tbuckley/cabot-search huggingface dataset:
A methodological approach for assessing the uptake of core outcome sets using ClinicalTrials.gov: findings from a review of randomised controlled trials of rheumatoid arthritis
Authors: Jamie J Kirkham, Mike Clarke, Paula R Williamson
Journal: BMJ (2017)

Objective To assess the uptake of the rheumatoid arthritis core outcome set using a new assessment method of calculating uptake from data in clinical trial registry entries.Design Review of randomised trials.Setting ClinicalTrials.gov.Subjects 273 randomised trials of drug interventions for the treatment of rheumatoid arthritis and registered in ClinicalTrials.gov between 2002 and 2016. Full publications were identified for completed studies from information in the trial registry or from an internet search using Google and the citation database Web of Science.Main outcome measure The percentage of trials reporting or planning to measure the rheumatoid arthritis core outcome set calculated from the information presented in the trial registry and compared with the percentage reporting the rheumatoid arthritis core outcome set in the resulting trial publications.Results The full rheumatoid arthritis core outcome set was reported in 81% (116/143) of trials identified on the registry as completed (or terminated) for which results were found in either the published literature or the registry. For trials identified on the registry as completed (or terminated), using information only available in the registry gives an estimate for uptake of 77% (145/189).Conclusions The uptake of the rheumatoid arthritis core outcome set in clinical trials has continued to increase over time. Using the information on outcomes listed for completed or terminated studies in a trial registry provides a reasonable estimate of the uptake of a core outcome set and is a more efficient and up-to-date approach than examining the outcomes in published trial reports. The method proposed may provide an efficient approach for an up-to-date assessment of the uptake of the 300 core outcome sets already published.
Sickle Cell Trait and Risk of Cognitive Impairment in African Americans: The Reasons for Geographic and Racial Differences in Stroke (REGARDS) Cohort
Authors: Christina Cahill, Marguerite Ryan Irvin, Neil A Zakai, Rakhi P. Naik, Leslie McClure, Frederick Unverzagt, Virginia Wadley, Hyacinth I Hyacinth, Jennifer Manly, William McClellan, Suzanne Judd, Mary Cushman
Journal: Blood (2016)
Metabolic Profiling of Adult Acute Myeloid Leukemia (AML)
Authors: Mahmoud A Bassal, Paul Leo, Saumya E Samaraweera, Kyaw Ze Ya Maung, Milena Babic, Parvathy Venugopal, Jesse Cheah, Christopher N Hahn, Hamish S Scott, Evgeny Glazov, Sarah C Bray, Diana Iarossi, Ing Soo Tiong, Mhairi Clout, Emma Duncan, L. Bik To, Paula Marlton, Ian D Lewis, Devinder S Gill, Thomas J Gonda, Anna L Brown, Richard D'Andrea
Journal: Blood (2016)
Clinical experience with Vemurafenib in pretreated melanoma (MEL): The results of open label multi center study from Turkey.
Authors: Ismail Celik, Nil Molinas Mandel, Erhan Gokmen, Olcun Umit Unal, Alper Sevinc, Hasan Senol Coskun, Suleyman Buyukberber, Huseyin Abali, Mustafa Ozguroglu, Gungor Utkan, Mahmut Gumus, Bahadir Pekin, Asligul Kendirci
Journal: Journal of Clinical Oncology (2015)

