tbuckley/cabot-search huggingface dataset:
The Greatest Generation
Authors: Gurpreet Dhaliwal
Journal: JAMA (2015)

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
Combination of the antiangiogenic agent aflibercept (VEGF Trap) with docetaxel or gemcitabine results in greater antitumor activity in tumor bearing mice.
Authors: Pascale Lejeune, Marielle Chiron, Ronan Le Moigne, Patricia Vrignaud, Marie-Christine Bissery
Journal: Cancer Research (2008)

1107  Aflibercept (VEGF Trap) is a potent angiogenesis inhibitor that binds and inactivates circulating VEGF. Aflibercept is in Phase 3 clinical trials either as a single agent or in combination with chemotherapy in several cancer indications. Preclinical studies were designed to determine the antitumor efficacy of aflibercept in combination with two cytotoxic agents: docetaxel (Taxotere®), a tubulin-binding agent that inhibits microtubule depolymerization, and the antimetabolite gemcitabine (Gemzar®). Three-arm dose-response studies were performed, the highest non-toxic dose (HNTD) being determined for each single cytotoxic agent and the combination. The key efficacy endpoint was the log cell kill value (log CK = tumor growth delay / 3.32 x tumor doubling time).  The combination of SC aflibercept with IV docetaxel was evaluated in BALB/c nude female mice bearing early stage B16 melanoma. Each single agent and the simultaneous combination were given on days 3, 6, and 9 post-tumor implantation. In this model, each single agent was active: 4.2 log CK at the highest dose tested (HDT) of aflibercept (40 mg/kg per day) and 1.5 log CK at the HNTD of docetaxel (15 mg/kg per day). The HNTD of the combination (aflibercept at 40 mg/kg per day with docetaxel at 9.4 mg/kg per day) resulted in a 5 log CK indicating that the combination was highly active and more potent than each single agent alone. When the combination was explored with the HNTD of docetaxel (15.2 mg/kg per day), the dose of aflibercept had to be reduced to 10 mg/kg per day indicating some overlap in host toxicity. The HNTD of docetaxel (15 mg/kg per day) induced 1.5 log CK, aflibercept (10 mg/kg per day) induced 2.5 log CK, and the combination of both agents at these doses was more active, inducing a 3.4 log CK. In another experiment, the simultaneous combination of SC aflibercept with IV gemcitabine was evaluated in SCID mice bearing advanced human colon carcinoma HCT 116 (120 mg at start of therapy), with aflibercept and gemcitabine given on days 8, 11 and 14 post-tumor implantation. Three doses of aflibercept were active (40, 25 and 10 mg/kg/day), producing 2.4, 1.8 and 1.5 log CK, respectively. The HNTD of gemcitabine (62.1 mg/kg/day) was active with 1.8 log CK. The HNTD of the combination was 260.5 mg/kg/day of gemcitabine with 40 mg/kg/day of aflibercept, indicating no overlap in host toxicity. This HNTD of the combination was active (2.6 log CK) and the activity was maintained even at a low dose of the combination (2.1 log CK for gemcitabine at 62.1 mg/kg with aflibercept at 2.5 mg/kg).  In conclusion, aflibercept displays enhanced activity at several dose levels when combined with docetaxel or gemcitabine. The results support the ongoing clinical trials of aflibercept in combination with cytotoxic agents in solid tumors, such as NSCLC, prostate and pancreatic cancers.
Cholesterol Efflux Capacity and Pre-Beta-1 HDL Concentrations Are Increased in Dyslipidemic Patients Treated With Evacetrapib
Authors: Stephen J. Nicholls, Giacomo Ruotolo, H. Bryan Brewer, John P. Kane, Ming-Dauh Wang, Kathryn A. Krueger, Steven J. Adelman, Steven E. Nissen, Daniel J. Rader
Journal: Journal of the American College of Cardiology (2015)

