tbuckley/cabot-search huggingface dataset:
SHP2 inhibition diminishes KRASG12C cycling and promotes tumor microenvironment remodeling
Authors: Carmine Fedele, Shuai Li, Kai Wen Teng, Connor J.R. Foster, David Peng, Hao Ran, Paolo Mita, Mitchell J. Geer, Takamitsu Hattori, Akiko Koide, Yubao Wang, Kwan Ho Tang, Joshua Leinwand, Wei Wang, Brian Diskin, Jiehui Deng, Ting Chen, Igor Dolgalev, Ugur Ozerdem, George Miller, Shohei Koide, Kwok-Kin Wong, Benjamin G. Neel
Journal: The Journal of Experimental Medicine (2020)

KRAS is the most frequently mutated human oncogene, and KRAS inhibition has been a longtime goal. Recently, inhibitors were developed that bind KRASG12C-GDP and react with Cys-12 (G12C-Is). Using new affinity reagents to monitor KRASG12C activation and inhibitor engagement, we found that an SHP2 inhibitor (SHP2-I) increases KRAS-GDP occupancy, enhancing G12C-I efficacy. The SHP2-I abrogated RTK feedback signaling and adaptive resistance to G12C-Is in vitro, in xenografts, and in syngeneic KRASG12C-mutant pancreatic ductal adenocarcinoma (PDAC) and non-small cell lung cancer (NSCLC). SHP2-I/G12C-I combination evoked favorable but tumor site-specific changes in the immune microenvironment, decreasing myeloid suppressor cells, increasing CD8+ T cells, and sensitizing tumors to PD-1 blockade. Experiments using cells expressing inhibitor-resistant SHP2 showed that SHP2 inhibition in PDAC cells is required for PDAC regression and remodeling of the immune microenvironment but revealed direct inhibitory effects on tumor angiogenesis and vascularity. Our results demonstrate that SHP2-I/G12C-I combinations confer a substantial survival benefit in PDAC and NSCLC and identify additional potential combination strategies.
Randomized Phase III KEYNOTE-181 Study of Pembrolizumab Versus Chemotherapy in Advanced Esophageal Cancer
Authors: Takashi Kojima, Manish A. Shah, Kei Muro, Eric Francois, Antoine Adenis, Chih-Hung Hsu, Toshihiko Doi, Toshikazu Moriwaki, Sung-Bae Kim, Se-Hoon Lee, Jaafar Bennouna, Ken Kato, Lin Shen, Peter Enzinger, Shu-Kui Qin, Paula Ferreira, Jia Chen, Gustavo Girotto, Christelle de la Fouchardiere, Helene Senellart, Raed Al-Rajabi, Florian Lordick, Ruixue Wang, Shailaja Suryawanshi, Pooja Bhagia, S. Peter Kang, Jean-Philippe Metges
Journal: Journal of Clinical Oncology (2020)

PURPOSE Patients with advanced esophageal cancer have a poor prognosis and limited treatment options after first-line chemotherapy. PATIENTS AND METHODS In this open-label, phase III study, we randomly assigned (1:1) 628 patients with advanced/metastatic squamous cell carcinoma or adenocarcinoma of the esophagus, that progressed after one prior therapy, to pembrolizumab 200 mg every 3 weeks for up to 2 years or chemotherapy (investigator’s choice of paclitaxel, docetaxel, or irinotecan). Primary end points were overall survival (OS) in patients with programmed death ligand-1 (PD-L1) combined positive score (CPS) ≥ 10, in patients with squamous cell carcinoma, and in all patients (one-sided α 0.9%, 0.8%, and 0.8%, respectively). RESULTS At final analysis, conducted 16 months after the last patient was randomly assigned, OS was prolonged with pembrolizumab versus chemotherapy for patients with CPS ≥ 10 (median, 9.3 v 6.7 months; hazard ratio [HR], 0.69 [95% CI, 0.52 to 0.93]; P = .0074). Estimated 12-month OS rate was 43% (95% CI, 33.5% to 52.1%) with pembrolizumab versus 20% (95% CI, 13.5% to 28.3%) with chemotherapy. Median OS was 8.2 months versus 7.1 months (HR, 0.78 [95% CI, 0.63 to 0.96]; P = .0095) in patients with squamous cell carcinoma and 7.1 months versus 7.1 months (HR, 0.89 [95% CI, 0.75 to 1.05]; P = .0560) in all patients. Grade 3-5 treatment-related adverse events occurred in 18.2% of patients with pembrolizumab versus 40.9% in those who underwent chemotherapy. CONCLUSION Pembrolizumab prolonged OS versus chemotherapy as second-line therapy for advanced esophageal cancer in patients with PD-L1 CPS ≥ 10, with fewer treatment-related adverse events.
Using Data to Achieve Organ Procurement Organization Accountability
Authors: J. Thomas Rosenthal
Journal: JAMA Surgery (2020)

