tbuckley/cabot-search huggingface dataset:
<i>BRAF</i>-Mutant Transcriptional Subtypes Predict Outcome of Combined BRAF, MEK, and EGFR Blockade with Dabrafenib, Trametinib, and Panitumumab in Patients with Colorectal Cancer
Authors: Gary Middleton, Yiqun Yang, Catarina D. Campbell, Thierry André, Chloe E. Atreya, Jan H.M. Schellens, Takayuki Yoshino, Johanna C. Bendell, Antoine Hollebecque, Autumn J. McRee, Salvatore Siena, Michael S. Gordon, Josep Tabernero, Rona Yaeger, Peter J. O'Dwyer, Filip De Vos, Eric Van Cutsem, John M. Millholland, Jan C. Brase, Fatima Rangwala, Eduard Gasal, Ryan B. Corcoran
Journal: Clinical Cancer Research (2020)

Abstract Purpose: The influence of the transcriptional and immunologic context of mutations on therapeutic outcomes with targeted therapy in cancer has not been well defined. BRAF V600E–mutant (BM) colorectal cancer comprises two main transcriptional subtypes, BM1 and BM2. We sought to determine the impact of BM subtype, as well as distinct biological features of those subtypes, on response to BRAF/MEK/EGFR inhibition in patients with colorectal cancer. Patients and Methods: Paired fresh tumor biopsies were acquired at baseline and on day 15 of treatment from all consenting patients with BM colorectal cancer enrolled in a phase II clinical trial of dabrafenib, trametinib, and panitumumab. For each sample, BM subtype, cell cycle, and immune gene signature expression were determined using RNA-sequencing (RNA-seq), and a Cox proportional hazards model was applied to determine association with progression-free survival (PFS). Results: Confirmed response rates, median PFS, and median overall survival (OS) were higher in BM1 subtype patients compared with BM2 subtype patients. Evaluation of immune contexture identified greater immune reactivity in BM1, whereas cell-cycle signatures were more highly expressed in BM2. A multivariate model of PFS incorporating BM subtype plus immune and cell-cycle signatures revealed that BM subtype encompasses the majority of the effect. Conclusions: BM subtype is significantly associated with the outcome of combination dabrafenib, trametinib, and panitumumab therapy and may serve as a standalone predictive biomarker beyond mutational status. Our findings support a more nuanced approach to targeted therapeutic decisions that incorporates assessment of transcriptional context.
Dysbiosis of intestinal microbiota mediates tubulointerstitial injury in diabetic nephropathy via the disruption of cholesterol homeostasis
Authors: Ze Bo Hu, Jian Lu, Pei Pei Chen, Chen Chen Lu, Jia Xiu Zhang, Xue Qi Li, Ben Yin Yuan, Si Jia Huang, Xiong Zhong Ruan, Bi Cheng Liu, Kun Ling Ma
Journal: Theranostics (2020)

Background: Our previous study demonstrated that the disruption of cholesterol homeostasis promotes tubulointerstitial injury in diabetic nephropathy (DN).This study aimed to further investigate the effects of gut microbiota dysbiosis on this process and explored its potential mechanism.Methods: Diabetic rats treated with broad-spectrum oral antibiotics or faecal microbiota transplantation (FMT) from the healthy donor group and human kidney 2 (HK-2) cells stimulated with sodium acetate were used to observe the effects of gut microbiota on cholesterol homeostasis.The gut microbiota distribution was measured by 16S rDNA sequencing with faeces.Serum acetate level was examined by gas chromatographic analysis.Protein expression of G protein coupled receptor 43 (GPR43) and molecules involved in cholesterol homeostasis were assessed by immunohistochemical staining, immunofluorescence staining, and Western Blotting.Results: Depletion of gut microbiota significantly attenuated albuminuria and tubulointerstitial injury.Interestingly, serum acetate levels were also markedly decreased in antibiotics-treated diabetic rats and positively correlated with the cholesterol contents in kidneys.An in vitro study demonstrated that acetate significantly increased cholesterol accumulation in HK-2 cells, which was caused by increased expression of proteins mainly modulating cholesterol synthesis and uptake.As expected, FMT effectively decreased serum acetate levels and alleviated tubulointerstitial injury in diabetic rats through overriding the disruption of cholesterol homeostasis.Furthermore, GPR43 siRNA treatment blocked acetate-mediated cholesterol homeostasis dysregulation in HK-2 cells through decreasing the expression of proteins governed cholesterol synthesis and uptake.Conclusion: Our studies for the first time demonstrated that the acetate produced from gut microbiota mediated the dysregulation of cholesterol homeostasis through the activation of GPR43, thereby contributing to the tubulointerstitial injury of DN, suggesting that gut microbiota reprogramming might be a new strategy for DN prevention and therapy.
Reliability and validity of the Vitiligo Signs of Activity Score (VSAS)
Authors: N. Geel, T. Passeron, A. Wolkerstorfer, R. Speeckaert, K. Ezzedine
Journal: British Journal of Dermatology (2020)

