tbuckley/cabot-search huggingface dataset:
EGFR amplification and outcome in a randomised phase III trial of chemotherapy alone or chemotherapy plus panitumumab for advanced gastro-oesophageal cancers
Authors: Elizabeth C Smyth, Georgios Vlachogiannis, Somaieh Hedayat, Alice Harbery, Sanna Hulkki-Wilson, Massimiliano Salati, Kyriakos Kouvelakis, Javier Fernandez-Mateos, George D Cresswell, Elisa Fontana, Therese Seidlitz, Clare Peckitt, Jens C Hahne, Andrea Lampis, Ruwaida Begum, David Watkins, Sheela Rao, Naureen Starling, Tom Waddell, Alicia Okines, Tom Crosby, Was Mansoor, Jonathan Wadsley, Gary Middleton, Matteo Fassan, Andrew Wotherspoon, Chiara Braconi, Ian Chau, Igor Vivanco, Andrea Sottoriva, Daniel E Stange, David Cunningham, Nicola Valeri
Journal: Gut (2020)

Objective Epidermal growth factor receptor (EGFR) inhibition may be effective in biomarker-selected populations of advanced gastro-oesophageal adenocarcinoma (aGEA) patients. Here, we tested the association between outcome and EGFR copy number (CN) in pretreatment tissue and plasma cell-free DNA (cfDNA) of patients enrolled in a randomised first-line phase III clinical trial of chemotherapy or chemotherapy plus the anti-EGFR monoclonal antibody panitumumab in aGEA ( NCT00824785 ). Design EGFR CN by either fluorescence in situ hybridisation (n=114) or digital-droplet PCR in tissues (n=250) and plasma cfDNAs (n=354) was available for 474 (86%) patients in the intention-to-treat (ITT) population. Tissue and plasma low-pass whole-genome sequencing was used to screen for coamplifications in receptor tyrosine kinases. Interaction between chemotherapy and EGFR inhibitors was modelled in patient-derived organoids (PDOs) from aGEA patients. Results EGFR amplification in cfDNA correlated with poor survival in the ITT population and similar trends were observed when the analysis was conducted in tissue and plasma by treatment arm. EGFR inhibition in combination with chemotherapy did not correlate with improved survival, even in patients with significant EGFR CN gains. Addition of anti-EGFR inhibitors to the chemotherapy agent epirubicin in PDOs, resulted in a paradoxical increase in viability and accelerated progression through the cell cycle, associated with p21 and cyclin B1 downregulation and cyclin E1 upregulation, selectively in organoids from EGFR -amplified aGEA. Conclusion EGFR CN can be accurately measured in tissue and liquid biopsies and may be used for the selection of aGEA patients. EGFR inhibitors may antagonise the antitumour effect of anthracyclines with important implications for the design of future combinatorial trials.
Significance of Vascular Nitric Oxide Synthase Pathways in Coronary Artery Disease: A Multiple-Level Biomarker Strategy⁎⁎Editorials published in the Journal of American College of Cardiologyreflect the views of the authors and do not necessarily represent the views of JACCor the American College of Cardiology.
Authors: Malte Kelm
Journal: Journal of the American College of Cardiology (2006)
New Statin Use and Mortality in Older Veterans—Reply
Authors: Ariela R. Orkaby, David R. Gagnon, Luc Djousse
Journal: JAMA (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 HomeNew OnlineCurrent IssueFor Authors Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More 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 journal
Two-Stage Turnbull-Cutait Pull-Through Coloanal Anastomosis for Low Rectal Cancers—Reply
Authors: Sebastiano Biondo, Loris Trenti, Esther Kreisler
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
Genetic Modification of Neural Stem Cells
Authors: Rahul Jandial, Ilyas Singec, Christopher P Ames, Evan Y Snyder
Journal: Molecular Therapy (2008)