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 Surgery 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 Surgery journal
Correspondence to ‘Normal human enthesis harbours conventional CD4+ and CD8+ T cells with regulatory features and inducible IL-17A and TNF expression’
Authors: Li-Tzu Wang, Kevin Sheng-Kai Ma
Journal: Annals of the Rheumatic Diseases (2020)

Correspondence to 'Normal human enthesis harbours conventional CD4+ and CD8+ T cells with regulatory features and inducible IL-17A and TNF expression'We read with great interest the work by Watad et al, 1 which the authors demonstrated the characterisation of enthesisresident T cells and their corresponding cytokine responses upon stimulation.This commendable work mimicked enthesitis-involved inflammatory pathogenesis of spondyloarthritis, for instance, psoriatic arthritis (PsA).Particularly, the authors proposed that entheseal T cells may secrete interleukin (IL)-17 and much more tumour necrosis factor α (TNF-α) in response to anti-CD3 and anti-CD28 (as suggested in figure 3 by Watad et al 1 ); furthermore, phosphodiesterase 4 (PDE4) inhibitors suppressed the expression of the above mentioned inflammatory cytokines (as suggested in figure 5 by Watad et al 1 ).As PDE4 inhibitors have been used to treat autoimmune diseases and advanced malignancies, 2 we are highly interested in whether infliximab, a neutralised antibody for TNF-α and a widely prescribed biologic disease-modifying antirheumatic drugs for a number of autoimmune diseases, would as well modulate the immunity of entheseal or synovial T cells in patients with PsA in clinical settings.We compared the RNA-sequencing profiles of synovial biopsies from patients with PsA naive to anti-TNF-α agents before and 10 weeks after infliximab treatment registered in the National Center for Biotechnology Information-Gene Expression Omnibus database.Overall, we identified 39 significantly expressed pathways using p value and Z-score visualisation, with 26 pathways up-regulated at a Z-score of above 1, and 13 pathways down-regulated at a Z-score of less than -1 (figure 1).Among the 26 upregulated pathways after infliximab treatment, well-documented immunomodulatory signalling pathways, including adrenomedullin signalling pathway, 3 transforming growth factor-β (TGF-β) signalling and aryl
Pharmacodynamic and Pharmacokinetic Effects of a Low Maintenance Dose Ticagrelor Regimen Versus Standard Dose Clopidogrel in Diabetes Mellitus Patients Without Previous Major Cardiovascular Events Undergoing Elective Percutaneous Coronary Intervention
Authors: Francesco Franchi, Fabiana Rollini, Latonya Been, Maryuri Briceno, Naji Maaliki, Mustafa Wali, Andrea Rivas, Andres M. Pineda, Siva Suryadevara, Daniel Soffer, Martin M. Zenni, Theodore A. Bass, Dominick J. Angiolillo
Journal: Circulation (2020)
Effect of school closures on mortality from coronavirus disease 2019: old and new predictions
Authors: Ken Rice, Ben Wynne, Victoria Martin, Graeme J Ackland
Journal: BMJ (2020)