The associations between disease activity and several clinical signs in vitiligo have been described, but a widely accepted and validated scoring system is lacking.To validate the Vitiligo Signs of Activity Score (VSAS) for physicians.Three visible clinical signs were scored on 15 body locations: confetti-like depigmentation (c), Koebner phenomenon (k) and hypochromic areas/borders (h). The inter- and intrarater reliability of the global VSAS and VSAS subscores (c-VSAS, k-VSAS and h-VSAS) were tested by four and three raters (physicians), respectively. Construct validity and feasibility were evaluated.The VSAS demonstrated good inter-rater reliability, with an intraclass correlation coefficient (ICC) of 0·87 in the first round and 0·90 in the second round. The intrarater reliability ICCs were all ≥ 0·86. The inter-rater reliabilities of the subscores were excellent for c-VSAS and fair for k-VSAS and h-VSAS (ICC 0·83, 0·51 and 0·53, respectively, in the first round). Evidence for construct validity was provided. The completion time by the raters (median 2·18 min per patient) improved during the second round (median 1·33 min per patient). A limitation of the study is the low number of patients, mainly of skin phototypes II-III, from a single tertiary centre.The VSAS appears to be a valid and reliable instrument to score visible clinical signs linked to disease activity in a standardized way. What is already known about this topic? Evidence exists for a possible link between several visible clinical signs in vitiligo and disease activity. A widely accepted and validated scoring system to quantify these clinical signs is lacking. What does this study add? The Vitiligo Signs of Activity Score (VSAS) underwent preliminary validation and may assist quantification of visible clinical signs linked to disease activity in a standardized way in clinical practice and trials. What are the clinical implications of this work? VSAS may be used for future trials that aim to establish the clinical significance of the specific visible clinical signs in vitiligo in a more controlled setting. Linked Comment: Eleftheriadou. Br J Dermatol 2020; 183:801-802.
The Use of Sex-Specific Factors in the Assessment of Women’s Cardiovascular Risk
Authors: Anandita Agarwala, Erin D. Michos, Zainab Samad, Christie M. Ballantyne, Salim S. Virani
Journal: Circulation (2020)

Cardiovascular disease (CVD) is the leading cause of death among women in the United States. As compared with men, women are less likely to be diagnosed appropriately, receive preventive care, or be treated aggressively for CVD. Sex differences between men and women have allowed for the identification of CVD risk factors and risk markers that are unique to women. The 2018 American Heart Association/American College of Cardiology Multi-Society cholesterol guideline and 2019 American College of Cardiology/American Heart Association guideline on the primary prevention of CVD introduced the concept of risk-enhancing factors that are specific to women and are associated with an increased risk of incident atherosclerotic CVD in women. These factors, if present, would favor more intensified lifestyle interventions and consideration of initiation or intensification of statin therapy for primary prevention to mitigate the increased risk. In this primer, we highlight sex-specific CVD risk factors in women, stress the importance of eliciting a thorough obstetrical and gynecological history during cardiovascular risk assessment, and provide a framework for how to initiate appropriate preventive measures when sex-specific risk factors are present.
Spatiotemporal single-cell analysis of gene expression in the mouse suprachiasmatic nucleus
Authors: Shao’ang Wen, Danyi Ma, Meng Zhao, Lucheng Xie, Qingqin Wu, Lingfeng Gou, Chuanzhen Zhu, Yuqi Fan, Haifang Wang, Jun Yan
Journal: Nature Neuroscience (2020)
Underexplored Heterogeneity and Publication Bias for the Electronic Cigarette and Marijuana Use Association—Reply
Authors: Nicholas Chadi, Sharon Levy
Journal: JAMA Pediatrics (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 Pediatrics 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 Pediatrics journal
It’s time to act on racism in the NHS
Authors: Victor Adebowale, Mala Rao
Journal: BMJ (2020)