e20085 Background: Activating mutations in BRAF gene are present in 40-60% of metastatic MEL patients (pts). VEM is an inhibitor of kinase domain in mutated BRAF. In previous trials VEM had been shown to increase PFS and OS. This is an open label, multicenter study to allow pts to access to VEM prior to approval in Turkey. Methods: A total of 111 pts accessed VEM as a part of expanded access program. The reassessment data to confirm response were not available due to safety rules of Turkish Local Regulatory Authority. Point estimates of survival were reported and subgroup analysis according to LDH, ECOG status and presence of brain metastases was performed. Overall and anatomic site specific side effects were recorded and analyzed using descriptive statistical methods (PFS/OS estimated using Kaplan-Meier method). Results: The median age of pts were 52 (18-91) years. At baseline, 54% had stage M1c disease, 9.9% had an ECOG PS ≧2 and 46% had elevated LDH; 77.5% of pts had received prior systemic therapy, 9.9% received prior ipilimumab, and 19.8% radiotherapy for brain metastases. Median PFS and OS were 5.7 (95% CI 4.8-6.9) and 9.7 (95% CI 7.4-13.6) months, respectively. Poor prognostic factors for OS, included increased lactate dehydrogenase, intracranial metastasis and high ECOG scores. In 30.6% of pts at least one grade ≥ 3 adverse effect was observed. Squamous cell carcinoma occurred in 5.4% of patients. AEs requiring dose reduction occurred in 11% of pts, and 2 pts (1.8%) experienced events leading to VEM withdrawal. Conclusions: This study confirms that VEM is a safe and effective treatment option. For several groups often not included in clinical trials including pts with previously treated brain metastases, ECOG PS ≧ 2 to 3 had benefit. The PFS was consistent across most of the subgroups (Table:1) and overall survival was lower in subgroups with markers of poor prognosis than in the overall population. These results were consistent with Global Safety Study results in terms of survival (1). 1. Larkin J, Del Vecchio M, Ascierto PA, et al. Vemurafenib in patients with BRAF(V600) mutated metastatic melanoma: an open-label, multicentre, safety study. Lancet Oncol. 2014 Apr; 15(4):436-44. Clinical trial information: NCT01307397.
Aspirin for Primary Prevention of Cardiovascular Events in People With Diabetes
Authors: Michael Pignone, Mark J. Alberts, John A. Colwell, Mary Cushman, Silvio E. Inzucchi, Debabrata Mukherjee, Robert S. Rosenson, Craig D. Williams, Peter W. Wilson, M. Sue Kirkman
Journal: Journal of the American College of Cardiology (2010)
Outside the Door
Authors: C. Nicholas Cuneo
Journal: JAMA Cardiology (2017)

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 Cardiology 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 Cardiology journal
Abstract B59: Control of invasion by PKC theta in triple-negative breast cancer
Authors: Lucie Chadelle, Valérie Cadamuro, Jiaying Liu, Xiaobo Wang, Karine Belguise
Journal: Cancer Research (2016)

Abstract Triple-negative breast cancers (TNBC: negative for oestrogen-receptor, progesterone-receptor and human-epidermal-growth-factor receptor 2 [HER2]) account for 15-20% of breast cancers and are characterized by an extremely aggressive phenotype. Currently, there is no efficient targeted therapy that can prevent the metastatic dissemination of TNBC. The serine threonine kinase PKCθ has recently been identified as a potential new marker of TNBC and as a strong inducer of cancer invasion. However, how PKCθ controls tumour invasion in TNBC is still unclear. Here our results suggest that PKCθ can promote invasion by activating the focal adhesion kinase (FAK) signalling that regulates the cycle of focal contact formation and disassembly. As a consequence of this activation, PKCθ enhances the dynamic of adhesion turnover, Rho GTPases activity and protrusions formation. We also have unravelled the molecular mechanisms by which PKCθ controls FAK: PKCθ interacts with and phosphorylates FAK thus leading to its opening and activation. We believe that the identified phosphorylation sites are implicated in the PKCθ controlled invasion. In the long term, this study could help develop new targeted therapy for TNBC such as PKCθ specific inhibitors that would limit metastasis formation. Citation Format: Lucie Chadelle, Valérie Cadamuro, Jiaying Liu, Xiaobo Wang, Karine Belguise. Control of invasion by PKC theta in triple-negative breast cancer. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr B59.
Abstract 189: Activation of Voltage-Dependent Anion Channel 2 Suppresses Ca <sup>2+</sup> -Induced Cardiac Arrhythmia
Authors: Jaunian Chen, Johann Schredelseker, Hirohito Shimizu, Jie Huang, Kui Lu, Sarah Franklin, Thomas Vondriska, Joshua I Goldhaber, Ohyun Kwon
Journal: Circulation Research (2012)

