tbuckley/cabot-search huggingface dataset:
A randomized phase III trial comparing adjuvant single-agent S1, S-1 with oxaliplatin, and postoperative chemoradiation with S-1 and oxaliplatin in patients with node-positive gastric cancer after D2 resection: the ARTIST 2 trial☆
Authors: S.H. Park, D.H. Lim, T.S. Sohn, J. Lee, D.Y. Zang, S.T. Kim, J.H. Kang, S.Y. Oh, I.G. Hwang, J.H. Ji, D.B. Shin, J.I. Yu, K.-M. Kim, J.Y. An, M.G. Choi, J.H. Lee, S. Kim, J.Y. Hong, J.O. Park, Y.S. Park, H.Y. Lim, J.M. Bae, W.K. Kang
Journal: Annals of Oncology (2020)

Adjuvant chemotherapy and chemoradiotherapy are some of the standards of care for gastric cancer (GC). The Adjuvant chemoRadioTherapy In Stomach Tumors (ARTIST) 2 trial compares two adjuvant chemotherapy regimens and chemoradiotherapy in patients with D2-resected, stage II or III, node-positive GC.The ARTIST 2 compared, in a 1:1:1 ratio, three adjuvant regimens: oral S-1 (40-60 mg twice daily 4 weeks on/2 weeks off) for 1 year, S-1 (2 weeks on/1 week off) plus oxaliplatin 130 mg/m2 every 3 weeks (SOX) for 6 months, and SOX plus chemoradiotherapy 45 Gy (SOXRT). Randomization was stratified according to surgery type (total or subtotal gastrectomy), pathologic stage (II or III), and Lauren histologic classification (diffuse or intestinal/mixed). The primary endpoint was disease-free survival (DFS) at 3 years; a reduction of 33% in the hazard ratio (HR) for DFS with SOX or SOXRT, when compared with S-1, was considered clinically meaningful. The trial is registered at clinicaltrials.gov (NCT0176146).A total of 546 patients were recruited between February 2013 and January 2018 with 182, 181, and 183 patients in the S-1, SOX, and SOXRT arms, respectively. Median follow-up period was 47 months, with 178 DFS events observed. Estimated 3-year DFS rates were 64.8%, 74.3%, and 72.8% in the S-1, SOX, and SOXRT arms, respectively. HR for DFS in the control arm (S-1) was shorter than that in the SOX and SOXRT arms: S-1 versus SOX, 0.692 (P = 0.042) and S-1 versus SOXRT, 0.724 (P = 0.074). No difference in DFS was found between SOX and SOXRT (HR 0.971; P = 0.879). Adverse events were as anticipated in each arm, and were generally well-tolerated and manageable.In patients with curatively D2-resected, stage II/III, node-positive GC, adjuvant SOX or SOXRT was effective in prolonging DFS, when compared with S-1 monotherapy. The addition of radiotherapy to SOX did not significantly reduce the rate of recurrence after D2 gastrectomy.
Bile Salts for the Treatment of Heart Failure: Out on a Limb for a Gut Feeling?⁎⁎Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
Authors: James M. McCabe, John R. Teerlink
Journal: Journal of the American College of Cardiology (2012)
18458 Immune Prognostic Index as a predictor of survival in patients with metastatic melanoma treated with immune checkpoint inhibitors
Authors: Igor Stukalin, Aleksi Suo, Isabelle A. Vallerand, Ryan Lewinson, Daniel Y.C. Heng, D. Gwyn Bebb, Don G. Morris, Tina Cheng
Journal: Journal of the American Academy of Dermatology (2020)
Financial Presentation of Alzheimer Disease and Related Dementias
Authors: Lauren Hersch Nicholas, Kenneth M. Langa, Julie P. W. Bynum, Joanne W. Hsu
Journal: JAMA Internal Medicine (2020)