Ethnic minority doctors and patients still face too many injustices in the NHS. The BMJ ’s special issue on racism in medicine (bmj.com/racism-in-medicine) maps some of them and asks how they might be overcome, from the fivefold higher maternal mortality among black women than among white women in the UK (doi:10.1136/bmj.m442; doi:10.1136/bmj.m424) to the gap in performance between white and ethnic minority students and doctors (doi:10.1136/bmj.m438) and the increased likelihood of disciplinary procedures against ethnic minority doctors (doi:10.1136/bmj.m338).

In a joint BMJ and BMA investigation Zosia Kmietowicz found that medical schools are poor at recording students’ complaints of racial …
Abstract P2-02-05: Sensitivity of screening mammography by density and texture: A cohort study from a population based screening programme in Denmark
Authors: My von Euler-Chelpin
Journal: Cancer Research (2020)

Abstract Background Screening mammography works better in fatty than in dense breast tissue. Computerized assessment of parenchymal texture is a non-subjective method to obtain a refined description of breast tissue, potentially valuable in addition to breast density scoring for identification of women in need of supplementary imaging. We studied sensitivity of screening mammography by a combination of radiologist assessed BI-RADS density score and computer assessed parenchymal texture marker, MTR, in a population-based screening program, Capital Region, Denmark. Methods Breast density was coded according to the 4th Edition of the BI-RADS density code, and MTR marker was divided into quartiles from 1 to 4. Screening data were followed-up for identification of screen-detected and interval cancers. We calculated sensitivity and specificity with 95% confidence intervals (CI) by BI-RADS density score, MTR marker, and combination hereof. Results In total, 55 350 women were screened from 1 November 2012 to 31 December 2013. Full data were available for 54 997 women, of whom 28% had BI-RADS density score 1, 40% score 2, 27% score 3, and 5% score 4. Density and texture were strongly correlated, but the combination led to identification of subgroups with different sensitivity. Sensitivity was high, about 80%, in women with BI-RADS density scores 1 and MTR markers 1 or 2.Sensitivity was low, 67%, in women with BI-RADS density score 2 and MTR marker 4. For women with BI-RADS density scores 3 and 4, the already low sensitivity was further decreased for women with MTR marker 4. Specificity was 97-99% in all subgroups. Conclusion Our study showed that women with low density constituted a heterogenous group. Classifying women for extra imaging based on density only might be a too crude approach. Screening sensitivity was systematically high in women with fatty and homogeneous breast tissue. Sensitivity and specificity by combination of density score (BI-RADS) and texture marker (MTR), Denmark 2012-13 MeasureSensitivity % (95% CI)Specificity % (95% CI)BI-RADS 178 (69-85)99 (98-99)MTR 181 (70-90)99 (98-99)MTR 271 (54-85)99 (99-99)MTR 382 (48-98)98 (98-99)MTR 4BI-RADS 275 (70-81)97 (97-97)MTR 173 (57-85)98 (97-98)MTR 277 (66-85)97 (97-97)MTR 380 (64-88)97 (97-98)MTR 467 (51-81)97 (97-98)BI-RADS 369 (62-76)97 (97-97)MTR 171 (52-86)97 (96-98)MTR 2MTR 377 (66-87)97 (97-98)MTR 461 (46-72)97 (97-98)BI-RADS 447 (30-65)98 (97-98)MTR 157 (29-82)98 (97-99)MTR 2MTR 3MTR 441 (21-64)97 (97-98) Citation Format: My von Euler-Chelpin. Sensitivity of screening mammography by density and texture: A cohort study from a population based screening programme in Denmark [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-02-05.
Influence of clarithromycin on the bactericidal effect of amoxicillin in patients infected with clarithromycin-resistant strains of <i>H. pylori</i>
Authors: Takahisa Furuta, Mihoko Yamade, Takuma Kagami, Takahiro Suzuki, Tomohiro Higuchi, Shinya Tani, Yasushi Hamaya, Moriya Iwaizumi, Hiroaki Miyajima, Kazuo Umemura, Satoshi Osawa, Ken Sugimoto
Journal: Gut (2020)