To replicate and analyse the information available to UK policymakers when the lockdown decision was taken in March 2020 in the United Kingdom.Independent calculations using the CovidSim code, which implements Imperial College London's individual based model, with data available in March 2020 applied to the coronavirus disease 2019 (covid-19) epidemic.Simulations considering the spread of covid-19 in Great Britain and Northern Ireland.About 70 million simulated people matched as closely as possible to actual UK demographics, geography, and social behaviours.Replication of summary data on the covid-19 epidemic reported to the UK government Scientific Advisory Group for Emergencies (SAGE), and a detailed study of unpublished results, especially the effect of school closures.The CovidSim model would have produced a good forecast of the subsequent data if initialised with a reproduction number of about 3.5 for covid-19. The model predicted that school closures and isolation of younger people would increase the total number of deaths, albeit postponed to a second and subsequent waves. The findings of this study suggest that prompt interventions were shown to be highly effective at reducing peak demand for intensive care unit (ICU) beds but also prolong the epidemic, in some cases resulting in more deaths long term. This happens because covid-19 related mortality is highly skewed towards older age groups. In the absence of an effective vaccination programme, none of the proposed mitigation strategies in the UK would reduce the predicted total number of deaths below 200 000.It was predicted in March 2020 that in response to covid-19 a broad lockdown, as opposed to a focus on shielding the most vulnerable members of society, would reduce immediate demand for ICU beds at the cost of more deaths long term. The optimal strategy for saving lives in a covid-19 epidemic is different from that anticipated for an influenza epidemic with a different mortality age profile.
Mobile health tool for monitoring cancer treatment complications.
Authors: Amit Sanyal, James M. Heun, Clemens walter Janssen, Jessica Sweeney
Journal: Journal of Clinical Oncology (2020)

297 Background: Side effects after cancer treatment are ubiquitous, seen in up to 98.3% of patients in one Phase III lymphoma trial. Additionally, cancer patients are at a greater risk of mortality from infections such as coronavirus disease 2019 (COVID-19), prompting recommendations for routine screening. Current care delivery model, reliant on self- triaging of symptoms by patients results in delayed management and avoidable emergency room visits and hospitalizations. Technology based symptom monitoring allows early identification of complications, reduces symptom burden, cost of care and enables early detection of relapse. We studied utility of a mobile-health tool for toxicity monitoring and COVID-19 screening. Methods: We developed an application that periodically delivers disease specific toxicity questionnaires to patients following cancer treatment. Based on NCI- PRO-CTCAE form builder, the questions are delivered through SMS or e-mail. Responses crossing pre-specified thresholds are flagged for manual care team follow-up. Patient and staff experience as well as medical interventions are captured. Results: Currently, 68 patients with different malignancies are enrolled. Median age 60 years (range 24-85), 35 males, 31 females. 72.35% patients rated user experience at 4 or higher (1-5 scale, 5 highest). Aggregate provider rating was 3.25 (1-5 scale, 5 highest). Of 639 captured responses, 157 reported fatigue, 145 no symptoms, 57 nausea/vomiting or diarrhea, 52 numbness/tingling and 48 shortness of breath. 76 responses were flagged for nurse follow-up calls. These resulted in 72 successful outpatient symptom management, 2 hospitalizations for neutropenic fever, 1 MRI diagnosis of radiation necrosis and 1 diagnosis of lymphoma progression. 92% of patients received a follow up within one business day. Median time between response recorded and follow up completed was 55 minutes. Of 1299 responses recorded by COVID-19 screening, 1175 reported no symptoms. All positive responses (47 cough, 52 diarrhea, 5 fever and 20 dyspnea) were false positives. Study is ongoing with recent implementation of a distress screening and survivorship modules. Conclusions: Electronic capture of symptoms using connected technology is feasible and can be used to screen cancer patients for treatment related complications as well as pandemic related illnesses.
Nonimmune Hydrops Fetalis — More Than Meets the Eye?
Authors: Mark D Kilby
Journal: New England Journal of Medicine (2020)

Nonimmune hydrops fetalis (NIHF) has a striking appearance on ultrasonography and is classically defined by the presence of pathologic fluid accumulation in at least two fetal sites, including the serous cavities (pericardial, pleural, and peritoneal), with associated skin edema. Its diagnosis is established by first ruling out maternal red-cell alloimmunization. NIHF occurs in up to 1 in 1700 fetuses and has multiple causes: chromosomal abnormalities, structural malformations (especially cardiac and thoracic), inborn errors of metabolism, and in utero infections.1 The phenotype is usually distinct, but recently, increased nuchal translucency and cystic hygroma during the first trimester have been added to . . .
Effect of resolvins on sensitisation of TRPV1 and visceral hypersensitivity in IBS
Authors: Eluisa Perna, Javier Aguilera-Lizarraga, Morgane V Florens, Piyush Jain, Stavroula A Theofanous, Nikita Hanning, Joris G De Man, Maya Berg, Benedicte De Winter, Yeranddy A Alpizar, Karel Talavera, Pieter Vanden Berghe, Mira Wouters, Guy Boeckxstaens
Journal: Gut (2020)