Potent cholesteryl ester transfer protein (CETP) inhibitors have been shown to substantially increase high-density lipoprotein cholesterol (HDL-C) and apolipoprotein A-I levels as monotherapy and combined with statins. However, data on the effects of this class of drugs on macrophage cholesterol efflux capacity (CEC), a functional assay that characterizes a key step in the process of reverse cholesterol transport, are limited. This study assessed the impact of evacetrapib, statins, or combination therapy on CEC. We analyzed samples from 377 subjects with elevated low-density lipoprotein cholesterol (LDL-C) or low HDL-C levels who were enrolled in a phase 2 trial of evacetrapib. Percent changes from baseline in CEC (total, non–ABCA1-, and ABCA1-specific) and HDL subpopulations were evaluated after 12 weeks of treatment with placebo, statin monotherapy, evacetrapib monotherapy, or evacetrapib combined with statins. Pre–beta-1 HDL levels were quantified by immunofixation and nondenaturing 2-dimensional gel electrophoresis (2DGE). Relative to placebo, evacetrapib monotherapy increased dose-dependent total and non–ABCA1-specific CEC up to 34% and 47%, respectively. Evacetrapib monotherapy also increased ABCA1-specific CEC up to 26%. Relative to statin monotherapy, evacetrapib with statins also increased total, non–ABCA1-, and ABCA1-specific CEC by 21%, 27%, and 15%, respectively. In contrast, rosuvastatin and simvastatin significantly reduced total and ABCA1-specific CEC, whereas atorvastatin had no significant effect. Consistent with ABCA1-specific CEC, evacetrapib monotherapy and evacetrapib combined with statins significantly increased pre–beta-1 HDL levels as measured by either method. Evacetrapib, as monotherapy and combined with statins, not only increased total CEC, but also increased ABCA1-specific CEC and pre–beta-1 HDL. The mechanisms by which potent CETP inhibition increases ABCA1-specific CEC and pre–beta-1 HDL require further study. (A Study of LY2484595 in Patients With High LDL-C or Low HDL-C; NCT01105975)
Estimating the Long-Term Treatment Benefits of Sacubitril–Valsartan
Authors: Brian Claggett, Milton Packer, John J.V. McMurray, Karl Swedberg, Jean Rouleau, Michael R. Zile, Pardeep Jhund, Martin Lefkowitz, Victor Shi, Scott D. Solomon
Journal: New England Journal of Medicine (2015)

Using actuarial data based on the results of the PARADIGM-HF trial, investigators found that the use of sacubitril–valsartan in patients with heart failure resulted in a mean of 1 to 2 additional years of survival, as compared with enalapril.
Abstract 14406: Cardiac Troponin T Should not be Used to Diagnose Myocardial Injury in Patients with Skeletal Muscle Diseases
Authors: Dylmitr Rittoo, Alan Jones, Duncan Neithercut
Journal: Circulation (2012)

Introduction: Cardiac Troponin (cTn) T and I assays are believed to have equally high sensitivity and specificity for the diagnosis of myocardial injury. However , unlike cTnI, it is known that cTn...
Mediation Analysis: A Practitioner's Guide
Authors: Tyler J. VanderWeele
Journal: Annual Review of Public Health (2015)

This article provides an overview of recent developments in mediation analysis, that is, analyses used to assess the relative magnitude of different pathways and mechanisms by which an exposure may affect an outcome. Traditional approaches to mediation in the biomedical and social sciences are described. Attention is given to the confounding assumptions required for a causal interpretation of direct and indirect effect estimates. Methods from the causal inference literature to conduct mediation in the presence of exposure-mediator interactions, binary outcomes, binary mediators, and case-control study designs are presented. Sensitivity analysis techniques for unmeasured confounding and measurement error are introduced. Discussion is given to extensions to time-to-event outcomes and multiple mediators. Further flexible modeling strategies arising from the precise counterfactual definitions of direct and indirect effects are also described. The focus throughout is on methodology that is easily implementable in practice across a broad range of potential applications.
Obesity is one of biggest risks to women’s health, says England’s chief medical officer
Authors: Gareth Iacobucci
Journal: BMJ (2015)

The UK government should add obesity to the national risk register to improve the health of women and the population as a whole, England’s chief medical officer has urged.

In her annual report for 2014, which focuses on women’s health, Sally Davies said that obesity was one of the biggest risks to women’s health and subsequently had a major effect on the health of those women’s children and grandchildren.1

The report said that 54% of women aged 34-44 and 62% of women aged 45-54 in England were classified as overweight or obese in 2013. Davies said that the problem was so serious that obesity should be included in national risk plans across government, which would place it alongside high risk areas such as terrorism and …
Personalized medicine: an update of salivary biomarkers for periodontal diseases
Authors: Dina L. Korte, Janet Kinney
Journal: Periodontology 2000 (2015)

