tbuckley/cabot-search huggingface dataset:
Rimegepant, an Oral Calcitonin Gene–Related Peptide Receptor Antagonist, for Migraine
Authors: Richard B. Lipton, Robert Croop, Elyse G. Stock, David A. Stock, Beth A. Morris, Marianne Frost, Gene M. Dubowchik, Charles M. Conway, Vladimir Coric, Peter J. Goadsby
Journal: New England Journal of Medicine (2019)

Calcitonin gene-related peptide receptor has been implicated in the pathogenesis of migraine. Rimegepant is an orally administered, small-molecule, calcitonin gene-related peptide receptor antagonist that may be effective in acute migraine treatment.In a multicenter, double-blind, phase 3 trial, we randomly assigned adults with at least a 1-year history of migraine and two to eight migraine attacks of moderate or severe intensity per month to receive rimegepant orally at a dose of 75 mg or matching placebo for the treatment of a single migraine attack. The primary end points were freedom from pain and freedom from the most bothersome symptom (other than pain) identified by the patient, both of which were assessed 2 hours after the dose of rimegepant or placebo was administered.A total of 1186 patients were randomly assigned to receive rimegepant (594 patients) or placebo (592 patients); of these, 537 patients in the rimegepant group and 535 patients in the placebo group could be evaluated for efficacy. The overall mean age of the patients evaluated for efficacy was 40.6 years, and 88.7% were women. In a modified intention-to-treat analysis, the percentage of patients who were pain-free 2 hours after receiving the dose was 19.6% in the rimegepant group and 12.0% in the placebo group (absolute difference, 7.6 percentage points; 95% confidence interval [CI], 3.3 to 11.9; P<0.001). The percentage of patients who were free from their most bothersome symptom 2 hours after the dose was 37.6% in the rimegepant group and 25.2% in the placebo group (absolute difference, 12.4 percentage points; 95% CI, 6.9 to 17.9; P<0.001). The most common adverse events were nausea and urinary tract infection.Treatment of a migraine attack with the oral calcitonin gene-related peptide receptor antagonist rimegepant resulted in a higher percentage of patients who were free of pain and free from their most bothersome symptom than placebo. (Funded by Biohaven Pharmaceuticals; ClinicalTrials.gov number, NCT03237845.).
Tumor mutational burden quantification from targeted gene panels: major advancements and challenges
Authors: Laura Fancello, Sara Gandini, Pier Giuseppe Pelicci, Luca Mazzarella
Journal: Journal for ImmunoTherapy of Cancer (2019)

Tumor mutational burden (TMB), the total number of somatic coding mutations in a tumor, is emerging as a promising biomarker for immunotherapy response in cancer patients. TMB can be quantitated by a number of NGS-based sequencing technologies. Whole Exome Sequencing (WES) allows comprehensive measurement of TMB and is considered the gold standard. However, to date WES remains confined to research settings, due to high cost of the large genomic space sequenced. In the clinical setting, instead, targeted enrichment panels (gene panels) of various genomic sizes are emerging as the routine technology for TMB assessment. This stimulated the development of various methods for panel-based TMB quantification, and prompted the multiplication of studies assessing whether TMB can be confidently estimated from the smaller genomic space sampled by gene panels. In this review, we inventory the collection of available gene panels tested for this purpose, illustrating their technical specifications and describing their accuracy and clinical value in TMB assessment. Moreover, we highlight how various experimental, platform-related or methodological variables, as well as bioinformatic pipelines, influence panel-based TMB quantification. The lack of harmonization in panel-based TMB quantification, of adequate methods to convert TMB estimates across different panels and of robust predictive cutoffs, currently represents one of the main limitations to adopt TMB as a biomarker in clinical practice. This overview on the heterogeneous landscape of panel-based TMB quantification aims at providing a context to discuss common standards and illustrates the strong need of further validation and consolidation studies for the clinical interpretation of panel-based TMB values.
Electronic Fetal Monitoring to Prevent Fetal Brain Injury
Authors: Emmet Hirsch
Journal: JAMA (2019)

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 HomeNew OnlineCurrent IssueFor Authors 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) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More 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 journal
Predictors of multidrug-resistant Pseudomonas aeruginosa in neutropenic patients with bloodstream infection
Authors: D. Viasus, P. Puerta-Alcalde, C. Cardozo, M. Suárez-Lledó, O. Rodríguez-Núñez, L. Morata, C. Fehér, F. Marco, M. Chumbita, E. Moreno-García, F. Fernández-Avilés, G. Gutiérrez-Garcia, J.A. Martínez, J. Mensa, M. Rovira, J. Esteve, A. Soriano, C. Garcia-Vidal
Journal: Clinical Microbiology and Infection (2019)
Breaking immune tolerance for the treatment of glioblastoma: Phase IIb clinical trial experience.
Authors: Larn Hwang, David Nam, Vuong N. Trieu
Journal: Journal of Clinical Oncology (2019)

