tbuckley/cabot-search huggingface dataset:
The Scientific Impact of Positive and Negative Phase 3 Cancer Clinical Trials
Authors: Joseph M. Unger, William E. Barlow, Scott D. Ramsey, Michael LeBlanc, Charles D. Blanke, Dawn L. Hershman
Journal: JAMA Oncology (2016)

<h3>Importance</h3> Positive phase 3 cancer clinical trials are widely hailed, while trials with negative results are often interpreted as scientific failures. We hypothesized that these interpretations would be reflected in the scientific literature. <h3>Objective</h3> To compare the scientific impact of positive vs negative phase 3 cancer clinical treatment trials. <h3>Design, Setting, and Participants</h3> We examined the phase 3 trial history of SWOG, a national cancer clinical trials consortium, over a 30-year period (1985-2014). Scientific impact was assessed according to multiple publication and citation outcomes. Citation data were obtained using Google Scholar. Citation counts were compared using generalized estimating equations for Poisson regression. Any trial that was formally evaluated for the randomized treatment comparison was included for analysis of publication and citation outcomes. Trials were categorized as positive if they achieved a statistically significant result in favor of the new experimental treatment for the protocol-specified primary end point. Trials were categorized as negative if they achieved a statistically significant result in favor of standard therapy or a null result with no statistically significant benefit for either the experimental or standard therapy. <h3>Main Outcomes and Measures</h3> Impact factors for the journals publishing the primary trial results, and the number of citations for the primary trial articles and all secondary articles associated with the trials. <h3>Results</h3> Ninety-four studies enrolling n = 46 424 patients were analyzed. Twenty-eight percent of trials were positive (26 of 94). The primary publications from positive trials were published in journals with higher mean (SD) 2-year impact factors (28 [19] vs 18 [13];<i>P</i> = .007) and were cited twice as often as negative trials (mean per year, 43 vs 21; relative risk, 2.0; 95% CI, 1.1-3.9;<i>P</i> = .03). However, the number of citations from all primary and secondary articles did not significantly differ between positive and negative trials (mean per year, 55 vs 45; relative risk, 1.2; 95% CI, 0.7-2.3;<i>P</i> = .53). <h3>Conclusions and Relevance</h3> The scientific impact of the primary articles from positive phase 3 randomized cancer clinical trials was twice as great as for negative trials. But when all of the articles associated with the trials were considered, the scientific impact between positive and negative trials was similar. Positive trials indicate clinical advances, but negative trials also have a sizeable scientific impact by generating important scientific observations and new hypotheses and by showing what new treatments should not be used.
Neuraminidase Inhibitors and Influenza Infection—Reply
Authors: Janice K. Louie, Harry Lampiris
Journal: JAMA Internal Medicine (2016)

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 Internal Medicine 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 Internal Medicine journal
Private practice
Authors: M. G Barrington
Journal: BMJ (1996)

Table 1-Self reported drug use and non-fatal overdose among 1018 drug injectors interviewed in Glasgow, 1993-4 Relative risk No (%) No (%) (95% confidence interval) Drug used or injected in using reporting compared with six months before Interview drug overdose rest of sample Injected heroin only 241 (24) 52 (22) 0.7 (0.5 to 0.9) Injected heroin and other drugs 661 (65) 213 (32) 2.2 (1.6 to 3.0) Injected drugs excluding heroin 116 (11) 11 (9) 0.3 (0.1 to 0.5) Methadone 453 (44) 132 (29) 1.2 (0.9 to 1.6)* Buprenorphine 413 (41) 109 (26) 0.9 (0.7 to 1.2)* Temazepam 793 (78) 244 (31) 2.7 (1.8 to 4.0) Cocaine 179 (18) 67 (37) 1.8 (1.3 to 2.5) Ecstasy 258 (25) 99 (38) 2.0 (1.5 to 2.8) *Not significant.
Role of GATA-1 in Proliferation and Differentiation of Definitive Erythroid and Megakaryocytic Cells In Vivo
Authors: Satoru Takahashi, Takuya Komeno, Naruyoshi Suwabe, Keigyo Yoh, Osamu Nakajima, Sigeko Nishimura, Takashi Kuroha, Toshiro Nagasawa, Masayuki Yamamoto
Journal: Blood (1998)
Modifiable Neighborhood Features Associated With Adolescent Homicide
Authors: Alison J. Culyba, Sara F. Jacoby, Therese S. Richmond, Joel A. Fein, Bernadette C. Hohl, Charles C. Branas
Journal: JAMA Pediatrics (2016)