<h3>Importance</h3> Alzheimer disease and related dementias (ADRD), currently incurable neurodegenerative diseases, can threaten patients' financial status owing to memory deficits and changes in risk perception. Deteriorating financial capabilities are among the earliest signs of cognitive decline, but the frequency and extent of adverse financial events before and after diagnosis have not been characterized. <h3>Objectives</h3> To describe the financial presentation of ADRD using administrative credit data. <h3>Design, Setting, and Participants</h3> This retrospective secondary data analysis of consumer credit report outcomes from 1999 to 2018 linked to Medicare claims data included 81 364 Medicare beneficiaries living in single-person households. <h3>Exposures</h3> Occurrence of adverse financial events in those with vs without ADRD diagnosis and time of adverse financial event from ADRD diagnosis. <h3>Main Outcomes and Measures</h3> Missed payments on credit accounts (30 or more days late) and subprime credit scores. <h3>Results</h3> Overall, 54 062 (17 890 [33.1%] men; mean [SD] age, 74 [7.3] years) were never diagnosed with ADRD during the sample period and 27 302 had ADRD for at least 1 quarter of observation (8573 [31.4%] men; mean [SD] age, 79.4 [7.5] years). Single Medicare beneficiaries diagnosed with ADRD were more likely to miss payments on credit accounts as early as 6 years prior to diagnosis compared with demographically similar beneficiaries without ADRD (7.7% vs 7.3%; absolute difference, 0.4 percentage points [pp]; 95% CI, 0.07-0.70:) and to develop subprime credit scores 2.5 years prior to diagnosis (8.5% vs 8.1%; absolute difference, 0.38 pp; 95% CI, 0.04-0.72). By the quarter after diagnosis, patients with ADRD remained more likely to miss payments than similar beneficiaries who did not develop ADRD (7.9% vs 6.9%; absolute difference, 1.0 pp; 95% CI, 0.67-1.40) and more likely to have subprime credit scores than those without ADRD (8.2% vs 7.5%; absolute difference, 0.70 pp; 95% CI, 0.34-1.1). Adverse financial events were more common among patients with ADRD in lower-education census tracts. The patterns of adverse events associated with ADRD were unique compared with other medical conditions (eg, glaucoma, hip fracture). <h3>Conclusions and Relevance</h3> Alzheimer disease and related dementias were associated with adverse financial events years prior to clinical diagnosis that become more prevalent after diagnosis and were most common in lower-education census tracts.
Pfizer considers appeal over Viagra ruling
Authors: Roger Dobson
Journal: BMJ (2000)

Pfizer is considering launching an appeal against a court ruling in London that removed patent protection from a key ingredient in Viagra. The patent on Viagra as a compound remains in place, but the patent covering the use of the phosphodiesterase 5 (PDE 5) inhibitor in the treatment of male erectile dysfunction has been overturned.

The court ruling that Viagra had no general patent protection on the PDE 5 inhibitor is seen …
Dynamics of the bacterial gut microbiota during controlled human infection with <i>Necator americanus</i> larvae
Authors: Q. R. Ducarmon, M. A. Hoogerwerf, J. J. Janse, A. R. Geelen, J. P. R. Koopman, R. D. Zwittink, J. J. Goeman, E. J. Kuijper, M. Roestenberg
Journal: Gut Microbes (2020)

Hookworms are soil-transmitted helminths that use immune-evasive strategies to persist in the human duodenum where they are responsible for anemia and protein loss. Given their location and immune regulatory effects, hookworms likely impact the bacterial microbiota. However, microbiota studies struggle to deconvolute the effect of hookworms from confounders such as coinfections and malnutrition. We thus used an experimental human hookworm infection model to explore temporal changes in the gut microbiota before and during hookworm infection. Volunteers were dermally exposed to cumulative dosages of 50, 100 or 150 L3 Necator americanus larvae. Fecal samples were collected for microbiota profiling through 16S rRNA gene amplicon sequencing at weeks zero, four, eight, fourteen and twenty. During the acute infection phase (trial week zero to eight) no changes in bacterial diversity were detected. During the established infection phase (trial week eight to twenty), bacterial richness (Chao1, p = .0174) increased significantly over all volunteers. No relation was found between larval dosage and diversity, stability or relative abundance of individual bacterial taxa. GI symptoms were associated with an unstable microbiota during the first eight weeks and rapid recovery at week twenty. Barnesiella, amongst other taxa, was more abundant in volunteers with more GI symptoms throughout the study. In conclusion, this study showed that clinical GI symptoms following N. americanus infection are associated with temporary microbiota instability and relative abundance of specific bacterial taxa. These results suggest a possible role of hookworm-induced enteritis on microbiota stability.
Abstract 15017: Patient-Specific Mapping of Left Atrial Thrombosis Risk by Computational Fluid Dynamics
Authors: Manuel Garcia-Villalba, Lorenzo Rossini, Alejandro Gonzalo, Davis Vigneault, Andrew M Kahn, Oscar Flores, Elliot McVeigh, Juan Carlos del Alamo de Pedro
Journal: Circulation (2018)