Abnormal Ca2+ handling in cardiac muscle cells is associated with a wide range of human cardiac diseases, including heart failure and cardiac arrhythmias. Zebrafish tremblor (tre) mutant embryos manifest unsynchronized cardiac contractions due to a Ca2+ extrusion defect in cardiomyocytes and thus are used as an animal model for aberrant Ca2+ homeostasis-induced cardiac arrhythmia. To further dissect molecular mechanisms regulating cardiac Ca2+ homeostasis, we conducted a chemical suppressor screen on tre and found that efsevin, a synthetic compound, potently suppresses cardiac fibrillation and restores rhythmic cardiac contractions in tre embryos. In addition, the treatment with efsevin blocks the propagation of arrhythmogenic Ca2+ waves and accelerates the decay phase of Ca2+ sparks in adult murine cardiomyocytes under Ca2+ overload conditions, demonstrating that efsevin modulates Ca2+ handling in both embryonic and adult cardiac tissues. Through a biochemical pulldown assay, we identified a direct interaction between efsevin and VDAC2, a mitochondrial outer membrane voltage dependent anion channel. Overexpression of VDAC2 restores synchronized cardiac contraction in tre and knocking down VDAC2 activity abolishes the rescue effect of efsevin on tre, suggesting that efsevin modulates cardiac Ca2+ homeostasis by potentiating VDAC2 activity. We further showed that enhancing mitochondria Ca2+ uptake by overexpressing MICU or MCU suppresses cardiac fibrillation in tre just like VDAC2 does. Interestingly, this suppressive effect is absent in tre/vdac2 double deficient embryos and co-expression of VDAC2 and MICU or MCU results in synergistic rescue effect on tre, indicating a critical role for mitochondria in regulating cardiac Ca2+ handling and rhythmicity and suggesting that VDAC2 functions as a gate for transporting Ca2+ across the outer membrane. Taken together, our findings identify efsevin as a potent pharmacological tool to modulate cardiac Ca2+ handling, suggest a critical role of mitochondria in the control of cardiac rhythmicity and establish VDAC2 as a modulator of cardiac Ca2+ handling and a potential therapeutic target for the treatment of arrhythmias.
In vitro chemosensitivity against enzastaurin correlates with gene expression of IL8 and GSK3-beta
Authors: O. Oberschmidt, U. Eismann, M. M. Lahn, J. Fleeth, F. Lüdtke, S. Struck, L. Schulz, J. Blatter, D. Ma, A. Hanauske
Journal: Journal of Clinical Oncology (2006)

13046 Background: Enzastaurin (E) is an active antitumoral agent which selectively inhibits the β-isoform of protein kinase C (PKC-β). The compound blocks the enzyme’s ATP-binding site and signal transmission is abrogated resulting in the inhibition of neovascularization. The aim of the present study was to correlate gene expression with in vitro chemosensitivity of freshly explanted human tumor specimens. Such correlations in tumors taken directly from patients will help to rationally design subsequent clinical trials. Methods: Soft-agar colony forming assays were performed on freshly biopsied tumor cells exposed to various concentrations of E. Corresponding pieces of tumor specimens were shock-frozen and prepared for RNA isolation and cDNA generation followed by multiplex real-time PCR experiments. Gene expression data were correlated against cloning assay results. Results: Gene expression data of PKC-β 1 , PKC-β 2 , IL8RA, IL8RB, IL8, GSK3-β, and TGF-β were correlated against in vitro chemosensitivity pattern of E from 66 samples. After 1h-drug exposure gene expressions in sensitive versus resistant specimens were statistically significant with p = 0.013 for IL8 [median copy number (mcn): 1881 vs. 694; n = 66] and p = 0.012 for GSK3-beta (mcn: 1.6 vs. 7.0; n = 66). No correlation was detected for PKC-β 1 , PKC-β 2 , IL8RA, and IL8RB. Detection of TGF-β failed in most samples. Conclusions: Low expression of GSK3-β and high expression of IL8 correlate statistically significantly with increased in vitro sensitivity to E in freshly explanted human tumors. These findings may help direct further clinical development of this compound. No significant financial relationships to disclose.
Identification of a plasma mi<scp>RNA</scp> biomarker signature for allergic asthma: A translational approach
Authors: K. Milger, J. Götschke, L. Krause, P. Nathan, F. Alessandrini, A. Tufman, R. Fischer, S. Bartel, F. J. Theis, J. Behr, S. Dehmel, N. S. Mueller, N. Kneidinger, S. Krauss‐Etschmann
Journal: Allergy (2017)

Abstract Background Asthma is a heterogeneous chronic disease with different phenotypes and treatment responses. Thus, there is a high clinical need for molecular disease biomarkers to aid in differentiating these distinct phenotypes. As Micro RNA s (mi RNA s), that regulate gene expression at the post‐transcriptional level, are altered in experimental and human asthma, circulating mi RNA s are attractive candidates for the identification of novel biomarkers. This study aimed to identify plasmatic mi RNA ‐based biomarkers of asthma, through a translational approach. Methods We prescreened mi RNA s in plasma samples from two different murine models of experimental asthma (ovalbumin and house dust mite); mi RNA s deregulated in both models were further tested in a human training cohort of 20 asthma patients and 9 healthy controls. Candidate mi RNA s were then validated in a second, independent group of 26 asthma patients and 12 healthy controls. Results Ten mi RNA ratios consisting of 13 mi RNA s were differentially regulated in both murine models. Measuring these mi RNA s in the training cohort identified a biomarker signature consisting of five mi RNA ratios (7 mi RNA s). This signature showed a good sensitivity and specificity in the test cohort with an area under the receiver operating characteristic curve ( AUC ) of 0.92. Correlation of mi RNA ratios with clinical characteristics further revealed associations with FVC % predicted, and oral corticosteroid or antileukotriene use. Conclusion Distinct plasma mi RNA s are differentially regulated both in murine and in human allergic asthma and were associated with clinical characteristics of patients. Thus, we suggest that mi RNA levels in plasma might have future potential to subphenotype patients with asthma.
Hepatocyte Nuclear Factor–1β Regulates Urinary Concentration and Response to Hypertonicity
Authors: Karam Aboudehen, Lama Noureddine, Patricia Cobo-Stark, Svetlana Avdulov, Shayan Farahani, Micah D. Gearhart, Daniel G. Bichet, Marco Pontoglio, Vishal Patel, Peter Igarashi
Journal: Journal of the American Society of Nephrology (2017)