Neural stem cells (NSCs) are the main vehicle for genetic and molecular therapies in the central nervous system (CNS). The sustainability of NSCs has been ensured through genetic manipulation both in vitro and in vivo. NSC lines have also been immortalized and controlled for cell growth in similar fashion. Their potential to differentiate and their genetic plasticity make them the modality of choice for cellular transplantation. After transplantation, NSCs also exhibit inherent long-distance migratory capabilities and a remarkable capacity to integrate into brain structures. This makes NSCs the ideal candidate for delivery and expression of therapeutic genes. Mouse models of CNS diseases have already demonstrated the efficacy of such NSC-mediated treatment, and further investigations are underway to bridge the gap into true clinical application. Finally, the imaging possibilities with NSC transplants are endless, and they will be a pivotal component to safe and effective human transplantation. This paper provides an overview on NSCs and the various methods in which they have been genetically manipulated for biological investigation.
Abstract 15487: Combined Effects of Lipoprotein(a) and Hypertension in Predicting Cardiovascular Outcomes in Patients With Coronary Artery Disease
Authors: Huihui Liu, Yexuan Cao, Jinglu Jin, Hui-Wen Zhang, Qi Hua, Yan-Fang Li, Yuan-Lin Guo, Cheng-Gang Zhu, Na-Qiong Wu, Qi Hua, Ying Gao, Rui-Xia Xu, Jing Sun, Jian-Jun Li
Journal: Circulation (2020)

Introduction: Although emerging data have suggested that circulating lipoprotein(a) [Lp(a)] could predict cardiovascular events (CVEs) in patients with cardiovascular disease, no study is currently available regarding the prognostic significance of Lp(a) in patients with hypertension. Hypothesis: We assessed the hypothesis that there is a prognostic linkage between hypertension and Lp(a) concentrations in patients with coronary artery disease (CAD). Methods: A total of 8668 patients with stable CAD were consecutively enrolled. Baseline Lp(a) concentrations of them were measured. All subjects were categorized according to Lp(a) levels of &lt;10 (low), 10-30 (medium) and 30 mg/dL (high) and were further stratified by hypertension status. They were regularly followed-up for the occurrence of cardiovascular death, non-fatal myocardial infarction and stroke. Results: Over an average of 54.81±18.60 months follow-up, 584 (6.7%) CVEs occurred. Kaplan-Meier and multivariate Cox regression analyses showed that elevated Lp(a) levels had a significant association with CVEs in hypertensive patients, regardless of the control status of blood pressure, but not in normotensive subjects. Moreover, when subgrouping according to both Lp(a) categories and hypertension status, the risk for CVEs was only significantly elevated in high Lp(a) plus hypertension group compared with the reference group with low Lp(a) levels and normotension (hazard ratio: 1.85, 95% confidence interval: 1.19-2.85). Conclusions: In conclusion, elevated Lp(a) was associated with higher risk for CVEs in CAD patients with hypertension and the coexistence of high Lp(a) concentrations and hypertension greatly worsened the clinical prognosis. Our findings may present a prognostic linkage between hypertension and Lp(a) concentrations in patients with CAD.
Abstract 16287: Clinical Characteristics, Treatment and Long-term Mortality of Patients With Congenital Coronary Fistulas
Authors: Miguel alejandro A Cutz, Manuel Gaxiola, Steaven Juarez
Journal: Circulation (2020)