Objective Resolvins (RvD1, RvD2 and RvE1) are endogenous anti-inflammatory lipid mediators that display potent analgesic properties in somatic pain by modulating transient receptor potential vanilloid 1 (TRPV1) activation. To what extent these molecules could also have a beneficial effect on TRPV1 sensitisation and visceral hypersensitivity (VHS), mechanisms involved in IBS, remains unknown. Design The effect of RvD1, RvD2 and RvE1 on TRPV1 activation and sensitisation by histamine or IBS supernatants was assessed on murine dorsal root ganglion (DRG) neurons using live Ca 2+ imaging. Based on the results obtained in vitro, we further studied the effect of RvD2 in vivo using a murine model of post-infectious IBS and a rat model of post-inflammatory VHS. Finally, we also tested the effect of RvD2 on submucosal neurons in rectal biopsies of patients with IBS. Results RvD1, RvD2 and RvE1 prevented histamine-induced TRPV1 sensitisation in DRG neurons at doses devoid of an analgesic effect. Of note, RvD2 also reversed TRPV1 sensitisation by histamine and IBS supernatant. This effect was blocked by the G protein receptor 18 (GPR18) antagonist O-1918 (3–30 µM) and by pertussis toxin. In addition, RvD2 reduced the capsaicin-induced Ca 2+ response of rectal submucosal neurons of patients with IBS. Finally, treatment with RvD2 normalised pain responses to colorectal distention in both preclinical models of VHS. Conclusions Our data suggest that RvD2 and GPR18 agonists may represent interesting novel compounds to be further evaluated as treatment for IBS.
Covid-19 elimination: should we force our young to sacrifice their freedoms so the older generation can live a bit longer?
Authors: Aodhan S Breathnach
Journal: BMJ (2020)

The debate about the control and possible elimination of covid-19 has focused on costs and harms versus benefits and has tended to overlook ethical questions about who benefits and who pays.The benefits of control measures will mainly apply to the middle aged and elderly, but the cost, in terms of long term economic disruption, unemployment, damaged educational prospects, and psychological illness, will hit the younger generation hardest.Public health policy decisions tend to be made by middle aged and elderly politicians, doctors, and academics; the young are not given a say and are shamed or even criminalised if they do not comply.We would not compel a young person to donate a kidney to an elderly relative, or to have any medical procedure that was not in their own best interests, but public health interventions seem to be in a different moral category: we are happy to force our young to sacrifice their economic, social, and psychological freedoms so that the older generation can live a bit longer.
Evaluation of a pharmacist-led actionable audit and feedback intervention for improving medication safety in UK primary care: An interrupted time series analysis
Authors: Niels Peek, Wouter T. Gude, Richard N. Keers, Richard Williams, Evangelos Kontopantelis, Mark Jeffries, Denham L. Phipps, Benjamin Brown, Anthony J. Avery, Darren M. Ashcroft
Journal: PLoS Medicine (2020)