Introduction: Atrial fibrillation is associated with increased risk of thrombus formation, especially in the left atrial appendage (LAA). This is thought to occur at least in part be due to abnorma...
Abstract PO-005: Tet2 inactivation enhances the anti-tumor efficiency of tumor-infiltrating lymphocytes (TILs)
Authors: Minjung Lee, Jiangfang Li, Shaohai Fang, Wei Han, Margarita Moczygemba, Yubin Zhou, Jia Li, Deqiang Sun, Yun Huang
Journal: Cancer Research (2020)

Abstract Inactivation of tumor infiltrating lymphocytes (TILs) is one of the mechanisms mitigating anti-tumor immunity during tumor onset and progression. Epigenetic abnormalities are regarded as a major culprit contributing to the dysfunction of TILs within tumor microenvironments. In this study, we used a murine model of melanoma to discover that Tet2 inactivation significantly enhances the anti-tumor activity of TILs, with the efficacy comparable to immune checkpoint inhibition imposed by anti-PD-L1 treatment. Single-cell RNA-seq analysis further revealed that Tet2-deficient TILs exhibit effector-like features. Transcriptomic and ATAC-seq analysis further demonstrated that Tet2 deletion reshapes the chromatin accessibility and favors the binding of transcription factors geared toward CD8+ T cell activation. In summary, our study establishes that Tet2 constitutes one of the epigenetic barriers contributing to dysfunction of TILs, and that Tet2 inactivation could benefit anti-tumor immunity to boost tumor suppression. Citation Format: Minjung Lee, Jiangfang Li, Shaohai Fang, Wei Han, Margarita Moczygemba, Yubin Zhou, Jia Li, Deqiang Sun, Yun Huang. Tet2 inactivation enhances the anti-tumor efficiency of tumor-infiltrating lymphocytes (TILs) [abstract]. In: Abstracts: AACR Special Virtual Conference on Epigenetics and Metabolism; October 15-16, 2020; 2020 Oct 15-16. Philadelphia (PA): AACR; Cancer Res 2020;80(23 Suppl):Abstract nr PO-005.
4MO Machine learning intratumoral and peritumoral magnetic resonance imaging radiomics for predicting disease-free survival in patients with early-stage breast cancer (RBC-01 Study)
Authors: W. Ren, Y. Yu, Y. Tan, Y. Chen, J. Liu, Z. He, A. Li, J. Ma, N. Lu, C. Li, X. Li, Q. Ou, K. Chen, Q. Hu, J. Ouyang, F. Su, C. Xie, E. Song, H. Yao
Journal: Annals of Oncology (2020)
circPARD3 drives malignant progression and chemoresistance of laryngeal squamous cell carcinoma by inhibiting autophagy through the PRKCI-Akt-mTOR pathway
Authors: Wei Gao, Huina Guo, Min Niu, Xiwang Zheng, Yuliang Zhang, Xuting Xue, Yunfeng Bo, Xiaoya Guan, Zhongxun Li, Yujia Guo, Long He, Yu Zhang, Li Li, Jimin Cao, Yongyan Wu
Journal: Molecular Cancer (2020)