Introduction: Congenital coronary fistulas (CCF) are rare (0.002% in general population) however under-diagnosis is frequent. Patient and fistula characteristics vary among different populations, treatment is controversial and the impact in survival is not well established. Purpose: This study aimed to describe clinical characteristics, treatment received and long-term mortality among different options of treatment for CCF. Methods: We identified all cases of CCF diagnosed from January 2009 to January 2019 in a single center. Clinical data was obtained from medical records and mortality was assessed according to clinical checkups or by phone call. Long-term mortality was defined after at least one-year follow-up. Descriptive statistics were applied to all cases. Results: 22 cases of CCF were diagnosed, medium age was 53.6 years, 65% were male and 31% had smoking history. At presentation 36% had angina and 27% had dyspnea. Only 13.6% had no significant past medical history, 20% had another congenital anomaly associated, 13.6 % had chronic heart failure and 45.4% were associated to coronary artery disease (CAD), usually anterior descending artery (ADA) was affected. Most frequent origin of fistula was from the ADA in 42.3% of the cases and drainage was frequent to the pulmonary artery in 53.4%, 80% had a single fistula and 45% presented small fistulas. Overall mortality was 13.6% (n=3) with median follow-up of 3.6 (1-9.9) years. Among patients treated, 72.8% of the patients received medical treatment with a 12.5% rate of long-term mortality, however only one patient died from cardiovascular cause (worsening heart failure). None of the patients who received interventional treatment (N=3) died at long-term, 13.6% had coronary artery bypass grafting for CAD (none had fistula ligation), only one patient died several years later of neurological cause. Conclusions: The most common origin of CCF was from the ADA and the drainage was common to the pulmonary artery. Long term mortality is low in patients with CCF despite treatment received, only one patient in the entire cohort died of cardiac disease even when 55% had medium to large coronary fistula and 86.4% had previous cardiovascular disease. Further studies are needed to establish treatment guidelines.
ABC Subtype, TP53 Mutation and BCL2 Overexpression are Associated with a Worse Outcome in Untreated Poor-Risk Young Diffuse Large B-Cell Lymphoma: Results from the Frontline Phase III BIO-DLBCL04 Study of the Fondazione Italiana Linfomi
Authors: Annalisa Chiappella, Claudio Agostinelli, Marco Ladetto, Andrea Evangelista, Maurizio Martelli, Emanuele Angelucci, Monica Balzarotti, Riccardo Bomben, Maria Giuseppina Cabras, Fary Diop, Marco Fabbri, Manuel Gotti, Federica Melle, Francesco Merli, Giovanna Motta, Luca Nassi, Domenico Novero, Simona Righi, Davide Rossi, Giuseppe Rossi, Caterina Stelitano, Valter Gattei, Gianluca Gaidano, Stefano A. Pileri, Umberto Vitolo
Journal: Blood (2017)
Tau accumulation in astrocytes of the dentate gyrus induces neuronal dysfunction and memory deficits in Alzheimer’s disease
Authors: Kevin Richetin, Pascal Steullet, Mathieu Pachoud, Romain Perbet, Enea Parietti, Mathischan Maheswaran, Sabiha Eddarkaoui, Séverine Bégard, Catherine Pythoud, Maria Rey, Raphaëlle Caillierez, Kim Q Do, Sophie Halliez, Paola Bezzi, Luc Buée, Geneviève Leuba, Morvane Colin, Nicolas Toni, Nicole Déglon
Journal: Nature Neuroscience (2020)
Covid-19–Associated Myopathy Caused by Type I Interferonopathy
Authors: Giovanna S. Manzano, Jared K. Woods, Anthony A. Amato
Journal: New England Journal of Medicine (2020)

Caused by Type I Interferonopathy][3] Whether the elevation in creatine kinase level is caused by viral infection of muscle, toxic effects of cytokines, or another mechanism is unclear.There are few reports of muscle-biopsy findings in patients with Covid-19. 4We describe a patient with Covid-19 infection and myopathy who had a muscle-biopsy specimen showing evidence of virus-induced type I interferonopathy.A 38-year-old man who had no recent history of illness or medication use presented with weakness, myalgias, and fever.He had generalized muscle weakness, which was more severe proximally than distally, and was unable to walk, abduct his shoulders, or flex his hips against gravity.Heliotrope rash, Gottron's sign or papules, and nail-bed changes were absent.He had bibasilar infiltrates and a positive reverse-transcriptase-polymerase-chain-reaction assay for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA.The serum level of creatine kinase was 29,800 U per liter (reference range, 39 to 308), high-sensitivity troponin T 3157 ng per liter (reference range, 0 to 14), and C-reactive protein 55 mg per liter (reference value, <10), and myoglobinuria was not present.Findings on electrocardiography, echocardiography, and cardiac magnetic resonance imaging were normal.A description of the methods used for the immunohistochemical analysis of muscle is provided in the Supplementary Appendix, available with the full text of this letter at NEJM.org.A biopsy specimen of his left deltoid muscle showed mild perivascular inflammation in a few vessels but no necrotic or regenerating fibers or perifascicular atrophy.Immunohistochemical
Factors Associated With Hepatitis A Mortality During Person‐to‐Person Outbreaks: A Matched Case–Control Study—United States, 2016‐2019
Authors: Megan G. Hofmeister, Jian Xing, Monique A. Foster, Ryan J. Augustine, Cole Burkholder, Jim Collins, Shannon McBee, Erica D. Thomasson, Douglas Thoroughman, Mark K. Weng, Philip R. Spradling
Journal: Hepatology (2020)