We read the manuscript written by Suzuki et al 1 with interest. They reported that the eradication rate of Helicobacter pylori attained by the dual therapy with vonoprazan and amoxicillin (VA-Dual) was almost the same as that attained by the triple therapy with vonoprazan, amoxicillin and clarithromycin (VAC-Triple), as previously reported by us.2 The most interesting point in this paper was that the VA-Dual therapy was superior to the VAC-Triple therapy in eradicating the clarithromycin-resistant strains of H. pylori . In this regard, the authors consider the possibilities of a type I error, the difference in the proportion of amoxicillin-resistant strains, and the excessive inhibition of gastric acid secretion …
Effect of Intravenous Interferon β-1a on Death and Days Free From Mechanical Ventilation Among Patients With Moderate to Severe Acute Respiratory Distress Syndrome
Authors: V. Marco Ranieri, Ville Pettilä, Matti K. Karvonen, Juho Jalkanen, Peter Nightingale, David Brealey, Jordi Mancebo, Ricard Ferrer, Alain Mercat, Nicolò Patroniti, Michael Quintel, Jean-Louis Vincent, Marjatta Okkonen, Ferhat Meziani, Giacomo Bellani, Niall MacCallum, Jacques Creteur, Stefan Kluge, Antonio Artigas-Raventos, Mikael Maksimow, Ilse Piippo, Kati Elima, Sirpa Jalkanen, Markku Jalkanen, Geoff Bellingan
Journal: JAMA (2020)

Acute respiratory distress syndrome (ARDS) is associated with high mortality. Interferon (IFN) β-1a may prevent the underlying event of vascular leakage.To determine the efficacy and adverse events of IFN-β-1a in patients with moderate to severe ARDS.Multicenter, randomized, double-blind, parallel-group trial conducted at 74 intensive care units in 8 European countries (December 2015-December 2017) that included 301 adults with moderate to severe ARDS according to the Berlin definition. The radiological and partial pressure of oxygen, arterial (Pao2)/fraction of inspired oxygen (Fio2) criteria for ARDS had to be met within a 24-hour period, and the administration of the first dose of the study drug had to occur within 48 hours of the diagnosis of ARDS. The last patient visit was on March 6, 2018.Patients were randomized to receive an intravenous injection of 10 μg of IFN-β-1a (144 patients) or placebo (152 patients) once daily for 6 days.The primary outcome was a score combining death and number of ventilator-free days at day 28 (score ranged from -1 for death to 27 if the patient was off ventilator on the first day). There were 16 secondary outcomes, including 28-day mortality, which were tested hierarchically to control type I error.Among 301 patients who were randomized (mean age, 58 years; 103 women [34.2%]), 296 (98.3%) completed the trial and were included in the primary analysis. At 28 days, the median composite score of death and number of ventilator-free days at day 28 was 10 days (interquartile range, -1 to 20) in the IFN-β-1a group and 8.5 days (interquartile range, 0 to 20) in the placebo group (P = .82). There was no significant difference in 28-day mortality between the IFN-β-1a vs placebo groups (26.4% vs 23.0%; difference, 3.4% [95% CI, -8.1% to 14.8%]; P = .53). Seventy-four patients (25.0%) experienced adverse events considered to be related to treatment during the study (41 patients [28.5%] in the IFN-β-1a group and 33 [21.7%] in the placebo group).Among adults with moderate or severe ARDS, intravenous IFN-β-1a administered for 6 days, compared with placebo, resulted in no significant difference in a composite score that included death and number of ventilator-free days over 28 days. These results do not support the use of IFN-β-1a in the management of ARDS.ClinicalTrials.gov Identifier: NCT02622724.
Use of the 21-Gene Recurrence Score to Predict Clinical Outcomes in Early Breast Cancer
Authors: Filippo Montemurro, Caterina Marchiò, Anna Sapino
Journal: JAMA Oncology (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 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 11253: Sacubitril/Valsartan Prevents Cardiac Dysfunction Induced by Oxidative Stress in a Novel Chemogenetic Model of Heart Failure
Authors: Andrea Sorrentino, Sachin Badole, Benjamin Steinhorn, Thomas Michel
Journal: Circulation (2018)