71 Background: Intratumoral heterogeneity (IH) resulting in the temporal and spatial diversification of tumor subclones. IH occurs progressively during tumor development inherent to the individual predilection to mutation and in the face of counterselections by exogenous therapies and/or endogenous immune surveillance. The xenogenization is countered by immunosuppression via overexpression of TGF-β. Here we compare the use of temozolomide (TMZ) and OT-101/TMZ to break immune tolerance to glioblastoma (GBM) for the cure. OT-101 is an antisense against TGF-β2. Methods: This is a phase IIb, multi-national, multi-center, open-label, active-controlled, randomized parallel group dose-finding study to evaluate the efficacy and safety of OT-101 in adult patients with recurrent high-grade glioma, administered intratumorally as continuous high-flow microperfusion over a 7-day period every other week. A total of 134 patients, 89 patients in the OT-101 test group and 45 patients in the standard chemotherapy (TMZ) control group were assessed. Results: Multiple rounds of TMZ broke the immune tolerance as shown by increase in overall survival (OS). mOS increased from 5.6 mos, 7.9 mos, to 36.6 mos with 1 round, 2 rounds, and 3 rounds of TMZ, respectively (p&lt;0.0001). For OT-101, mOS increased from 4.6 mos to 21.6 mos with just one round of TMZ (p&lt;0.0001) reducing the negative side effects of TMZ. Treatment sequencing was important as lead-in OT101 followed with subsequent TMZ was more effective than TMZ prior to OT-101 (26.2 mos vs. 4.8 mos, p&lt;0.0001). Conclusions: The MOA for OT-101/TMZ is consistent with the reactivation of immunity during TGF-β suppression and subsequent boosting/expansion of immunity during TMZ. Contrary to traditional tumor vaccine- this is universally applicable to all patients.
Exposure to Court-Ordered Tobacco Industry Antismoking Advertisements Among US Adults
Authors: Onyema Greg Chido-Amajuoyi, Robert K. Yu, Israel Agaku, Sanjay Shete
Journal: JAMA Network Open (2019)

<h3>Importance</h3> In 2006, US District Judge Gladys Kessler ordered tobacco companies to make corrective statements through paid advertisements informing the public of their deceptive practices. This landmark ruling and its subsequent execution represent the first time the tobacco industry sponsored a nationwide corrective advertising campaign against its own products. <h3>Objective</h3> To assess the reach of the court-ordered antismoking advertisements within the US adult population, stratified by demographic characteristics and tobacco use. <h3>Design, Setting, and Participants</h3> This nationally representative, population-based cross-sectional survey of US adults included respondents to the 2018 Health Information National Trends Survey 5, Cycle 2. Respondents were representatives of households selected by equal-probability sampling of the Marketing Systems Group database of addresses that included all nonvacant US residential addresses. Data collection was conducted from January to May 2018, and analysis took place from December 2018 to April 2019. <h3>Main Outcomes and Measures</h3> Self-reported exposure to court-ordered antismoking advertisements. <h3>Results</h3> The overall sample of 3484 respondents included 2054 women (weighted percentage, 50.8%), 1976 non-Hispanic white respondents (weighted percentage, 59.9%), 2952 respondents who lived in urban US areas (weighted percentage, 84.9%), and 450 current smokers (weighted percentage, 15.6%). Estimated exposure to court-ordered antismoking advertisements was 40.6% (95% CI, 37.5%-43.7%) among the full sample and 50.5% (95% CI, 41.4%-59.6%) among current smokers. Exposure was lowest among those aged 18 to 34 years (37.4%; 95% CI, 28.0%-46.8%), those with a high school education or less (34.5%; 95% CI, 29.3%-39.8%), and those with household annual income less than $35 000 (37.5%; 95% CI, 32.0%-42.9%). Among current smokers, Hispanic respondents had lower exposure rates (42.2%; 95% CI, 18.5%-65.9%) than non-Hispanic white respondents (51.7%; 95% CI, 40.4%-63.1%). As the advertising campaign's duration increased, exposure rates increased. Individuals with a high school education or less had lower odds of antismoking advertisement exposure than those with college or postgraduate degrees (adjusted odds ratio, 0.67; 95% CI, 0.48-0.94). Current smokers had higher odds of exposure than never smokers (adjusted odds ratio, 1.81; 95% CI, 1.17-2.80). Among those exposed to antismoking advertisements, 70.5% saw multiple antismoking messages. <h3>Conclusions and Relevance</h3> Approximately 1 of 2 smokers reported exposure to the federal court–ordered antismoking advertisements. However, exposure was relatively lower among several subgroups, including individuals aged 18 to 34 years, only one-third of whom reported exposure. Increasing the duration of antismoking advertisements as well as expanding their coverage to youth-oriented media may increase their potential public health impact.
BRD4 Promotes Gastric Cancer Progression and Metastasis through Acetylation-Dependent Stabilization of Snail
Authors: Zhong-yi Qin, Tao Wang, Siyuan Su, Li-ting Shen, Guang-xi Zhu, Qin Liu, Liang Zhang, Ke-wei Liu, Yue Zhang, Zhi-hua Zhou, Xiao-ning Zhang, Liang-zhi Wen, Yue-liang Yao, Wen-jing Sun, Yan Guo, Kai-jun Liu, Lei Liu, Xing-wei Wang, Yan-ling Wei, Jun Wang, Hua-liang Xiao, Pengda Liu, Xiu-wu Bian, Dong-feng Chen, Bin Wang
Journal: Cancer Research (2019)