Laryngeal squamous cell carcinoma (LSCC) is the second most common malignant tumor in head and neck. Autophagy and circular RNAs (circRNAs) play critical roles in cancer progression and chemoresistance. However, the function and mechanism of circRNA in autophagy regulation of LSCC remain unclear. The autophagy-suppressive circRNA circPARD3 was identified via RNA sequencing of 107 LSCC tissues and paired adjacent normal mucosal (ANM) tissues and high-content screening. RT-PCR, Sanger sequencing, qPCR and fluorescence in situ hybridization were performed to detect circPARD3 expression and subcellular localization. Biological functions of circPARD3 were assessed by proliferation, migration, invasion, autophagic flux, and chemoresistance assays using in vitro and in vivo models. The mechanism of circPARD3 was investigated by RNA immunoprecipitation, RNA pulldown, luciferase reporter assays, western blotting and immunohistochemical staining. Autophagy was inhibited in LSCC, and circPARD3 was upregulated in the LSCC tissues (n = 100, p < 0.001). High circPARD3 level was associated with advanced T stages (p < 0.05), N stages (p = 0.001), clinical stages (p < 0.001), poor differentiation degree (p = 0.025), and poor prognosis (p = 0.002) of LSCC patients (n = 100). Functionally, circPARD3 inhibited autophagy and promoted LSCC cell proliferation, migration, invasion and chemoresistance. We further revealed that activation of the PRKCI-Akt-mTOR pathway through sponging miR-145-5p was the main mechanism of circPARD3 inhibited autophagy, promoting LSCC progression and chemoresistance. Our study reveals that the novel autophagy-suppressive circPARD3 promotes LSCC progression and chemoresistance through the PRKCI-Akt-mTOR pathway, providing new insights into circRNA-mediated autophagy regulation and potential biomarker and target for LSCC treatment.
New global physical activity guidelines for a more active and healthier world: the WHO Regional Offices perspective
Authors: Riitta-Maija Hämäläinen, João Breda, Fabio da Silva Gomes, Gyanendra Gongal, Wasiq Khan, Romeu Mendes, Leo Nederveen, Nivo Ramanandraibe, Binta Sako, Stephen Whiting
Journal: British Journal of Sports Medicine (2020)

The WHO Global Action Plan on Physical Activity 2018–2030: more active people for a healthier world (GAPPA)1 was launched in 2018 to support countries to achieve a 15% relative reduction in prevalence of insufficient physical activity (PA) by 2030. GAPPA has raised awareness of the need for a whole-of-society response and a systems-based approach to achieve a paradigm shift in supporting all people to be physically active across the life course. Updating the WHO global PA guidelines was a key proposed action of this plan and requested by WHO Member States in the 2018 World Health Assembly.

Guidelines are an important part of PA policy development. Implementing evidence-based PA guidelines can improve health outcomes at individual and population levels. For example, specific recommendations can help health professionals to assess PA and sedentary behaviour as a vital sign and provide counselling towards more physical active lifestyle to their patients in the primary care. More broadly, guidelines are essential tools for conducting monitoring and surveillance of PA and to help policymakers develop optimal policies and programmes to improve public health.1 However, the existence of PA guidelines at global level, or even national level, is alone unlikely to …
Hormonal contraception and the risk of severe asthma exacerbation: 17-year population-based cohort study
Authors: Bright I Nwaru, Holly Tibble, Syed A Shah, Rebecca Pillinger, Susannah McLean, Dermot P Ryan, Hilary Critchley, David B Price, Catherine M Hawrylowicz, Colin R Simpson, Ireneous N Soyiri, Francis Appiagyei, Aziz Sheikh
Journal: Thorax (2020)