Homicide is a leading cause of adolescent mortality. To our knowledge, relatively little has been studied in terms of the association between environmental neighborhood features, such as streets, buildings, and natural surroundings, and severe violent injury among youth.
Abstract P392: Utilization of Electronic Medical Records to Identify Risk Factors for Abdominal Aortic Aneurysm
Authors: Diane T Smelser, Gerardus Tromp, James R Elmore, S. H Kuivaniemi, David P Franklin, David J Carey
Journal: Circulation (2012)

Introduction: Electronic medical records (EMR) contain a wealth of phenotypic information with high potential to replace costly traditional epidemiological methods for purposes such as determining disease risk factors. EMRs designed for clinical and billing applications frequently do not meet the standardization and quality of data essential for biomedical research. Hypothesis: Using abdominal aortic aneurysm (AAA) as a model, we assessed the hypothesis that utilizing EMR in a retrospective study is comparable to traditional epidemiologic methods for risk factor assessment of a complex disease. Methods: The Geisinger Health System is the main health provider serving a highly stable population in central and northeastern Pennsylvania. Clinical and diagnostic data from January 2004 to December 2009 were extracted from the Geisinger EMR. The study population consisted of cases diagnosed with AAA ( n =964) and controls without AAA from the Geisinger MyCode ® biobanking repository ( n =14,555). The de-identified dataset was cleaned and formatted for research purposes. Data were analyzed unmatched, then cases were matched to controls on the confounders of sex, age, body mass index and smoking status. Matching was performed randomly, by propensity score and by group-frequency procedures. Bootstrap replication procedures (with and without replacement) confirmed the reproducibility of the results. Results: We replicated the direction and magnitude of several risk factors commonly noted in traditional epidemiologic AAA studies. Type 2 diabetes was associated with a decreased risk (OR=0.61, 95%CI 0.40–0.93). Peripheral artery disease (OR=2.94, 95%CI 1.81–4.78), kidney disease (OR=2.78, 95%CI 1.68–4.61), coronary occlusive disease (OR=2.64, 95%CI 1.79–3.88), cranial artery occlusive disease (OR=4.82, 95%CI 2.84–8.16), and pulmonary disease (OR=2.14, 95%CI 1.44–3.20) were all associated with an increased risk of AAA. In our population, the diagnosis of benign neoplasms was significantly inversely associated with AAA, a novel finding (OR=0.55, 95%CI 0.38–0.80). Pulse pressure was the most significant measure of hypertension associated with AAA (OR of 1.25 per 10 mmHg). Conclusions: This study demonstrated that EMR data can be feasibly used to assess risk factors and identify new associations. These findings could serve to enhance the current AAA screening guidelines to more efficiently target patients and increase screening utilization.
HDAC Inhibitors Enhance T-Cell Chemokine Expression and Augment Response to PD-1 Immunotherapy in Lung Adenocarcinoma
Authors: Hong Zheng, Weipeng Zhao, Cihui Yan, Crystina C. Watson, Michael Massengill, Mengyu Xie, Chris Massengill, David R. Noyes, Gary V. Martinez, Roha Afzal, Zhihua Chen, Xiubao Ren, Scott J. Antonia, Eric B. Haura, Brian Ruffell, Amer A. Beg
Journal: Clinical Cancer Research (2016)

A significant limitation of checkpoint blockade immunotherapy is the relatively low response rate (e.g., ∼20% with PD-1 blockade in lung cancer). In this study, we tested whether strategies that increase T-cell infiltration to tumors can be efficacious in enhancing immunotherapy response.We performed an unbiased screen to identify FDA-approved oncology agents with an ability to enhance T-cell chemokine expression with the goal of identifying agents capable of augmenting immunotherapy response. Identified agents were tested in multiple lung tumor models as single agents and in combination with PD-1 blockade. Additional molecular and cellular analysis of tumors was used to define underlying mechanisms.We found that histone deacetylase (HDAC) inhibitors (HDACi) increased expression of multiple T-cell chemokines in cancer cells, macrophages, and T cells. Using the HDACi romidepsin in vivo, we observed increased chemokine expression, enhanced T-cell infiltration, and T-cell-dependent tumor regression. Importantly, romidepsin significantly enhanced the response to PD-1 blockade immunotherapy in multiple lung tumor models, including nearly complete rejection in two models. Combined romidepsin and PD-1 blockade also significantly enhanced activation of tumor-infiltrating T cells.These results provide evidence for a novel role of HDACs in modulating T-cell chemokine expression in multiple cell types. In addition, our findings indicate that pharmacologic induction of T-cell chemokine expression represents a conceptually novel approach for enhancing immunotherapy response. Finally, these results suggest that combination of HDAC inhibitors with PD-1 blockade represents a promising strategy for lung cancer treatment. Clin Cancer Res; 22(16); 4119-32. ©2016 AACR.
A Regulatory Feedback between Plasmacytoid Dendritic Cells and Regulatory B Cells Is Aberrant in Systemic Lupus Erythematosus
Authors: Madhvi Menon, Paul A. Blair, David A. Isenberg, Claudia Mauri
Journal: Immunity (2016)