Abstract This article provides an up‐to‐date review of the more robust salivary biomarkers, as well as of panels of combinatorial markers and periodontal pathogens, that reveal high sensitivity and specificity for enhancing clinical decision‐making in periodontal disease progression, risk and diagnosis. Periodontal diseases are complex and require an inflammatory response to bacterial pathogens in a susceptible host to stimulate tissue destruction. When used alone, traditional clinical assessments provide a diagnosis of periodontitis only after the biologic onset of the disease process, and are unable to substantiate disease activity or future risk. New technologies are becoming available that are capable of measuring combinations of inflammatory cytokines and proteinases for rapid chair‐side testing. Utilizing saliva to identify and measure specific phenotypes and host‐derived mediators will allow highly individualized diagnosis, prognosis and treatments for periodontal diseases. This personalized medicine approach will strengthen the power of the clinical oral examination and medical history assessments, providing patients with evidence‐based, targeted risk care.
British Thoracic Society community-acquired pneumonia care bundle: results of a national implementation project: Table 1
Authors: Wei Shen Lim, Chamira Rodrigo, Alice M Turner, Sally Welham, James M Calvert
Journal: Thorax (2015)

In 2013, 16 U.K. hospital trusts participated in a quality improvement programme involving implementation of a community-acquired pneumonia (CAP) care bundle. High-level data were collected on 14,962 patients admitted with CAP; bundle implementation increased from 1% in October 2012 to 20% by September 2013. Analysis of patient-level data on 2118 adults (median age 75.3 years) found that in the bundle-implementation group, significantly more patients received antibiotics within 4 h of admission (adjusted OR 1.52, 95% CI 1.08 to 2.14, p=0.016) and 30-day inpatient mortality was lower (8.8% vs. 13.6%; adjusted OR 0.59, 95% CI 0.37 to 0.95, p=0.03).
Discovery of Novel Blood-Brain Barrier Targets to Enhance Brain Uptake of Therapeutic Antibodies
Authors: Y. Joy Yu Zuchero, Xiaocheng Chen, Nga Bien-Ly, Daniela Bumbaca, Raymond K. Tong, Xiaoying Gao, Shuo Zhang, Kwame Hoyte, Wilman Luk, Melanie A. Huntley, Lilian Phu, Christine Tan, Dara Kallop, Robby M. Weimer, Yanmei Lu, Donald S. Kirkpatrick, James A. Ernst, Ben Chih, Mark S. Dennis, Ryan J. Watts
Journal: Neuron (2015)
“No way Jose!” Clinicians must have authority over patient care: the manager's scope of practice does not cover medical decisions
Authors: Lise-Ann O'Neill
Journal: British Journal of Sports Medicine (2015)

This editorial uses a Premier League example but it discusses an international issue that transcends all levels of sport. What is the role of the team health professional? In the opening round of the 2015 English Premier League, Chelsea manager Jose Mourinho publicly attacked his medical team in the post-game media interview. Mourinho expressed his frustration with his medical team after they were beckoned on (twice) by the referee to attend to player Eden Hazard. This was in the dying minutes of stoppage time, leaving Chelsea exposed with only nine players on to defend a Swansea set piece.

Mourinho reportedly said “I wasn’t happy with my medical staff because even if you are a medical doctor or secretary on the bench, you have to understand the game… My medical department left me with eight fit outfield players in a counter …
Linkage study of the D5 dopamine receptor gene (DRD5) in multiplex Icelandic and English schizophrenia pedigrees
Authors: G Kalsi, R Sherrington, B S Mankoo, J Brynjolfsson, T Sigmundsson, D Curtis, T Read, P Murphy, R Butler, H Petursson, H M Gurling
Journal: American Journal of Psychiatry (1996)

The authors investigated the possibility that genetic variation or mutation of the dopamine D5 receptor gene might modify susceptibility to schizophrenia.Twenty-three Icelandic and English pedigrees containing multiple cases of schizophrenia were genotyped by using a highly informative microsatellite for the D5 dopamine receptor gene DRD5.By means of three different affection models, negative lod scores were obtained under assumptions of autosomal dominant and recessive inheritance. There was no evidence for locus heterogeneity. Nonparametric extended relative pair analysis also produced negative results.These data indicate that mutations of the D5 dopamine receptor gene are not a major cause of schizophrenia in these pedigrees. Because of the probable existence of locus heterogeneity, the D5 receptor gene may be of etiologic importance in other families with schizophrenia.
Physical mechanisms may be as important as brain mechanisms in evolution of speech
Authors: Bart de Boer, Marcus Perlman
Journal: Behavioral and Brain Sciences (2014)

Abstract We present two arguments why physical adaptations for vocalization may be as important as neural adaptations. First, fine control over vocalization is not easy for physical reasons, and modern humans may be exceptional. Second, we present an example of a gorilla that shows rudimentary voluntary control over vocalization, indicating that some neural control is already shared with great apes.
The progress in understanding and treatment of diabetic retinopathy
Authors: Alan W. Stitt, Timothy M. Curtis, Mei Chen, Reinhold J. Medina, Gareth J. McKay, Alicia Jenkins, Thomas A. Gardiner, Timothy J. Lyons, Hans-Peter Hammes, Rafael Simó, Noemi Lois
Journal: Progress in Retinal and Eye Research (2015)
LAG-3 and 4-1BB identify dysfunctional antigen-specific T cells in the tumor microenvironment and combinatorial LAG-3/4-1BB targeting gives synergistic tumor control
Authors: Jason B Williams, Brendan Horton, Yan Zheng, Thomas F Gajewski
Journal: Journal for ImmunoTherapy of Cancer (2015)