During 2016-2020, the United States experienced person-to-person hepatitis A outbreaks that are unprecedented in the vaccine era, during which case-fatality ratios reported by some jurisdictions exceeded those historically associated with hepatitis A.
A clinical score for identifying active tuberculosis while awaiting microbiological results: Development and validation of a multivariable prediction model in sub-Saharan Africa
Authors: Yeonsoo Baik, Hannah M. Rickman, Colleen F. Hanrahan, Lesego Mmolawa, Peter J. Kitonsa, Tsundzukana Sewelana, Annet Nalutaaya, Emily A. Kendall, Limakatso Lebina, Neil Martinson, Achilles Katamba, David W. Dowdy
Journal: PLoS Medicine (2020)

Background In highly resource-limited settings, many clinics lack same-day microbiological testing for active tuberculosis (TB). In these contexts, risk of pretreatment loss to follow-up is high, and a simple, easy-to-use clinical risk score could be useful. Methods and findings We analyzed data from adults tested for TB with Xpert MTB/RIF across 28 primary health clinics in rural South Africa (between July 2016 and January 2018). We used least absolute shrinkage and selection operator regression to identify characteristics associated with Xpert-confirmed TB and converted coefficients into a simple score. We assessed discrimination using receiver operating characteristic (ROC) curves, calibration using Cox linear logistic regression, and clinical utility using decision curves. We validated the score externally in a population of adults tested for TB across 4 primary health clinics in urban Uganda (between May 2018 and December 2019). Model development was repeated de novo with the Ugandan population to compare clinical scores. The South African and Ugandan cohorts included 701 and 106 individuals who tested positive for TB, respectively, and 686 and 281 randomly selected individuals who tested negative. Compared to the Ugandan cohort, the South African cohort was older (41% versus 19% aged 45 years or older), had similar breakdown of biological sex (48% versus 50% female), and had higher HIV prevalence (45% versus 34%). The final prediction model, scored from 0 to 10, included 6 characteristics: age, sex, HIV (2 points), diabetes, number of classical TB symptoms (cough, fever, weight loss, and night sweats; 1 point each), and &gt;14-day symptom duration. Discrimination was moderate in the derivation (c-statistic = 0.82, 95% CI = 0.81 to 0.82) and validation (c-statistic = 0.75, 95% CI = 0.69 to 0.80) populations. A patient with 10% pretest probability of TB would have a posttest probability of 4% with a score of 3/10 versus 43% with a score of 7/10. The de novo Ugandan model contained similar characteristics and performed equally well. Our study may be subject to spectrum bias as we only included a random sample of people without TB from each cohort. This score is only meant to guide management while awaiting microbiological results, not intended as a community-based triage test (i.e., to identify individuals who should receive further testing). Conclusions In this study, we observed that a simple clinical risk score reasonably distinguished individuals with and without TB among those submitting sputum for diagnosis. Subject to prospective validation, this score might be useful in settings with constrained diagnostic resources where concern for pretreatment loss to follow-up is high.
Abstract 14527: Utility of Routine Invasive Coronary Angiography Prior to Transcatheter Aortic Valve Replacement
Authors: Brian C Case, Charan Yerasi, Brian J Forrestal, Anees Musallam, Chava Chezar Azerrad, Joshua Hahm, Sant Kumar, Lowell F Satler, itsik ben-dor, Hayder Hashim, Ron Waksman, Toby Rogers
Journal: Circulation (2020)