The transcription factor hepatocyte nuclear factor–1 β (HNF-1 β ) is essential for normal kidney development and function. Inactivation of HNF-1 β in mouse kidney tubules leads to early-onset cyst formation and postnatal lethality. Here, we used Pkhd1/Cre mice to delete HNF-1 β specifically in renal collecting ducts (CDs). CD-specific HNF-1 β mutant mice survived long term and developed slowly progressive cystic kidney disease, renal fibrosis, and hydronephrosis. Compared with wild-type littermates, HNF-1 β mutant mice exhibited polyuria and polydipsia. Before the development of significant renal structural abnormalities, mutant mice exhibited low urine osmolality at baseline and after water restriction and administration of desmopressin. However, mutant and wild-type mice had similar plasma vasopressin and solute excretion levels. HNF-1 β mutant kidneys showed increased expression of aquaporin-2 mRNA but mislocalized expression of aquaporin-2 protein in the cytoplasm of CD cells. Mutant kidneys also had decreased expression of the UT-A urea transporter and collectrin, which is involved in apical membrane vesicle trafficking. Treatment of HNF-1 β mutant mIMCD3 cells with hypertonic NaCl inhibited the induction of osmoregulated genes, including Nr1h4 , which encodes the transcription factor FXR that is required for maximal urinary concentration. Chromatin immunoprecipitation and sequencing experiments revealed HNF-1 β binding to the Nr1h4 promoter in wild-type kidneys, and immunoblot analysis revealed downregulated expression of FXR in HNF-1 β mutant kidneys. These findings reveal a novel role of HNF-1 β in osmoregulation and identify multiple mechanisms, whereby mutations of HNF-1 β produce defects in urinary concentration.
IgG4-Related Disease
Authors: Vinay S. Mahajan, Hamid Mattoo, Vikram Deshpande, Shiv S. Pillai, John H. Stone
Journal: Annual Review of Pathology Mechanisms of Disease (2013)

Immunoglobulin G4 (IgG4)-related disease (IgG4-RD) is an immune-mediated condition that can affect almost any organ and is now being recognized with increasing frequency. IgG4-RD is characterized by a lymphoplasmacytic infiltrate composed of IgG4(+) plasma cells, storiform fibrosis, obliterative phlebitis, and mild to moderate eosinophilia. The diagnosis of IgG4-RD unifies many eponymous fibroinflammatory conditions that had previously been thought to be confined to single organs. IgG4-RD lesions are infiltrated by T helper cells, which likely cause progressive fibrosis and organ damage. IgG4 antibodies are generally regarded as noninflammatory. Although autoreactive IgG4 antibodies are observed in IgG4-RD, there is no evidence that they are directly pathogenic. Rituximab-induced B cell depletion in IgG4-RD leads to rapid clinical and histological improvement accompanied by swift declines in serum IgG4 concentrations. Although IgG autoantibodies against various exocrine gland antigens have been described in IgG4-RD, whether they are members of the IgG4 subclass is unknown. The contribution of autoantibodies to IgG4-RD remains unclear.
Multigene Panel Testing Provides a New Perspective on Lynch Syndrome
Authors: Carin R. Espenschied, Holly LaDuca, Shuwei Li, Rachel McFarland, Chia-Ling Gau, Heather Hampel
Journal: Journal of Clinical Oncology (2017)