Background Longitudinal studies investigating impact of exogenous sex steroids on clinical outcomes of asthma in women are lacking. We investigated the association between use of hormonal contraceptives and risk of severe asthma exacerbation in reproductive-age women with asthma. Methods We used the Optimum Patient Care Research Database, a population-based, longitudinal, anonymised primary care database in the UK, to construct a 17-year (1 January 2000–31 December 2016) retrospective cohort of reproductive-age (16–45 years, n=83 084) women with asthma. Using Read codes, we defined use, subtypes and duration of use of hormonal contraceptives. Severe asthma exacerbation was defined according to recommendations of the European Respiratory Society/American Thoracic Society as asthma-related hospitalisation, accident and emergency department visits due to asthma and/or oral corticosteroid prescriptions. Analyses were done using multilevel mixed-effects Poisson regression with QR decomposition. Results The 17-year follow-up resulted in 456 803 person-years of follow-up time. At baseline, 34% of women were using any hormonal contraceptives, 25% combined (oestrogen/progestogen) and 9% progestogen-only contraceptives. Previous (incidence rate ratio (IRR) 0.94, 95% CI 0.92 to 0.97) and current (IRR 0.96, 95% CI 0.94 to 0.98) use of any, previous (IRR 0.92, 95% CI 0.87 to 0.97) and current use of combined (IRR 0.93, 95% CI 0.91 to 0.96) and longer duration of use (3–4 years: IRR 0.94, 95% CI 0.92 to 0.97; 5+ years: IRR 0.91, 95% CI 0.89 to 0.93) of hormonal contraceptives, but not progestogen-only contraceptives, were associated with reduced risk of severe asthma exacerbation compared with non-use. Conclusions Use of hormonal contraceptives may reduce the risk of severe asthma exacerbation in reproductive-age women. Mechanistic studies investigating the biological basis for the influence of hormonal contraceptives on clinical outcomes of asthma in women are required. Protocol registration number European Union electronic Register of Post-Authorisation Studies (EUPAS22967).
Detecting COVID-19 infection hotspots in England using large-scale self-reported data from a mobile application: a prospective, observational study
Authors: Thomas Varsavsky, Mark S Graham, Liane S Canas, Sajaysurya Ganesh, Joan Capdevila Pujol, Carole H Sudre, Benjamin Murray, Marc Modat, M Jorge Cardoso, Christina M Astley, David A Drew, Long H Nguyen, Tove Fall, Maria F Gomez, Paul W Franks, Andrew T Chan, Richard Davies, Jonathan Wolf, Claire J Steves, Tim D Spector, Sebastien Ourselin
Journal: The Lancet Public Health (2020)
15910 Efficacy and safety of long-term tildrakizumab for plaque psoriasis: 4-year results from reSURFACE 2
Authors: Richard G. Langley, Melinda Gooderham, Kim Alexander Papp, Paul Yamauchi, Diamant Thaci, Jeff Parno, Alan M. Mendelsohn, Stephen J. Rozzo, Alan Menter
Journal: Journal of the American Academy of Dermatology (2020)
Using Bayesian Methods to Augment the Interpretation of Critical Care Trials. An Overview of Theory and Example Reanalysis of the Alveolar Recruitment for Acute Respiratory Distress Syndrome Trial
Authors: Fernando G. Zampieri, Jonathan D. Casey, Manu Shankar-Hari, Frank E. Harrell, Michael O. Harhay
Journal: American Journal of Respiratory and Critical Care Medicine (2020)

Most randomized trials are designed and analyzed using frequentist statistical approaches such as null hypothesis testing and
16899 Use of facial care products and frontal fibrosing alopecia: Is it coincidence or true association?
Authors: Kanchalit Thanomkitti, Waroonphan Leecharoen, Rattapon Tuangthong, Supenya Varothai, Daranporn Triwongwaranat, Kanokvalai Kulthanan, Sukhum Jiamton
Journal: Journal of the American Academy of Dermatology (2020)
GPs call for partners to receive same pay rise as salaried colleagues
Authors: Abi Rimmer
Journal: BMJ (2020)

The BMA’s General Practitioners Committee (GPC) in England should negotiate a pay rise for all GPs of at least 2.8%, backdated to April 2020, doctors have said.

Delegates at the annual LMC England conference, held online on 27 November, voted in favour of a motion which said that any deal where employees received a pay rise with no additional funding for their employer was a failure.

In July this year …
Ubiquitin dependent degradation of cyclin D1 occurs via distinct nuclear and cytoplasmic pathways in MCF-7 breast cancer cells treated with the histone deacetylase inhibitor trichostatin A
Authors: John Patrick Alao, Alexandra V. Stavropoulou, Eric W.-F. Lam, R. Charles Coombes, David M. Vigushin
Journal: Cancer Research (2005)