Cancer metastasis, a leading cause of death in patients, is associated with aberrant expression of epigenetic modifiers, yet it remains poorly defined how epigenetic readers drive metastatic growth and whether epigenetic readers are targetable to control metastasis. Here, we report that bromodomain-containing protein 4 (BRD4), a histone acetylation reader and emerging anticancer therapeutic target, promotes progression and metastasis of gastric cancer. The abundance of BRD4 in human gastric cancer tissues correlated with shortened metastasis-free gastric cancer patient survival. Consistently, BRD4 maintained invasiveness of cancer cells in vitro and their dissemination at distal organs in vivo. Surprisingly, BRD4 function in this context was independent of its putative transcriptional targets such as MYC or BCL2, but rather through stabilization of Snail at posttranslational levels. In an acetylation-dependent manner, BRD4 recognized acetylated lysine 146 (K146) and K187 on Snail to prevent Snail recognition by its E3 ubiquitin ligases FBXL14 and β-Trcp1, thereby inhibiting Snail polyubiquitination and proteasomal degradation. Accordingly, genome-wide transcriptome analyses identified that BRD4 and Snail regulate a partially shared metastatic gene signature in gastric cancer cells. These findings reveal a noncanonical posttranscriptional regulatory function of BRD4 in maintaining cancer growth and dissemination, with immediate translational implications for treating gastric metastatic malignancies with clinically available bromodomain inhibitors. SIGNIFICANCE: These findings reveal a novel posttranscriptional regulatory function of the epigenetic reader BRD4 in cancer metastasis via stabilizing Snail, with immediate translational implication for treating metastatic malignancies with clinically available bromodomain inhibitors. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/79/19/4869/F1.large.jpg.
Enhancing safety of cytomegalovirus-based vaccine vectors by engaging host intrinsic immunity
Authors: Emily E. Marshall, Daniel Malouli, Scott G. Hansen, Roxanne M. Gilbride, Colette M. Hughes, Abigail B. Ventura, Emily Ainslie, Andrea N. Selseth, Julia C. Ford, David Burke, Craig N. Kreklywich, Jennie Womack, Alfred W. Legasse, Michael K. Axthelm, Christoph Kahl, Daniel Streblow, Paul T. Edlefsen, Louis J. Picker, Klaus Früh
Journal: Science Translational Medicine (2019)

Live-attenuated, spread-deficient rhesus CMV vectors retain T cell immunogenicity.
Association Between Declared Hurricane Disasters and Survival of Patients With Lung Cancer Undergoing Radiation Treatment
Authors: Leticia M. Nogueira, Liora Sahar, Jason A. Efstathiou, Ahmedin Jemal, K. Robin Yabroff
Journal: JAMA (2019)