Purpose Most existing literature describes Lynch syndrome (LS) as a hereditary syndrome leading to high risks of colorectal cancer (CRC) and endometrial cancer mainly as a result of mutations in MLH1 and MSH2. Most of these studies were performed on cohorts with disease suggestive of hereditary CRC and population-based CRC and endometrial cancer cohorts, possibly biasing results. We aimed to describe a large cohort of mismatch repair (MMR) mutation carriers ascertained through multigene panel testing, evaluate their phenotype, and compare the results with those of previous studies. Methods We retrospectively reviewed clinical histories of patients who had multigene panel testing, including the MMR and EPCAM genes, between March 2012 and June 2015 (N = 34,981) and performed a series of statistical comparisons. Results Overall, MSH6 mutations were most frequent, followed by PMS2, MSH2, MLH1, and EPCAM mutations, respectively. Of 528 patients who had MMR mutations, 63 (11.9%) had breast cancer only and 144 (27.3%) had CRC only. When comparing those with breast cancer only to those with CRC only, MSH6 and PMS2 mutations were more frequent than MLH1 and MSH2 mutations ( P = 2.3 × 10-5). Of the 528 patients, 22.2% met BRCA1 and BRCA2 ( BRCA1/2) testing criteria and not LS criteria, and 5.1% met neither BRCA1/2 nor LS testing criteria. MSH6 and PMS2 mutations were more frequent than MLH1 and MSH2 mutations among patients who met BRCA1/2 testing criteria but did not meet LS testing criteria ( P = 4.3 × 10-7). Conclusion These results provide a new perspective on LS and suggest that individuals with MSH6 and PMS2 mutations may present with a hereditary breast and ovarian cancer phenotype. These data also highlight the limitations of current testing criteria in identifying these patients, as well as the need for further investigation of cancer risks in patients with MMR mutations.
Idiopathic Pulmonary Fibrosis
Authors: STEVEN E. GAY, ELLA A. KAZEROONI, GALEN B. TOEWS, JOSEPH P. LYNCH, BARRY H. GROSS, PHILLIP N. CASCADE, DAVID L. SPIZARNY, ANDREW FLINT, M. ANTHONY SCHORK, RICHARD I. WHYTE, JOHN POPOVICH, ROBERT HYZY, FERNANDO J. MARTINEZ
Journal: American Journal of Respiratory and Critical Care Medicine (1998)

Idiopathic pulmonary fibrosis (IPF) is associated with significant morbidity and mortality despite aggressive therapy. Thirty-eight patients with biopsy-proven IPF were studied to identify pretreatment features that could be used to predict short-term improvement in pulmonary function and improved longer term survival. In all patients, a pretreatment clinical (dyspnea), radiographic (chest radiograph), and physiologic (pulmonary function including exercise saturation) score was generated (CRP). A high-resolution CT scan (HRCT) was independently scored by four radiologists for ground glass (CT-alv) and linear opacity (CT-fib) on a scale of 0–4. Open lung biopsy samples were scored for cellular infiltration, interstitial fibrosis, desquamation, and granulation by an experienced pulmonary pathologist. All patients were treated with 3 mo of high-dose steroids and the CRP scoring repeated. Patients were divided into three groups: responders with a greater than 10-point drop in CRP (n = 10); stable with ± 10 point change in CRP (n = 14); and nonresponders with > 10 point rise in CRP or death (n = 14). Those responding to steroids were treated for 18 mo in a tapering fashion. In all others, steroids were tapered quickly and oral cyclophosphamide prescribed. Responders (10 of 38) had a lower age (45.1 ± 4.3 yr) than nonresponders (61.4 ± 3.5 yr) or those remaining stable (53.1 ± 3.3 yr) (p = 0.01). Pretreatment CRP was higher in responders (58.8 ± 5.6) than nonresponders (40.5 ± 4.7) or stable individuals (37.6 ± 4.7) (p = 0.01). Cellular infiltration score of the open lung biopsies was higher in responders (7.6 ± 0.6) than stable individuals (5.7 ± 0.5) (p = 0.04). The CT-alv scores were higher and CT-fib scores were lower in responders than nonresponders. Receiver operating curve (ROC) analysis was employed to identify pretreatment features of longer term survival (follow-up of 29.1 ± 2.3 mo). Only CT-fib (p = 0.009) and pathology fibrosis score (p = 0.03) were able to predict mortality. A pretreatment CT-fib score ⩾ 2.0 demonstrated 80% sensitivity and 85% specificity in predicting survival. Those patients who did not respond to initial steroid therapy demonstrated a worse long-term survival and greater likelihood of decreased pulmonary function. We demonstrate that pretherapy pulmonary function, pathologic and radiographic parameters are different in individuals who respond to initial prednisone therapy. Only HRCT imaging and pathologic fibrosis were able to reliably predict long-term survival in patients with biopsy-proven IPF.