present early with ILI during influenza season. Our findings therefore do not support early co-amoxiclav use in children with seasonal ILI.
An old weapon with a new function: PIWI-interacting RNAs in neurodegenerative diseases
Authors: Xiaobing Huang, Garry Wong
Journal: Translational Neurodegeneration (2021)

PIWI-interacting RNAs (piRNAs) are small non-coding transcripts that are highly conserved across species and regulate gene expression through pre- and post-transcriptional processes. piRNAs were originally discovered in germline cells and protect against transposable element expression to promote and maintain genome stability. In the recent decade, emerging roles of piRNAs have been revealed, including the roles in sterility, tumorigenesis, metabolic homeostasis, neurodevelopment, and neurodegenerative diseases. In this review, we summarize piRNA biogenesis in C. elegans, Drosophila, and mice, and further elaborate upon how piRNAs mitigate the harmful effects of transposons. Lastly, the most recent findings on piRNA participation in neurological diseases are highlighted. We speculate on the mechanisms of piRNA action in the development and progression of neurodegenerative diseases. Understanding the roles of piRNAs in neurological diseases may facilitate their applications in diagnostic and therapeutic practice.
Trends in Well-Child Visits With Out-of-Pocket Costs in the US Before and After the Affordable Care Act
Authors: Paul R. Shafer, Alex Hoagland, Heather E. Hsu
Journal: JAMA Network Open (2021)

This cross-sectional study uses national claims data to assess trends in well-child care visits with out-of-pocket costs before and after passage of the Affordable Care Act.
Living to Dream—Reply
Authors: Eileen B. Leary, Katie L. Stone, Emmanuel Mignot
Journal: JAMA Neurology (2021)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Neurology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Neurology journal
Part 16: Education, Implementation, and Teams
Authors: Farhan Bhanji, Mary E. Mancini, Elizabeth Sinz, David L. Rodgers, Mary Ann McNeil, Theresa A. Hoadley, Reylon A. Meeks, Melinda Fiedor Hamilton, Peter A. Meaney, Elizabeth A. Hunt, Vinay M. Nadkarni, Mary Fran Hazinski
Journal: Circulation (2010)

Optimizing the links in the Chain of Survival improves outcomes and saves lives. The use of evidence-based education and implementation strategies will allow organizations and communities to strengthen these links in the most effective and efficient manner.
A hotspot mutation in transcription factor IKZF3 drives B cell neoplasia via transcriptional dysregulation
Authors: Gregory Lazarian, Shanye Yin, Elisa ten Hacken, Tomasz Sewastianik, Mohamed Uduman, Alba Font-Tello, Satyen H. Gohil, Shuqiang Li, Ekaterina Kim, Heather Joyal, Leah Billington, Elizabeth Witten, Mei Zheng, Teddy Huang, Mariano Severgnini, Valerie Lefebvre, Laura Z. Rassenti, Catherine Gutierrez, Katia Georgopoulos, Christopher J. Ott, Lili Wang, Thomas J. Kipps, Jan A. Burger, Kenneth J. Livak, Donna S. Neuberg, Fanny Baran-Marszak, Florence Cymbalista, Ruben D. Carrasco, Catherine J. Wu
Journal: Cancer Cell (2021)