tbuckley/cabot-search huggingface dataset:
Prognostic value of tertiary lymphoid structure and tumour infiltrating lymphocytes in oral squamous cell carcinoma
Authors: Qunxing Li, Xiangqi Liu, Dikan Wang, Yanqiong Wang, Huanzi Lu, Shuqiong Wen, Juan Fang, Bin Cheng, Zhi Wang
Journal: International Journal of Oral Science (2020)

Abstract Tertiary lymphoid structures (TLS) are ectopic lymphoid structures in cancers that are largely associated with favourable prognosis. However, the prognostic value of TLSs in oral squamous cell carcinoma (OSCC) is largely unknown, and the association between tumour infiltrating lymphocytes (TILs) and TLSs has been rarely explored in OSCC. In this study, associated markers of TLS, including peripheral node address (PNAd) in high endothelial venules, CD20 in B cells and CD3 in T cells, were examined in 168 OSCC patients, and survival analysis was performed between TLS-positive and TLS-negative cohorts. We detected the presence of TILs by staining CD8+ cytotoxic T cells and CD57+ NK cells as well. TLSs appeared as highly organized structures in 45 (26.8%) cases. TLS-positive patients had a better 5-year overall survival (OS) rate (88.9% vs. 56.1%, P &lt; 0.001) and relapse-free survival (RFS) rate (88.9% vs. 63.4%, P = 0.002). Moreover, the presence of TLS was an independent prognostic factor for both the 5-year OS rate (hazard ratio [HR] = 3.784; 95% confidence interval [CI], 1.498–9.562) and RFS rate (HR = 3.296; 95% CI, 1.279–8.490) in multivariate analysis. Furthermore, a higher density of CD8+ T cells and CD57+ NK cells was found in TLS-positive sections than in TLS-negative counterparts ( P &lt; 0.001), and their combination provided a higher predictive accuracy (AUC = 0.730; 95% CI, 0.654–0.805). In conclusion, our results suggest that TLS is an independent positive prognostic factor for OSCC patients. These findings provide a theoretical basis for the future diagnostic and therapeutic value of TLSs in OSCC treatment.
Effects of once-weekly subcutaneous semaglutide on kidney function and safety in patients with type 2 diabetes: a post-hoc analysis of the SUSTAIN 1–7 randomised controlled trials
Authors: Johannes F E Mann, Thomas Hansen, Thomas Idorn, Lawrence A Leiter, Steven P Marso, Peter Rossing, Jochen Seufert, Sayeh Tadayon, Tina Vilsbøll
Journal: The Lancet Diabetes & Endocrinology (2020)
IL-21 from high-affinity CD4 T cells drives differentiation of brain-resident CD8 T cells during persistent viral infection
Authors: Heather M. Ren, Elizabeth M. Kolawole, Mingqiang Ren, Ge Jin, Colleen S. Netherby-Winslow, Quinn Wade, None Shwetank, Ziaur S. M. Rahman, Brian D. Evavold, Aron E. Lukacher
Journal: Science Immunology (2020)

High-affinity CD4 T cells produce IL-21 to help CD8 T cells differentiate into tissue-resident memory cells in the brain.
Isradipine Versus Placebo in Early Parkinson Disease
Journal: Annals of Internal Medicine (2020)

Studies suggest that dihydropyridine calcium-channel blockers may be associated with reduced risk for Parkinson disease (PD).To assess the effect of isradipine, a dihydropyridine calcium-channel blocker, on the rate of clinical progression of PD.Multicenter, randomized, parallel-group, double-blind, placebo-controlled trial. (ClinicalTrials.gov: NCT02168842).57 Parkinson Study Group sites in North America.Patients with early-stage PD (duration <3 years) who were not taking dopaminergic medications at enrollment.5 mg of immediate-release isradipine twice daily or placebo for 36 months.The primary outcome was change in the Unified Parkinson's Disease Rating Scale (UPDRS) parts I to III score measured in the antiparkinson medication "ON" state between baseline and 36 months. Secondary outcomes included time to initiation and use of antiparkinson medications, time to onset of motor complications, change in nonmotor disability, and quality-of-life measures.336 patients were randomly assigned (mean age, 62 years [SD, 9]; 68% men; disease duration, 0.9 year [SD, 0.7]; mean UPDRS part I to III score, 23.1 [SD, 8.6]); 95% of patients completed the study. Adjusted least-squares mean changes in total UPDRS score in the antiparkinson medication ON state over 36 months for isradipine and placebo recipients were 2.99 (95% CI, 0.95 to 5.03) points versus 3.26 (CI, 1.25 to 5.26) points, respectively, with a treatment effect of -0.27 (CI, -3.02 to 2.48) point (P = 0.85). Statistical adjustment for antiparkinson medication use did not change the findings. Secondary outcomes showed no effect of isradipine treatment. The most common adverse effects of isradipine were edema and dizziness.The isradipine dose may have been insufficient to engage the target calcium channels associated with neuroprotective effects.Long-term treatment with immediate-release isradipine did not slow the clinical progression of early-stage PD.National Institute of Neurological Disorders and Stroke.
Upper Gastrointestinal Bleeding Due to a Peptic Ulcer
Authors: Loren Laine
Journal: New England Journal of Medicine (2016)