This study uses National Cancer Database data to estimate associations between hurricane disaster declarations, which could disrupt electrical power, and survival of patients undergoing radiotherapy for nonoperative locally advanced non–small cell lung cancer between 2004 and 2014.
Safety and antitumor activity from the phase Ib study of ramucirumab plus pembrolizumab in treatment-naïve advanced gastric or gastroesophageal junction (G/GEJ) adenocarcinoma (JVDF)
Authors: I. Chau, J. Bendell, A. Soriano, H. Arkenau, J. Cultrera, R. Santana-Davila, E. Calvo, C. Le Tourneau, L. Zender, G. Mi, W. Schelman, D. Ferry, R. Herbst, C. Fuchs
Journal: Annals of Oncology (2019)
Physically active individuals have a 23% lower risk of any colorectal neoplasia and a 27% lower risk of advanced colorectal neoplasia than their non-active counterparts: systematic review and meta-analysis of observational studies
Authors: Jingjing Wang, Liwen Huang, Yang Gao, Yanhong Wang, Shanquan Chen, Junjie Huang, Wenjing Zheng, Pingping Bao, Yangming Gong, Yanfeng Zhang, Mei Wang, Martin Chi Sang Wong
Journal: British Journal of Sports Medicine (2019)

Background Few studies have examined the associations between physical activity (PA), sedentary behaviour (SB) and risk of colorectal neoplasia (CN). Methods We systematically searched Medline, Embase, PsyInfo, Cochrane and other sources from their inception to 30 September 2018 for cohort, case-control and cross-sectional studies that evaluated these associations in asymptomatic, average-risk subjects. Random-effect models were used to estimate relative risks (RRs) of any-type CN, advanced CN, and non-advanced CN, respectively, in individuals with the highest versus the lowest level of PA and SB. Dose-response analyses and subgroup analyses were conducted. The I 2 statistic was used to examine heterogeneity among studies. Results We identified 32 observational studies, including 17 cross-sectional studies, 10 case-control studies and five longitudinal studies. PA (highest vs lowest) was inversely associated with risk for any-type CN (n=23 studies) and advanced CN (n=15 studies), with a RR of 0.77 (95% CI=0.71 to 0.83, I 2 =57.5%) and 0.73 (95% CI=0.63 to 0.82, I 2 =45.5%), respectively. There was no association between PA and non-advanced CN (n=5 studies). There was an as association between PA and any-type CN in both sexes, and also for the distal colon. We found no dose–response relationship between PA and any-type or advanced CN. Based on three studies identified, SB time (longest vs shortest) was associated with an increased risk of advanced CN (RR=1.24, 95% CI 1.04 to 1.49, I 2 =14.4%). No publication bias was detected by Begg’s test. Conclusion We report a 23% lower relative risk of any type of CN and a 27% lower risk of advanced CN in people with the highest level of PA compared with those in the lowest.
David Oliver: Don’t blame GPs for late cancer diagnoses
Authors: David Oliver
Journal: BMJ (2019)

Being a GP isn’t easy. Under-resourcing, workforce gaps, the rising complexity and volume of work, and a media narrative too often laden with blame add to the challenges. On 28 June the Daily Telegraph ran a column entitled, “GPs failing to spot two thirds of cancers.”1 The article was more measured than the headline. But readers’ fear and anger are rarely tempered by less conspicuous details.

It reported a Cancer Research UK study, which had focused on two common cancers (lung and bowel), analysing 135 000 cases.2 The Telegraph mentioned “average waits of more than eight weeks for diagnosis,” adding that “the vast majority of cases that turned out to be cancer were never suspected by family doctors.”

The study, …
Practical guidelines for gut microbiome analysis in microbiota-gut-brain axis research
Authors: Mireia Valles-Colomer, Gwen Falony, Sara Vieira-Silva, Jeroen Raes
Journal: Behavioral and Brain Sciences (2019)

Abstract The microbiota-gut-brain (MGB) axis field is at an exciting stage, but the most recent developments in microbiota research still have to find their way into MGB studies. Here we outline the standards for microbiome data generation, the appropriate statistical techniques, and the covariates that should be included in MGB studies to optimize discovery and translation to clinical applications.
Regulation of CD137 expression through K‐Ras signaling in pancreatic cancer cells
Authors: Christophe Glorieux, Peng Huang
Journal: Cancer Communications (2019)