Meeting abstracts Although the presence of tumor-infiltrating lymphocytes (TILs) indicates an endogenous anti-tumor response, immune regulatory pathways can subvert the effector phase and enable tumor escape. One possible negative regulatory pathway is T cell-intrinsic anergy. Recently, we have
Long term survivors and immune biomarker analysis of Phase IIa, randomized study of GVAX pancreas and crs-207 immunotherapy in patients with metastatic pancreatic cancer
Authors: Nitya Nair, Ed Lemmens, Amanda Enstrom, Shih-Yu Chen, Serena Chang, Dung Le, Elizabeth M Jaffee, Holden Maecker, Aimee L Murphy, Dirk G Brockstedt, Chan Whiting
Journal: Journal for ImmunoTherapy of Cancer (2015)

Meeting abstracts Non-clinical and clinical combination studies with GVAX and live-attenuated, double-deleted (LADD) Listeria monocytogenes strains engineered to express tumor-associated antigens resulted in survival benefit and induction of cellular mediated immune responses. In a Phase IIa
Sex Differences in the Cardiovascular Consequences of Diabetes Mellitus
Authors: Judith G. Regensteiner, Sherita Golden, Amy G. Huebschmann, Elizabeth Barrett-Connor, Alice Y. Chang, Deborah Chyun, Caroline S. Fox, Catherine Kim, Nehal Mehta, Jane F. Reckelhoff, Jane E.B. Reusch, Kathryn M. Rexrode, Anne E. Sumner, Francine K. Welty, Nanette K. Wenger, Blair Anton
Journal: Circulation (2015)
Re S. S. Virtanen et al., Alendronate inhibits invasion of PC-3 prostate cancer cells by affecting the mevalonate pathway. Cancer Res 2002;62 : 2708-14 - Re K. Sawada et al., Alendronate inhabits lysophosphatidic acid-induced migration of human ovarian cancer cells by attenuating the activation of Rho. Cancer Res 2002;62 : 6015-20 - Reply
Authors: PT Lakkakorpi, HK Vaananen, Pirkko Härkönen
Journal: Cancer Research (2004)
The Comparative Effectiveness of Diabetes Prevention Strategies to Reduce Postpartum Weight Retention in Women With Gestational Diabetes Mellitus: The Gestational Diabetes’ Effects on Moms (GEM) Cluster Randomized Controlled Trial
Authors: Assiamira Ferrara, Monique M. Hedderson, Susan D. Brown, Cheryl L. Albright, Samantha F. Ehrlich, Ai-Lin Tsai, Bette J. Caan, Barbara Sternfeld, Nancy P. Gordon, Julie A. Schmittdiel, Erica P. Gunderson, Ashley A. Mevi, William H. Herman, Jenny Ching, Yvonne Crites, Charles P. Quesenberry
Journal: Diabetes Care (2015)