Peptic ulcers, often due to Helicobacter pylori or the use of nonsteroidal antiinflammatory drugs (NSAIDs), commonly cause upper gastrointestinal bleeding. Endoscopic therapy, proton-pump inhibitors, therapy for H. pylori infection, and nonuse of NSAIDs are described.
Molecular imaging of Alzheimer’s disease–related gamma-secretase in mice and nonhuman primates
Authors: Yulong Xu, Changning Wang, Hsiao-Ying Wey, Yingxia Liang, Zude Chen, Se Hoon Choi, Chongzhao Ran, Kevin D. Rynearson, Daniela R. Bernales, Robert E. Koegel, Stephanie A. Fiedler, Robin Striar, Steven L. Wagner, Rudolph E. Tanzi, Can Zhang
Journal: The Journal of Experimental Medicine (2020)

The pathogenesis of Alzheimer’s disease (AD) is primarily driven by brain accumulation of the amyloid-β-42 (Aβ42) peptide generated from the amyloid-β precursor protein (APP) via cleavages by β- and γ-secretase. γ-Secretase is a prime drug target for AD; however, its brain regional expression and distribution remain largely unknown. Here, we are aimed at developing molecular imaging tools for visualizing γ-secretase. We used our recently developed γ-secretase modulators (GSMs) and synthesized our GSM-based imaging agent, [11C]SGSM-15606. We subsequently performed molecular imaging in rodents, including AD transgenic animals, and macaques, which revealed that our probe displayed good brain uptake and selectivity, stable metabolism, and appropriate kinetics and distribution for imaging γ-secretase in the brain. Interestingly, rodents and macaques shared certain brain areas with high γ-secretase expression, suggesting a functional conservation of γ-secretase. Collectively, we have provided the first molecular brain imaging of γ-secretase, which may not only accelerate our drug discovery for AD but also advance our understanding of AD.
Testing structural models of psychopathology at the genomic level
Authors: Irwin D. Waldman, Holly E. Poore, Justin M. Luningham, Jingjing Yang
Journal: World Psychiatry (2020)

Genome‐wide association studies (GWAS) have revealed hundreds of genetic loci associated with the vulnerability to major psychiatric disorders, and post‐GWAS analyses have shown substantial genetic correlations among these disorders. This evidence supports the existence of a higher‐order structure of psychopathology at both the genetic and phenotypic levels. Despite recent efforts by collaborative consortia such as the Hierarchical Taxonomy of Psychopathology (HiTOP), this structure remains unclear. In this study, we tested multiple alternative structural models of psychopathology at the genomic level, using the genetic correlations among fourteen psychiatric disorders and related psychological traits estimated from GWAS summary statistics. The best‐fitting model included four correlated higher‐order factors – externalizing, internalizing, thought problems, and neurodevelopmental disorders – which showed distinct patterns of genetic correlations with external validity variables and accounted for substantial genetic variance in their constituent disorders. A bifactor model including a general factor of psychopathology as well as the four specific factors fit worse than the above model. Several model modifications were tested to explore the placement of some disorders – such as bipolar disorder, obsessive‐compulsive disorder, and eating disorders – within the broader psychopathology structure. The best‐fitting model indicated that eating disorders and obsessive‐compulsive disorder, on the one hand, and bipolar disorder and schizophrenia, on the other, load together on the same thought problems factor. These findings provide support for several of the HiTOP higher‐order dimensions and suggest a similar structure of psychopathology at the genomic and phenotypic levels.
Adjuvant nivolumab versus ipilimumab in resected stage IIIB–C and stage IV melanoma (CheckMate 238): 4-year results from a multicentre, double-blind, randomised, controlled, phase 3 trial
Authors: Paolo A Ascierto, Michele Del Vecchio, Mario Mandalá, Helen Gogas, Ana M Arance, Stephane Dalle, C Lance Cowey, Michael Schenker, Jean-Jacques Grob, Vanna Chiarion-Sileni, Iván Márquez-Rodas, Marcus O Butler, Michele Maio, Mark R Middleton, Luis de la Cruz-Merino, Petr Arenberger, Victoria Atkinson, Andrew Hill, Leslie A Fecher, Michael Millward, Nikhil I Khushalani, Paola Queirolo, Maurice Lobo, Veerle de Pril, John Loffredo, James Larkin, Jeffrey Weber
Journal: The Lancet Oncology (2020)
The Importance of Assessing Mental Health Issues and Preventing Suicidality in Studies on Healthy Participants
Authors: Bianca Kollmann, Tanja Darwiesh, Oliver Tüscher, Klaus Lieb
Journal: The American Journal of Bioethics (2020)