Abstract Background The interaction between CD137 and its ligand (CD137L) plays a major role in the regulation of immune functions and affects cancer immunotherapy. CD137 is a cell surface protein mainly located on activated T cells, and its regulation and functions in immune cells are well established. However, the expression of CD137 and its regulation in cancer cells remain poorly understood. The main purposes of this study were to examine the expression of CD137 in pancreatic cancer cells and to investigate its underlying mechanisms. Methods Cells containing inducible K‐Ras G12V expression vector or with different K‐Ras mutational statuses were used as in vitro models to examine the regulation of CD137 expression by K‐Ras. Various molecular assays were employed to explore the regulatory mechanisms. Tumor specimens from 15 pancreatic cancer patients and serum samples from 10 patients and 10 healthy donors were used to test if the expression of CD137 could be validated in clinical samples. Results We found that the CD137 protein was expressed on the cell surface in pancreatic cancer tissues and cancer cell lines. Enzyme‐linked immunosorbent assay revealed no difference in the levels of secreted CD137 in the sera of patients and healthy donors. By using the K‐Ras inducible cell system, we further showed that oncogenic K‐Ras up‐regulated CD137 through the activation of MAPK (mitogen‐activated protein kinases) and NF‐κB (nuclear factor kappa‐light‐chain‐enhancer of activated B cells) pathways, as evidenced by significantly reduced CD137 mRNA expression led by genetic silencing of MAPK1 and p65, the key proteins involved in the respective pathways. Furthermore, we also found that the NF‐κB pathway was mainly stimulated by the K‐Ras‐induced secretion of interleukin‐1α (IL‐1α) which promoted the transcription of the CD137 gene in pancreatic cancer cell lines. Analysis of the TCGA (the cancer genome atlas) database also revealed a significant correlation between IL‐1α and CD137 expression ( r = 0.274) in tumor samples from pancreatic cancer patients ( P &lt; 0.001). Conclusions The present study has demonstrated that the CD137 protein was expressed on pancreatic cancer cell surface, and has identified a novel mechanism by which K‐Ras regulates CD137 in pancreatic cancer cells through MAPK and NF‐κB pathways stimulated by IL‐1α.
Implications and outcomes of MRD-negative multiple myeloma patients with immunofixation positivity.
Authors: Marcella Tschautscher, Dragan Jevremovic, Francis Buadi, Martha Lacy, Morie A. Gertz, Angela Dispenzieri, Prashant Kapoor, David Dingli, Suzanne R. Hayman, John Anthony Lust, Stephen J. Russell, Nelson Leung, Ronald S. Go, Yi Lin, Wilson I. Gonsalves, Taxiarchis Kourelis, Rahma M. Warsame, Robert A. Kyle, S. Vincent Rajkumar, Shaji Kumar
Journal: Journal of Clinical Oncology (2019)

8034 Background: Minimal residual disease (MRD) assessment in multiple myeloma (MM) has improved our ability to assess disease activity, resulting in more advanced prognostication. While MRD assessment remains confined to the bone marrow (BM) plasma cell population, serum studies including immunofixation (IFE) are required to complete response evaluation. The significance of those who are MRD neg yet have detectable monoclonal protein through IFE remains unclear. Methods: We retrospectively studied 256 MM patients who had MRD assessment via the Euroflow multiparametric flow cytometry on the BM with concomitant serum IFE testing. Patients who were MRD neg were included in the study. Outcomes included probability of disease progression (PD) at 1 year. The Cox-proportional hazards model was used to compare probability of PD among different groups. Time to progression (TTP) was calculated as the difference from date of MFC analysis to PD in months. Results: Among the entire cohort, 178 (70%) patients were MRD neg and median follow-up from MRD assessment was 6.3 months. Among these patients, 74 (42%) had a positive IFE at the time of MRD analysis. Within the MRD neg /IFE pos group, 31 (42%) patients remained IFE pos after a median follow up of 5.5 mo from initial MRD/IFE testing while 34 patients eventually became IFE neg after a median of 2.8 mo with no subsequent IFE available in 9 patients. The 1 year probability of PD in the MRD neg /IFE neg group was 20% compared to 41% in the MRD neg /IFE pos group (P &lt; 0.01, Wilcoxon test). When comparing subsequent IFE status in those who were MRD neg /IFE pos , those who remained IFE pos had a trend towards shorter TTP compared to patients who later became IFE neg . Conclusions: Persistent monoclonal protein in the face of MRD negativity predicts for a shorter TTP. This likely reflects persistent disease that was not sampled on the BM aspirate in many of these patients compared to those who eventually become IFE neg with a trend towards longer TTP owing to the prolonged half-life and therefore clearance of M protein. This supports the current strategy of assessing for MRD at the time of suspected complete response to reduce the chance of positive MRD tests and thus avoidance of multiple BM exams.
Micropattern-based platform as a physiologically relevant model to study epithelial morphogenesis and nephrotoxicity
Authors: Minerva Bosch-Fortea, Alejo E. Rodriguez-Fraticelli, Gonzalo Herranz, Mariam Hachimi, Maria D. Barea, Joanne Young, Benoit Ladoux, Fernando Martin-Belmonte
Journal: Biomaterials (2019)