Signals controlling the generation of regulatory B (Breg) cells remain ill-defined. Here we report an "auto"-regulatory feedback mechanism between plasmacytoid dendritic cells (pDCs) and Breg cells. In healthy individuals, pDCs drive the differentiation of CD19+CD24hiCD38hi (immature) B cells into IL-10-producing CD24+CD38hi Breg cells and plasmablasts, via the release of IFN-α and CD40 engagement. CD24+CD38hi Breg cells conversely restrained IFN-α production by pDCs via IL-10 release. In systemic lupus erythematosus (SLE), this cross-talk was compromised; pDCs promoted plasmablast differentiation but failed to induce Breg cells. This defect was recapitulated in healthy B cells upon exposure to a high concentration of IFN-α. Defective pDC-mediated expansion of CD24+CD38hi Breg cell numbers in SLE was associated with altered STAT1 and STAT3 activation. Both altered pDC-CD24+CD38hi Breg cell interactions and STAT1-STAT3 activation were normalized in SLE patients responding to rituximab. We propose that alteration in pDC-CD24+CD38hi Breg cell interaction contributes to the pathogenesis of SLE.
Permissive HLA-DPB1 Mismatching Compared to a Non-Permissive Mismatching Significantly Improves Overall Survival Following Allogeneic Transplantation In Patients with Both 10/10 and 9/10 Matched Unrelated Donors
Authors: Bronwen E. Shaw, Katharina Fleischhauer, Mari Malkki, Theodore Gooley, Elisabetta Zino, Stephen Spellman, Yasuo Morishima, Andrea Velardi, Peter Bardy, Jean-denis Bignon, J. Alejandro Madrigal, Effie W. Petersdorf
Journal: Blood (2010)
Thrombosis History and Relationship with Low Thrombocytosis, Leukocytosis, and Jak2 V617F Mutation In A Cohort of 977 Patients with Essential Thrombocythemia (ET): Preliminary Report of the Registro Italiano Trombocitemia(RIT),
Authors: Luigi Gugliotta, Alessia Tieghi, Alessandra Iurlo, Anna Candoni, Giorgina Specchia, Monia Lunghi, Elisa Rumi, Potito R Scalzulli, Alfredo Dragani, Vincenzo Martinelli, Maria Luigia Randi, Nilla Maschio, Anna Marina Liberati, Fausto Palmieri, Cristina Santoro, Alfonso Maria D'Arco, Angela Rago, Chiara Chiozzotto, Lucia Mastrullo, Emma Cacciola, Rossella Cacciola, Francesco Lanza, Katia Codeluppi, Chiara De Philippis, Andrea Patriarca, Rosanna Ciancia, Mauro Fiacchini, Gabriele Gugliotta, Giuseppe Cimino, Gianluca Gaidano, Maria Gabriella Mazzucconi, Francesco Passamonti, Alessandro M. Vannucchi, Nicola Vianelli
Journal: Blood (2011)
Abstract 18888: 2-Methoxyestrone Retards the Progression of Angioproliferative Pulmonary Hypertension in Rats - Role of 17beta-Hydroxysteroid Dehydrogenase Pathway
Authors: Jian Hu, Olga Rafikova, Frank Schneider, Edwin K Jackson, Stevan Tofovic
Journal: Circulation (2015)