Recent studies show that 10% of the general population indicate to have had suicidal thoughts at least once in their life (e.g. Voss et al. 2019, here in adolescents and young adults). Risk for sui...
MMR vaccination and autism 1998
Authors: R Roberts, M R Kiln, J Selway
Journal: BMJ (1998)

Editor—Nichol et al considerably understate their case when they write “chance alone dictates that some cases [of autism] will appear shortly after vaccination.”1 Such a temporal association is unremarkable, given the epidemiology of autism and MMR vaccine. 

Over the time described by Wakefield et al2 MMR vaccine was given to around 600 000 children each year in Britain3 and the prevalence of autistic spectrum disorders was 91/100 000.4

Assuming that the diagnosis of autism is evenly distributed over the second and third years of life and that the incidence over this period approximates to the current prevalence,5 over the eight years that the reported cases represent autism would have been diagnosed in around 364 cases in the two months after MMR vaccination (the time that the authors regard as noteworthy—(((91/100 000) ×600 000)×8)×(2/24)=364). The reported cases therefore represent a fraction of the cases of autism whose onset coincides with the administration of MMR vaccine.
Successful recovery of COVID-19-associated recurrent diarrhea and gastrointestinal hemorrhage using convalescent plasma
Authors: Li-Bo Zhang, Rong-Rong Pang, Qing-Hua Qiao, Zhi-Hua Wang, Xin-Yi Xia, Chang-Jun Wang, Xiao-Li Xu
Journal: Military Medical Research (2020)

Abstract Background Gastrointestinal symptoms are not rare among coronavirus disease 2019 (COVID-19) patients, but there have been no reports regarding convalescent plasma therapy for the recovery of gastrointestinal problems in COVID-19 patients. Case presentation We present two cases of patients with COVID-19-associated recurrent diarrhea and positive fecal occult blood who successfully recovered after a one-time convalescent plasma administration. Conclusion When COVID-19 patients develop recurrent or refractory gastrointestinal symptoms and fail to respond to the available treatment, alternative therapy with convalescent plasma administration may be considered.
Cardiac cellularity is dependent upon biological sex and is regulated by gonadal hormones
Authors: Galen T Squiers, Micheal A McLellan, Alexei Ilinykh, Jane Branca, Nadia A Rosenthal, Alexander R Pinto
Journal: Cardiovascular Research (2020)

Sex differences have been consistently identified in cardiac physiology and incidence of cardiac disease. However, the underlying biological causes for the differences remain unclear. We sought to characterize the cardiac non-myocyte cellular landscape in female and male hearts to determine whether cellular proportion of the heart is sex-dependent and whether endocrine factors modulate the cardiac cell proportions.
Construction of Aptamer‐siRNA Chimera/PEI/5‐FU/Carbon Nanotube/Collagen Membranes for the Treatment of Peritoneal Dissemination of Drug‐Resistant Gastric Cancer
Authors: Wen Chen, Sainan Yang, Xia Wei, Zailin Yang, Dongxu Liu, Xin Pu, Silian He, Yong Zhang
Journal: Advanced Healthcare Materials (2020)