Introduction: Despite the high prevalence of CAD in patients with severe aortic stenosis (AS), the optimal management of concomitant coronary artery disease (CAD) before trasncatheter aortic valve replacement (TAVR) remains controversial. Hypothesis: To characterize the contemporary, real-world burden of CAD in contemporary TAVR patients and to evaluate revascularization practices at a high-volume center in the United States. Methods: Analysis of all adult patients referred for TAVR at our center between January 2019 and January 2020. Presence of significant coronary artery disease (stenosis &gt;50%) and subsequent management (medical therapy versus revascularization) were recorded. Presenting symptoms, use of non-invasive and invasive ischemia testing and pre-TAVR computed tomography (CT) imaging were all analyzed. Results: A total of 394 patients with severe AS were referred to our institution for TAVR. Thirty-nine patients (9.9%) instead underwent surgical aortic valve replacement (SAVR), of which only 5 (1.3%) underwent SAVR plus coronary artery bypass surgery. Of the remaining 355 patients (77.3 ± 9.3 years old and 59.7% males), 218 patients (61.4%) had insignificant CAD. Of the 137 patients (38.6%) with significant CAD, only 30 (8.5%) underwent percutaneous coronary intervention (PCI). Of these, less than half had anginal symptoms, a third had CAD in proximal segments and a third underwent ischemia testing prior to PCI. Pre-TAVR CT accurately identified significant CAD in 28/30 patients (93.3%) who ultimately underwent PCI. Conclusions: Only 1 in 25 contemporary TAVR patients had significant CAD and anginal symptoms requiring intervention, questioning the utility of routine invasive coronary angiography before TAVR. A Heart Team approach integrating anginal symptoms and ischemia testing is needed to guide the need, timing and strategy of revascularization. The pre-TAVR CT images could identify significant proximal segment CAD needing PCI.
Metabolic-Pathway-Based Subtyping of Triple-Negative Breast Cancer Reveals Potential Therapeutic Targets
Authors: Yue Gong, Peng Ji, Yun-Song Yang, Shao Xie, Tian-Jian Yu, Yi Xiao, Ming-Liang Jin, Ding Ma, Lin-Wei Guo, Yu-Chen Pei, Wen-Jun Chai, Da-Qiang Li, Fan Bai, François Bertucci, Xin Hu, Yi-Zhou Jiang, Zhi-Ming Shao
Journal: Cell Metabolism (2020)
Abstract 14629: Rare Variants for Electrocardiographic Traits Identify Arrhythmia Susceptibility Genes
Authors: Sean J Jurgens, Seung Hoan Choi, Christopher M Haggerty, Amelia W Hall, Jennifer Halford, Valerie Morrill, Lu Chen Weng, Braxton Lagerman, Tooraj Mirshahi, Mary Pettinger, Xiuqing Guo, Jelena Kornej, Honghuang Lin, Arden Moscati, Girish Nadkarni, Jennifer Brody, Kerri Wiggins, Brian E Cade, Jiwon Lee, Christina Austin-Tse, Tom Blackwell, Mark Chaffin, Christina J Lee, Heidi Rehm, Susan Redline, Braxton D Mitchell, Nona Sotoodehnia, Bruce M Psaty, Susan R Heckbert, Ruth J Loos, Ramachandran S Vasan, Emelia J Benjamin, Adolfo Correa, Eric Boerwinkle, Dan E Arking, Jerome I Rotter, Stephen Rich, Eric A Whitsel, Marco V Perez, Charles Kooperberg, Brandon Fornwalt, Kathryn Lunetta, Patrick T Ellinor, Steven A Lubitz
Journal: Circulation (2020)

Introduction: Electrocardiogram (ECG) intervals are quantitative and heritable endophenotypes for arrhythmias and sudden cardiac death (SCD). Studying rare sequence variation related to ECG intervals may help identify the genetic underpinnings of cardiac conduction and SCD. Methods: Using a discovery sample of 29,000 individuals with whole-genome sequences from TOPMed and a replication sample of about 100,000 individuals with whole-exome sequence data from the UK Biobank and MyCode, we examined associations between low-frequency (MAF&lt;1%) and rare (MAF&lt;0.1%) coding variants with 5 routinely ascertained ECG intervals (RR, P-wave, PR, QRS, and QTc intervals). We further assessed pathogenic variants in identified genes using ClinVar. Results: In low-frequency single variant analysis, we observed associations for PR interval in PAM ( P =2x10 -7 ) and MFGE8 ( P =5x10 -8 ). In gene-based tests, we identified rare coding variation associated with marked effects in established SCD genes KCNQ1, KCNH2, SCN5A and KCNE1 . For example, loss-of-function or pathogenic variants in KCNQ1 and KCNH2 were carried in 0.2% of individuals, were associated with 29 ms longer QTc intervals ( P =2x10 -82 ) and conferred up to 23-fold increased odds of marked QTc prolongation ( P =4x10 -25 ). Nevertheless, over 75% of carriers had normal QTc intervals. Similarly, loss-of-function or pathogenic variants in SCN5A , carried by 0.1% of individuals, conferred marked PR prolongation (31 ms), yet less than 30% of carriers had first-degree atrioventricular block. Discussion: This study demonstrates the value of studying ECGs in large sequenced biobanks for identifying rare variants predisposing to cardiac arrhythmias. Results define the frequency of pathogenic variation in SCD genes in the population and document incomplete penetrance of such variation. Our findings may serve as a benchmark for future population-based analyses aimed at discovering clinically actionable variants and genes.