Background: 2-Methoxyestradiol (2ME2; major non-estrogenic metabolite of estradiol) attenuates monocrotaline (MCT)- and SU5416+hypoxia (SU/Hx)-induced pulmonary arterial hypertension (PH). 2ME2 is dehydrogenated by type-2 17β-hydroxysteroid dehydrogenase (17-HSD2) to 2-methoxyestrone (2ME1), a metabolite with no biological activity. However, in vivo 2ME1 may be converted back to 2ME2 by type-1 17β-HSD (17-HSD1). Our recent study indicates that 2ME-2 and all-trans retinoic acid (atRA; a 17HSD1 inducer) have synergistic therapeutic effects in MCT-induced PH.&lt; Methods: To study the role of 17β-HSD metabolic pathway on development of PH, first we examined the effects of 2-ME1 on proliferation of human pulmonary artery smooth muscle cells (hPASMC), lung fibroblasts (hLF) and hela cells, in the presence or absence of atRA. Next, in male rats, we studied the effects of 2ME1 on progression of MCT-induced PH (Day14-28 post MCT). Finally, we investigated the effects of 2ME1 on SU/Hx-induced PH. Ten days into hypoxia, intact (F) and ovariectomized (OVX) female rats were implanted minipumps delivering vehicle (PEG-400 0.5μl/h; F-SU and OVX-SU groups) or 2-ME1 (20μg/kg/h; F-2ME1 and OVX-2ME1 groups) Results: In hPASMC, hLF and hela cells 2ME1 had no/modest antimitogenic effect at a high pharmacological concentration, whereas in the presence of atRA, 2ME1 exhibited strong and concentration-dependent inhibition of cells growth. In male rats, 2ME1 retarded the progression of MCT-PH, and attenuated right ventricle (RV) and pulmonary vascular remodeling. In female rats SU/Hx induced severe angioproliferative PAH (RVPSP: F=23+2 vs F-SU = 116+10mmHg) and 2ME1 reduced PAH. Ovariectomy attenuated PAH (RVPSP: F-SU= 116+10 vs F-2ME1=96+10mmHg and in OVX-SU rats 2ME1 significantly retarded the progression of disease (RVPSP: OVX-SU= 99+9 mmHg vs. OVX-2ME1= 71+4) and markedly reduces RV remodeling (RV/LV+S: OVX-SU=0.715+0.021 vs. OVX-2ME1=0.555+0.026; p&lt;0.001) Conclusions: This study provides the first evidence that in vivo 2ME1 is biologically active and has therapeutic effects in angioproliferative PAH. Presented data suggest that 17β-HSD pathway of estradiol metabolism may play significant role in development and/or progression of PH.
Acalabrutinib (ACP-196): a selective second-generation BTK inhibitor
Authors: Jingjing Wu, Mingzhi Zhang, Delong Liu
Journal: Journal of Hematology & Oncology (2016)

More and more targeted agents become available for B cell malignancies with increasing precision and potency. The first-in-class Bruton's tyrosine kinase (BTK) inhibitor, ibrutinib, has been in clinical use for the treatment of chronic lymphocytic leukemia, mantle cell lymphoma, and Waldenstrom's macroglobulinemia. More selective BTK inhibitors (ACP-196, ONO/GS-4059, BGB-3111, CC-292) are being explored. Acalabrutinib (ACP-196) is a novel irreversible second-generation BTK inhibitor that was shown to be more potent and selective than ibrutinib. This review summarized the preclinical research and clinical data of acalabrutinib.
Abstract 17100: MicroRNAs and Risk of Myocardial Infarction: Prospective Results from the Bruneck Study
Authors: Anna Zampetaki, Peter Willeit, Lindsey Tilling, Ignat Drozdov, Agnes Mayr, Siegfried Weger, Ajay Shah, Chantal Boulanger, Johann Willeit, Philip Chowienczyk, Stefan Kiechl, Manuel Mayr
Journal: Circulation (2012)

Background: Circulating microRNAs (miRNAs) are emerging as promising biomarkers in cardiovascular diseases. We have previously identified a miRNA signature for type 2 diabetes in the general population (Zampetaki et al, Circ Res, 2010). Objective: Our aim was to investigate the association between baseline levels of miRNAs (1995) and incident myocardial infarction (1995-2005) in the Bruneck cohort, determine their cellular origin and explore their role in the pathogenesis of the disease. Methods and Results: Following RNA extraction, a total of nineteen circulating miRNAs were quantified by real time polymerase chain reactions in 820 participants. In multivariable Cox regression analysis, three miRNAs were consistently and significantly related with incident myocardial infarction: miR-126 showed a positive association (multivariable hazard ratio 2.69 [95%CI 1.45-5.01], P=0.002) while miR-223 and miR-197 were inversely associated with disease risk (multivariable hazard ratio 0.47 [95% CI 0.29-0.75], P=0.00...
Abstract 15184: Prevalence, Predictors and Clinical Outcomes of Unknown Coronary Artery Disease Among the Patients Undergoing Lower Extremity Endovascular Intervention
Authors: Sung-Jin Hong, Byung Ok Kim, Hye Young Lee, In Hyun Jung, Young Sup Byun, Kun Joo Rhee
Journal: Circulation (2015)