Abstract Due to extensive metastasis, poor blood supply, and drug‐resistant, there is still no effective clinical means to treat peritoneal dissemination of gastric cancer. Here, an aptamer‐siRNA chimera (Chim)/polyethyleneimine (PEI)/5‐fluorouracil (5‐FU)/carbon nanotube (CNT)/collagen membrane is constructed, which could be divided into 15 layers with a thickness of 70–100 µm. Sustained release experiments show that the collagen membranes can control 5‐FU release for more than 2 weeks. Aptamer‐siRNA chimera can specifically bind to gastric cancer cells, enabling targeted delivery of 5‐FU and silencing drug‐resistant gene. In vitro experiments demonstrated that Chim/PEI/5‐FU/CNT nanoparticles promoted the apoptosis of 5‐FU‐resistant gastric cancer cells, inhibited their invasion and proliferation. Animal experiments show that Chim/PEI/5‐FU/CNT/collagen membrane significantly inhibits the expression of mitogen‐activated protein kinase (MAPK), and effectively treats peritoneal dissemination of 5‐FU‐resistant gastric cancer. Compared with siRNA/PEI/5‐FU/CNT group, ki‐67 proliferation index, and matrix metallopeptidase 9 (MMP9) expression are significantly decreased in the Chim/PEI/5‐FU/CNT group, while the proportion of apoptotic cells is markly increased. In conclusion, a chimera/PEI/5‐FU/CNT/collagen membrane is constructed, which can effectively treat peritoneal dissemination of drug‐resistant gastric cancer. The study provides a new therapeutic approach for relevant clinical treatment.
Validation of a survival-risk score (SRS) in relapsed/refractory CLL patients treated with idelalisib–rituximab
Authors: Massimo Gentile, Enrica Antonia Martino, Andrea Visentin, Marta Coscia, Gianluigi Reda, Paolo Sportoletti, Francesca Romana Mauro, Luca Laurenti, Marzia Varettoni, Roberta Murru, Annalisa Chiarenza, Ernesto Vigna, Francesco Mendicino, Eugenio Lucia, Sabrina Bossio, Anna Grazia Recchia, Riccardo Moia, Daniela Pietrasanta, Giacomo Loseto, Ugo Consoli, Ilaria Scortechini, Francesca Maria Rossi, Antonella Zucchetto, Hamdi Al-Janazreh, Candida Vitale, Giovanni Tripepi, Graziella D’Arrigo, Ilaria Angeletti, Riccardo Bomben, Antonino Neri, Giovanna Cutrona, Gilberto Fronza, Francesco Di Raimondo, Gianluca Gaidano, Antonio Cuneo, Robin Foà, Manlio Ferrarini, Livio Trentin, Valter Gattei, Fortunato Morabito
Journal: Blood Cancer Journal (2020)
The COVID-19 Pandemic and the JAMA Network
Authors: Michael Berkwits, Annette Flanagin, Howard Bauchner, Phil B. Fontanarosa
Journal: JAMA (2020)