2274  Glycogen synthase kinase (GSK) 3β has been reported to migrate into the nucleus where it phosphorylates CDK4/6-bound cyclin D1 on threonine residue 286 (T286) resulting in the enhanced ubiquitylation, nuclear export and subsequent degradation of cyclin D1 within the cytoplasm. Mutant cyclin D1 in which the T286 residue has been replaced with alanine (T286A) is sequestered in the nucleus and is refractory to GSK3β mediated nuclear export. Nevertheless, constitutively nuclear cyclin D1 variants lacking the C-terminal regulatory domain have been shown by others not to demonstrate enhanced stability. These observations suggest that cyclin D1 regulation at the post-translational level is more complex than previously thought and may not necessarily be dependent on GSK3β. We have previously reported that the histone deacetylase inhibitor trichostatin A (TSA) promotes the ubiquitin dependent proteasomal degradation of cyclin D1 in MCF-7 cells. In this study, we set out to determine if GSK3β dependent phosphorylation on T286 and subsequent nuclear export is required for the rapid ubiquitin dependent proteolysis of cyclin D1 induced by TSA. In MCF-7 cells transiently expressing GFP-cyclin D1, co-treatment with TSA and the proteasomal inhibitor MG132 resulted in the increased nuclear exclusion of the recombinant protein. T286A but not T288A mutation abolished this effect, although wild type and mutant GFP-cyclin D1 were still subject to ubiquitin dependent degradation. Inactivation of GSK3β by siRNA or SB216763 only partially inhibited the rapid TSA induced degradation of endogenous cyclin D1. In contrast, proteasomal inhibition effectively abolished the cyclin D1 degradation response to TSA. Cyclin D1 was still rapidly degraded following inhibition of protein synthesis with cycloheximide despite pharmacological inhibition of GSK3β. However, leptomycin B, an inhibitor of CRM1 dependent nuclear export, did not affect the rate of degradation of the cyclin in cycloheximide treated cells. Based on our observations, we conclude that T286 phosphorylation by GSK3β enhances but is not essential for the TSA induced ubiquitin dependent degradation of cyclin D1 in MCF-7 cells. Our findings suggest that GSK3β induced nuclear export is only a partial requirement for cyclin D1 degradation in MCF-7 cells and demonstrate that the nuclear and cytoplasmic degradation of cyclin D1 occurs via distinct pathways. E.W.-F. Lam is supported by Cancer Research UK
Coronavirus disease 2019 outcomes among patients with rheumatic diseases 6 months into the pandemic
Authors: Naomi Serling-Boyd, Kristin M D’Silva, Tiffany YT Hsu, Rachel Wallwork, Xiaoqing Fu, Ellen M Gravallese, April M Jorge, Yuqing Zhang, Hyon Choi, Jeffrey A Sparks, Zachary S Wallace
Journal: Annals of the Rheumatic Diseases (2020)

Objective In earlier studies, patients with rheumatic and musculoskeletal disease (RMD) who got infected with COVID-19 had a higher risk of mechanical ventilation than comparators. We sought to determine COVID-19 outcomes among patients with RMD 6 months into the pandemic. Methods We conducted a cohort study at Mass General Brigham in Boston, Massachusetts, of patients with RMD matched to up to five comparators by age, sex and COVID-19 diagnosis date (between 30 January 2020 and 16 July 2020) and followed until last encounter or 18 August 2020. COVID-19 outcomes were compared using Cox regression. Risk of mechanical ventilation was compared in an early versus a recent cohort of patients with RMD. Results We identified 143 patients with RMD and with COVID-19 (mean age 60 years; 76% female individuals) and 688 comparators (mean age 59 years; 76% female individuals). There were no significantly higher adjusted risks of hospitalisation (HR: 0.87, 95% CI: 0.68–1.11), intensive care unit admission (HR: 1.27, 95% CI: 0.86–1.86), or mortality (HR: 1.02, 95% CI: 0.53–1.95) in patients with RMD versus comparators. There was a trend towards a higher risk of mechanical ventilation in the RMD cohort versus comparators, although not statistically significant (adjusted HR: 1.51, 95% CI: 0.93–2.44). There was a trend towards improvement in mechanical ventilation risk in the recent versus early RMD cohort (10% vs 19%, adjusted HR: 0.44, 95% CI: 0.17–1.12). Conclusions Patients with RMD and comparators had similar risks of poor COVID-19 outcomes after adjusting for race, smoking and comorbidities. The higher risk of mechanical ventilation in the early RMD cohort was no longer detected in a recent cohort, suggesting improved management over time.