Background We evaluated the impact of the pharmacist-led Safety Medication dASHboard (SMASH) intervention on medication safety in primary care. Methods and findings SMASH comprised (1) training of clinical pharmacists to deliver the intervention; (2) a web-based dashboard providing actionable, patient-level feedback; and (3) pharmacists reviewing individual at-risk patients, and initiating remedial actions or advising general practitioners on doing so. It was implemented in 43 general practices covering a population of 235,595 people in Salford (Greater Manchester), UK. All practices started receiving the intervention between 18 April 2016 and 26 September 2017. We used an interrupted time series analysis of rates (prevalence) of potentially hazardous prescribing and inadequate blood-test monitoring, comparing observed rates post-intervention to extrapolations from a 24-month pre-intervention trend. The number of people registered to participating practices and having 1 or more risk factors for being exposed to hazardous prescribing or inadequate blood-test monitoring at the start of the intervention was 47,413 (males: 23,073 [48.7%]; mean age: 60 years [standard deviation: 21]). At baseline, 95% of practices had rates of potentially hazardous prescribing (composite of 10 indicators) between 0.88% and 6.19%. The prevalence of potentially hazardous prescribing reduced by 27.9% (95% CI 20.3% to 36.8%, p < 0.001) at 24 weeks and by 40.7% (95% CI 29.1% to 54.2%, p < 0.001) at 12 months after introduction of SMASH. The rate of inadequate blood-test monitoring (composite of 2 indicators) reduced by 22.0% (95% CI 0.2% to 50.7%, p = 0.046) at 24 weeks; the change at 12 months (23.5%) was no longer significant (95% CI −4.5% to 61.6%, p = 0.127). After 12 months, 95% of practices had rates of potentially hazardous prescribing between 0.74% and 3.02%. Study limitations include the fact that practices were not randomised, and therefore unmeasured confounding may have influenced our findings. Conclusions The SMASH intervention was associated with reduced rates of potentially hazardous prescribing and inadequate blood-test monitoring in general practices. This reduction was sustained over 12 months after the start of the intervention for prescribing but not for monitoring of medication. There was a marked reduction in the variation in rates of hazardous prescribing between practices.
Short duration response-guided treatment is effective for most individuals with recent hepatitis C infection: the ATAHC II Study
Authors: Marianne Martinello, Margaret Hellard, David Shaw, Kathy Petoumenos, Tanya L Applegate, Jason Grebely, Barbara Y Yeung, Laurence Maire, David M Iser, Andrew R Lloyd, Alexander J Thompson, Joe Sasadeusz, Paul Haber, Gregory J Dore, Gail Matthews
Journal: Hepatology (2014)
Inter-professional and inter-departmental alcoholism rehabilitation program
Authors: Masahiro Kikuchi, Naomi Matsutani, Ryota Ishihara, Masako Sugihara, Yuuki Mizuno, Chiyo Chiba, Takahiro Ohta, Eri Yamada, Sota Oguro, Yasuko Sato, Hiroki Bessho, Yoshinori Horie
Journal: Clinical and Molecular Hepatology (2020)

A 3-month alcoholism rehabilitation program at psychiatric hospitals is common in Japan for patients with alcohol use disorder (AUD). However, many AUD patients are often hospitalized for the treatment of digestive disorders due to alcohol-related liver diseases and pancreatitis. In this sense, AUD patients need to be better supported by professionals and departments in general hospitals. Here we analyzed the problems in alcohol-related medical care in Japan and examined the measures to be taken at general hospitals.
Exit from germinal center to become quiescent memory B cells depends on metabolic reprograming and provision of a survival signal
Authors: Takeshi Inoue, Ryo Shinnakasu, Chie Kawai, Wataru Ise, Eiryo Kawakami, Nicolas Sax, Toshihiko Oki, Toshio Kitamura, Kazuo Yamashita, Hidehiro Fukuyama, Tomohiro Kurosaki
Journal: The Journal of Experimental Medicine (2020)

A still unanswered question is what drives the small fraction of activated germinal center (GC) B cells to become long-lived quiescent memory B cells. We found here that a small population of GC-derived CD38intBcl6hi/intEfnb1+ cells with lower mTORC1 activity favored the memory B cell fate. Constitutively high mTORC1 activity led to defects in formation of the CD38intBcl6hi/intEfnb1+ cells; conversely, decreasing mTORC1 activity resulted in relative enrichment of this memory-prone population over the recycling-prone one. Furthermore, the CD38intBcl6hi/intEfnb1+ cells had higher levels of Bcl2 and surface BCR that, in turn, contributed to their survival and development. We also found that downregulation of Bcl6 resulted in increased expression of both Bcl2 and BCR. Given the positive correlation between the strength of T cell help and mTORC1 activity, our data suggest a model in which weak help from T cells together with provision of an increased survival signal are key for GC B cells to adopt a memory B cell fate.