Sacubitril/Valsartan, an angiotensin receptor-neprilysin inhibitor (ARNi), is clinically effective in the treatment of patients with HFrEF. Despite the positive results obtained in clinical trials,...
Analysis of Unregulated Sale of Lifesaving Prescription Drugs Online in the United States
Authors: Akram Ahamed, Kimberly C. Kullmann, Rosemary Frasso, Jennifer N. Goldstein
Journal: JAMA Internal Medicine (2020)

In analyses stratified by state Medicaid expansion, the results illustrated in Figure 1 remained very similar, whereas those in Figure 2 were qualitatively consistent, but hospitals in states that expanded Medicaid provided substantially less total charity care than other hospitals-$12.0 vs $37.8 (uninsured) and $8.7 vs $11.0 (insured) for every $100 of overall net income.Discussion | For both insured and uninsured patients, nonprofit hospitals with superior financial performance provided disproportionately low levels of charity care.Hospitals in states that expanded Medicaid provided less charity care than hospitals in other states.This study was limited by potential data inaccuracies of Medicare cost reports, self-reported by hospitals and not required to be audited by accounting firms.Under the current legal and regulatory requirements in the Affordable Care Act, Internal Revenue Code, and state laws, nonprofit hospitals have discretion in designing their own financial assistance policies for uninsured and underinsured patients.Nonprofit hospitals with substantial financial strength should consider more generous financial assistance eligibility criteria to reduce the financial risk exposure of disadvantaged uninsured and underinsured patients.
TSPO imaging-guided characterization of the immunosuppressive myeloid tumor microenvironment in patients with malignant glioma
Authors: Bastian Zinnhardt, Michael Müther, Wolfgang Roll, Philipp Backhaus, Astrid Jeibmann, Claudia Foray, Cristina Barca, Christian Döring, Bertrand Tavitian, Frédéric Dollé, Matthias Weckesser, Alexandra Winkeler, Sven Hermann, Stefan Wagner, Heinz Wiendl, Walter Stummer, Andreas H Jacobs, Michael Schäfers, Oliver M Grauer
Journal: Neuro-Oncology (2020)

Abstract Background Tumor-associated microglia and macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs) are potent immunosuppressors in the glioma tumor microenvironment (TME). Their infiltration is associated with tumor grade, progression, and therapy resistance. Specific tools for image-guided analysis of spatiotemporal changes in the immunosuppressive myeloid tumor compartments are missing. We aimed (i) to evaluate the role of fluorodeoxyglucose (18F)DPA-714* (translocator protein [TSPO]) PET-MRI in the assessment of the immunosuppressive TME in glioma patients, and (ii) to cross-correlate imaging findings with in-depth immunophenotyping. Methods To characterize the glioma TME, a mixed collective of 9 glioma patients underwent [18F]DPA-714-PET-MRI in addition to [18F]fluoro-ethyl-tyrosine (FET)-PET-MRI. Image-guided biopsy samples were immunophenotyped by multiparametric flow cytometry and immunohistochemistry. In vitro autoradiography was performed for image validation and assessment of tracer binding specificity. Results We found a strong relationship (r = 0.84, P = 0.009) between the [18F]DPA-714 uptake and the number and activation level of glioma-associated myeloid cells (GAMs). TSPO expression was mainly restricted to human leukocyte antigen D related–positive (HLA-DR+) activated GAMs, particularly to tumor-infiltrating HLA-DR+ MDSCs and TAMs. [18F]DPA-714–positive tissue volumes exceeded [18F]FET-positive volumes and showed a differential spatial distribution. Conclusion [18F]DPA-714-PET may be used to non-invasively image the glioma-associated immunosuppressive TME in vivo. This imaging paradigm may also help to characterize the heterogeneity of the glioma TME with respect to the degree of myeloid cell infiltration at various disease stages. [18F]DPA-714 may also facilitate the development of new image-guided therapies targeting the myeloid-derived TME.