Journal editors sit at the crossroads of new ideas and findings, deciding which are worth refining and making public in their journals and which are best saved for another time and place.The global arrival of coronavirus disease 2019 (COVID-19) has brought an increase in manuscript submissions describing and evaluating the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and its morbidity and mortality, distilling what seems like years of science and policy into several months.JAMA Network editors were quickly reeducated in principles of epidemiology and public health related to epidemics and pandemics: containment, mitigation, quarantine, case-fatality, transmission coefficients, contact tracing, and whether the then-novel coronavirus was or was not like pandemic influenza.With arrival of the pandemic to the US questions multiplied, about supply chains, rationing, asymptomatic spread, transmission via droplets vs aerosolization, "flattening the curve," telehealth, markers and duration of immunity, health inequities, and clinical concerns of pathophysiology and prospects for treatment and prevention.Since the publication of JAMA's first article responding to the emergence of the novel coronavirus in Hubei province, China, by Fauci and colleagues in January 2020, 1 the JAMA Network journals have received more than 49 000 submissions, a 98% increase over submissions in 2019, and so far have published 777 articles related to COVID-19-including 236 research investigations, 28 reviews, and 395 opinion articles-all free access to the world.In addition, JAMA has interviewed clinicians, public health authorities, and policy experts about the rapidly evolving pandemic on live interviews broadcast onto JAMA's social media channels and published on JAMA Network websites.During this time JAMA Network editors have worked diligently and expeditiously to evaluate, peer review, and guide revisions for manuscripts most likely to inform clinicians, change practice, and improve public health.The work contributed to and is in part fueled by the news cycle as the editors work with investigators and public health authorities to stand up an evidence and policy base for patients, clinicians, families, communities, and governments confronting this new infection.In 13 Viewpoints in this issue, 2-14 JAMA Network editors reflect on the clinical, public health, operational, and workforce issues related to COVID-19 in each of their specialties.Questions and concerns they identify in their clinical communities include the following: • Benefits and harms of treatments and identifying mortality risk markers beyond age and comorbidities • Cardiovascular consequences of COVID-19 infection, including risks to those with comorbid hypertension and risks for myocardial injury
Therapeutic efficacy and safety of a human fusion construct targeting the TWEAK receptor Fn14 and containing a modified granzyme B
Authors: Ana Alvarez de Cienfuegos, Lawrence H Cheung, Khalid A Mohamedali, Timothy G Whitsett, Jeffrey A Winkles, Walter N Hittelman, Michael G Rosenblum
Journal: Journal for ImmunoTherapy of Cancer (2020)

Background Antibody-drug conjugates are an exceptional and useful therapeutic tool for multiple diseases, particularly for cancer treatment. We previously showed that the fusion of the serine protease granzyme B (GrB), the effector molecule or T and B cells, to a binding domain allows the controlled and effective delivery of the cytotoxic payload into the target cell. The production of these constructs induced the formation of high molecular aggregates with a potential impact on the efficacy and safety of the protein. Methods Our laboratory designed a new Fn14 targeted fusion construct designated GrB(C210A)-Fc-IT4 which contains a modified GrB payload for improved protein production and preserved biological activity. We assessed the construct’s enzymatic activity, as well as in vitro cytotoxicity and internalization into target cells. We also assessed pharmacokinetics, efficacy and toxicology parameters in vivo. Results GrB(C210A)-Fc-IT4 protein exhibited high affinity and selective cytotoxicity within the nanomolar range when tested against a panel of Fn14-positive human cancer cell lines. The construct rapidly internalized into target cells, activating the caspase cascade and causing mitochondrial membrane depolarization. Pharmacokinetic studies in mice revealed that GrB(C210A)-Fc-IT4 displayed a bi-exponential clearance from plasma with a fast initial clearance (t 1/2 α=0.36 hour) followed by a prolonged terminal-phase plasma half-life (t 1/2 β=35 hours). Mice bearing MDA-MB-231 orthotopic tumor xenografts treated with vehicle or GrB(C210A)-Fc-IT4 construct (QODx5) demonstrated tumor regression and long-term (&gt;80 days) suppression of tumor growth. Treatment of mice bearing established, subcutaneous A549 lung tumors showed impressive, long-term tumor suppression compared with a control group treated with vehicle alone. Administration of GrB(C210A)-Fc-IT4 (100 mg/kg total dose) was well-tolerated by mice and resulted in significant reduction of tumor burden in a lung cancer patient-derived xenograft model. Toxicity studies revealed no statistically significant changes in aspartate transferase, alanine transferase or lactate dehydrogenase in treated mice. Histopathological analysis of tissues from treated mice did not demonstrate any specific drug-related changes. Conclusion GrB(C210A)-Fc-IT4 demonstrated excellent, specific cytotoxicity in vitro and impressive in vivo efficacy with no significant toxicity in normal murine models. These studies show GrB(C210A)-Fc-IT4 is an excellent candidate for further preclinical development.
Baloxavir Protects Against Household Influenza Spread
Authors: Anita Slomski
Journal: JAMA (2020)

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Covid-19: What’s in a name? Isolating the term “quarantine” from other contamination
Authors: Shyan Goh
Journal: BMJ (2020)

Although “quarantine” and “self-isolation” involve similar measures,1 their purposes are quite different. The World Health Organization states: “The quarantine of persons is the restriction of activities of or the separation of persons who are not ill but who may [have] been exposed to an infectious agent or disease, with the objective of monitoring their symptoms and ensuring the early detection of cases. Quarantine is different from isolation, which is the separation of ill or infected persons from others to …