To compare the effectiveness of diabetes prevention strategies addressing postpartum weight retention for women with gestational diabetes mellitus (GDM) delivered at the health system level: mailed recommendations (usual care) versus usual care plus a Diabetes Prevention Program (DPP)-derived lifestyle intervention.This study was a cluster randomized controlled trial of 44 medical facilities (including 2,280 women with GDM) randomized to intervention or usual care. The intervention included mailed gestational weight gain recommendations plus 13 telephone sessions between 6 weeks and 6 months postpartum. Primary outcomes included the following: proportion meeting the postpartum goals of 1) reaching pregravid weight if pregravid BMI <25.0 kg/m(2) or 2) losing 5% of pregravid weight if BMI ≥25.0 kg/m(2); and pregravid to postpartum weight change.On average, over the 12-month postpartum period, women in the intervention had significantly higher odds of meeting weight goals than women in usual care (odds ratio [OR] 1.28 [95% CI 1.10, 1.47]). The proportion meeting weight goals was significantly higher in the intervention than usual care at 6 weeks (25.5 vs. 22.4%; OR 1.17 [1.01, 1.36]) and 6 months (30.6 vs. 23.9%; OR 1.45 [1.14, 1.83]). Condition differences were reduced at 12 months (33.0 vs. 28.0%; OR 1.25 [0.96, 1.62]). At 6 months, women in the intervention retained significantly less weight than women in usual care (mean 0.39 kg [SD 5.5] vs. 0.95 kg [5.5]; mean condition difference -0.64 kg [95% CI -1.13, -0.14]) and had greater increases in vigorous-intensity physical activity (mean condition difference 15.4 min/week [4.9, 25.8]).A DPP-derived lifestyle intervention modestly reduced postpartum weight retention and increased vigorous-intensity physical activity.
Genetic Landscapes of Relapsed and Refractory Diffuse Large B-Cell Lymphomas
Authors: Ryan D. Morin, Sarit Assouline, Miguel Alcaide, Arezoo Mohajeri, Rebecca L. Johnston, Lauren Chong, Jasleen Grewal, Stephen Yu, Daniel Fornika, Kevin Bushell, Torsten Holm Nielsen, Tina Petrogiannis-Haliotis, Michael Crump, Axel Tosikyan, Bruno M. Grande, David MacDonald, Caroline Rousseau, Maryam Bayat, Pierre Sesques, Remi Froment, Marco Albuquerque, Yury Monczak, Kathleen Klein Oros, Celia Greenwood, Yasser Riazalhosseini, Madeleine Arseneault, Errol Camlioglu, André Constantin, Qiang Pan-Hammarstrom, Roujun Peng, Koren K. Mann, Nathalie A. Johnson
Journal: Clinical Cancer Research (2015)

Abstract Purpose: Relapsed or refractory diffuse large B-cell lymphoma (rrDLBCL) is fatal in 90% of patients, and yet little is known about its biology. Experimental Design: Using exome sequencing, we characterized the mutation profiles of 38 rrDLBCL biopsies obtained at the time of progression after immunochemotherapy. To identify genes that may be associated with relapse, we compared the mutation frequency in samples obtained at relapse to an unrelated cohort of 138 diagnostic DLBCLs and separately amplified specific mutations in their matched diagnostic samples to identify clonal expansions. Results: On the basis of a higher frequency at relapse and evidence for clonal selection, TP53, FOXO1, MLL3 (KMT2C), CCND3, NFKBIZ, and STAT6 emerged as top candidate genes implicated in therapeutic resistance. We observed individual examples of clonal expansions affecting genes whose mutations had not been previously associated with DLBCL including two regulators of NF-κB: NFKBIE and NFKBIZ. We detected mutations that may be affect sensitivity to novel therapeutics, such as MYD88 and CD79B mutations, in 31% and 23% of patients with activated B-cell–type of rrDLBCL, respectively. We also identified recurrent STAT6 mutations affecting D419 in 36% of patients with the germinal center B (GCB) cell rrDLBCL. These were associated with activated JAK/STAT signaling, increased phospho-STAT6 protein expression and increased expression of STAT6 target genes. Conclusions: This work improves our understanding of therapeutic resistance in rrDLBCL and has identified novel therapeutic opportunities especially for the high-risk patients with GCB-type rrDLBCL. Clin Cancer Res; 22(9); 2290–300. ©2015 AACR.
Counterpoint: Implementing Population Genetic Screening for Lynch Syndrome Among Newly Diagnosed Colorectal Cancer Patients—Will the Ends Justify the Means?
Authors: Michael J. Hall
Journal: Journal of the National Comprehensive Cancer Network (2010)

Inherited mutations in 1 of 4 known mismatch repair genes ( MLH1, MSH2, MSH6, PMS2 ) are associated with various cancer risks collectively referred to as Lynch syndrome . Roughly 3 of every 100 new colorectal cancers (CRCs) have an underlying Lynch mutation. Tumor-based screening for Lynch among all patients with newly diagnosed CRC could theoretically improve the ability to identify Lynch and prevent cancer among at-risk family members, but the patient-level and social implications of this approach must be carefully considered before adopting this strategy. Poorly addressed issues include the role/timing of informed consent for testing, access and cost barriers associated with genetic counseling and DNA testing, psychosocial burdens to the thousands of middle-aged and elderly patients with CRC coping with surgical and chemotherapy treatments and poor prognosis, the need for providers to warn third-party relatives of risk for Lynch syndrome, limited effectiveness of screening, and the cost burden to society when poor DNA testing uptake, test limitations, and modest screening compliance are considered. Diverse barriers to the success of a population-based Lynch screening program in the United States remain (e.g., clinical resource needs, financial limitations, clinical expertise gaps, educational deficits). Data supporting clinical efficacy (feasibility) and effectiveness (real-life performance) are critical before important policy changes are adopted, especially where issues of hereditary cancer risk and genetic privacy are involved.