Introduction: The prevalence and clinical outcomes of unknown coronary artery disease (CAD) among the patients with peripheral artery disease, particularly for those undergoing lower extremity endovascular intervention, were not well evaluated. Methods: Between 2006 and 2014, a total of 208 consecutive patients (73±10 years, 165 men) without angina and prior coronary revascularization, were underwent lower extremity endovascular intervention. All patients evaluated coronary angiography without simutaneous coronary revascularization. CAD was defined as angiographically significant (≥50%) stenosis. All-cause mortality and major adverse cardiac and cerebrovascular event (MACCE) rate were compared between the patients with CAD and those without CAD. MACCE included cardiac death, cerebrovascular death, myocardial infarction, stroke, or heart failure. Results: Of the 208 patients, 103 patients (50%) had CAD; 1-VD (17%); 2-VD (17%); 3-VD (15%). Independent predictors of CAD were critical limb ischemia (OR=2.4) and below-the-knee lesions (OR=2.0). During the median follow-up of 1.2 years, all-cause mortality and MACCE rate at 3 year were 16.3% and 19.8%. At 3 year, patients with CAD had significantly higher mortality (19% vs. 14%, P=0.018) and higher MACCE rate (28% vs. 9%, P=0.001) compared to those without CAD. The severity of CAD had graded relations with the mortality and MACCE rate (Figure). Presence of CAD was an independent predictor of mortality (HR=1.5, P=0.025) and MACCE rate (HR=1.9, P&lt;0.001). Conclusions: Previously unknown CAD was detected in half of the patients undergoing lower extremity endovascular intervention and associated with higher mortality and MACCE rate. Detection of CAD might be important for risk stratification for these patients, especially with below-the-knee lesions.
Metabolomic Profiling of Statin Use and Genetic Inhibition of HMG-CoA Reductase
Authors: Peter Würtz, Qin Wang, Pasi Soininen, Antti J. Kangas, Ghazaleh Fatemifar, Tuulia Tynkkynen, Mika Tiainen, Markus Perola, Therese Tillin, Alun D. Hughes, Pekka Mäntyselkä, Mika Kähönen, Terho Lehtimäki, Naveed Sattar, Aroon D. Hingorani, Juan-Pablo Casas, Veikko Salomaa, Mika Kivimäki, Marjo-Riitta Järvelin, George Davey Smith, Mauno Vanhala, Debbie A. Lawlor, Olli T. Raitakari, Nish Chaturvedi, Johannes Kettunen, Mika Ala-Korpela
Journal: Journal of the American College of Cardiology (2016)

Statins are first-line therapy for cardiovascular disease prevention, but their systemic effects across lipoprotein subclasses, fatty acids, and circulating metabolites remain incompletely characterized. This study sought to determine the molecular effects of statin therapy on multiple metabolic pathways. Metabolic profiles based on serum nuclear magnetic resonance metabolomics were quantified at 2 time points in 4 population-based cohorts from the United Kingdom and Finland (N = 5,590; 2.5 to 23.0 years of follow-up). Concentration changes in 80 lipid and metabolite measures during follow-up were compared between 716 individuals who started statin therapy and 4,874 persistent nonusers. To further understand the pharmacological effects of statins, we used Mendelian randomization to assess associations of a genetic variant known to mimic inhibition of HMG-CoA reductase (the intended drug target) with the same lipids and metabolites for 27,914 individuals from 8 population-based cohorts. Starting statin therapy was associated with numerous lipoprotein and fatty acid changes, including substantial lowering of remnant cholesterol (80% relative to low-density lipoprotein cholesterol [LDL-C]), but only modest lowering of triglycerides (25% relative to LDL-C). Among fatty acids, omega-6 levels decreased the most (68% relative to LDL-C); other fatty acids were only modestly affected. No robust changes were observed for circulating amino acids, ketones, or glycolysis-related metabolites. The intricate metabolic changes associated with statin use closely matched the association pattern with rs12916 in the HMGCR gene (R2 = 0.94, slope 1.00 ± 0.03). Statin use leads to extensive lipid changes beyond LDL-C and appears efficacious for lowering remnant cholesterol. Metabolomic profiling, however, suggested minimal effects on amino acids. The results exemplify how detailed metabolic characterization of genetic proxies for drug targets can inform indications, pleiotropic effects, and pharmacological mechanisms.