tbuckley/cabot-search huggingface dataset:
Magnetic Resonance Spectroscopy Markers of Disease Progression in Multiple Sclerosis
Authors: Sara Llufriu, John Kornak, Helene Ratiney, Joonmi Oh, Don Brenneman, Bruce A. Cree, Mehul Sampat, Stephen L. Hauser, Sarah J. Nelson, Daniel Pelletier
Journal: JAMA Neurology (2014)

Predicting disease evolution is becoming essential for optimizing treatment decision making in multiple sclerosis (MS). Multiple sclerosis pathologic damage typically includes demyelination, neuro-axonal loss, and astrogliosis.To evaluate the potential of magnetic resonance markers of central nervous system injury to predict brain-volume loss and clinical disability in multiple sclerosis.Participants were selected from the Multiple Sclerosis Center at the University of California-San Francisco. The preliminary data set included 59 patients with MS and 43 healthy control individuals. The confirmatory data set included 220 patients from an independent, large genotype-phenotype research project.Baseline N-acetylaspartate (NAA) level, myo-inositol (mI) in normal-appearing white and gray matter, myelin water fraction in normal-appearing white matter, markers of axonal damage, astrogliosis, and demyelination were evaluated as predictors in a preliminary data set. Potential predictors were subsequently tested for replication in a confirmatory data set. Clinical scores and percentage of brain-volume change were obtained annually over 4 years as outcomes. Predictors of outcomes were assessed using linear models, linear mixed-effects models, and logistic regression.N-acetylaspartate and mI both had statistically significant effects on brain volume, prompting the use of the mI:NAA ratio in normal-appearing white matter as a predictor. The ratio was a predictor of brain-volume change in both cohorts (annual slope in the percentage of brain-volume change/unit of increase in the ratio: -1.68; 95% CI, -3.05 to -0.30; P = .02 in the preliminary study cohort and -1.08; 95% CI, -1.95 to -0.20; P = .02 in the confirmatory study cohort). Furthermore, the mI:NAA ratio predicted clinical disability (Multiple Sclerosis Functional Composite evolution: -0.52 points annually, P < .001; Multiple Sclerosis Functional Composite sustained progression: odds ratio, 2.76/SD increase in the ratio; 95% CI, 1.32 to 6.47; P = .01) in the preliminary data set and predicted Multiple Sclerosis Functional Composite evolution (-0.23 points annually; P = .01), Expanded Disability Status Scale evolution (0.57 points annually; P = .04), and Expanded Disability Status Scale sustained progression (odds ratio, 1.46; 95% CI, 1.10 to 1.94; P = .009) in the confirmatory data set. Myelin water fraction did not show predictive value.The mI:NAA ratio in normal-appearing white matter has consistent predictive power on brain atrophy and neurological disability evolution. The combined presence of astrogliosis and axonal damage in white matter has cardinal importance in disease severity.
Effect of smoking cessation on cough reflex sensitivity
Authors: P. V. Dicpinigaitis, B. Sitkauskiene, K. Stravinskaite, D. W. Appel, A. Negassa, R. Sakalauskas
Journal: European Respiratory Journal (2006)

Recent studies have shown that cigarette smokers have diminished cough reflex sensitivity compared with nonsmokers. The current authors proposed a mechanism of chronic cigarette smoke-induced desensitisation of airway cough receptors. To investigate this hypothesis, cough sensitivity to inhaled capsaicin (C5) in chronic smokers was measured both while they were actively smoking and 2, 6, 12 and 24 weeks after smoking cessation. In total, 29 subjects underwent baseline capsaicin challenge while smoking and 2 weeks after smoking cessation. Mean+/-sem log C5 fell from 1.86+/-0.12 to 1.60+/-0.12, demonstrating significant enhancement of cough reflex sensitivity. Of the total, 20, 18 and 14 subjects successfully abstained from smoking for 6, 12 and 24 weeks, respectively. Mean log C5 values after 12 and 24 weeks of smoking cessation were significantly diminished from baseline. In a control group of smokers, mean log C5 did not decrease from baseline after 6, 12 and 24 weeks. Overall, the log C5 profile of the smoking cessation group showed a clear, linearly decreasing trend over time compared with the control group. Even after many years of smoking, cough sensitivity is enhanced as early as 2 weeks after smoking cessation. Given the importance of an intact cough reflex, these changes may provide clinical benefit.
Basal nitric oxide modulates vascular effects of a peptide activating protease-activated receptor 2
Authors: Carla Cicala, Silvana Morello, Valentina Vellecco, Beatrice Severino, Ludovico Sorrentino, Giuseppe Cirino
Journal: Cardiovascular Research (2003)

Protease-activated receptor 2 (PAR2) is a G-protein-coupled receptor proteolytically activated by trypsin, tryptase or factor Xa. Alternatively, PAR2 can be activated by synthetic peptides whose sequence mimics the tethered ligand exposed after receptor cleavage. It is known that PAR2 modulates vascular reactivity, both in vitro and in vivo. The present study was designed to investigate the role of basal nitric oxide and cyclic nucleotides, adenosine 3'5'cyclic monophosphate (cAMP) and guanosine 3'5' cyclic monophosphate (cGMP), in the vasorelaxation induced by a PAR2-activating peptide (PAR2-AP; SLIGRL-NH(2)) on rat aorta in vitro.A concentration-response curve to PAR2-AP was performed on rat thoracic aorta with or without a functional endothelium, and the effect of inhibitors was evaluated. The effect of PAR2-AP (10(-7)-3 x 10(-5) M) on endothelium-denuded aorta was also evaluated after tissue incubation with sodium nitroprusside.PAR2-AP (10(-7)-3 x 10(-5) M) caused an endothelium-dependent relaxation abolished by N(omega)-nitro-L-arginine methyl ester, L-NAME, and by the guanylyl cyclase inhibitor, 1H-[1,2,4] oxadiazolo [4,3-a] quinoxalin-1-one (ODQ), but unaffected by geldanamycin. Vasorelaxant effect of PAR2-AP was only partially inhibited by the adenylyl cyclase inhibitor, 9-(tetrahydro-2-furanyl)-9H-purin-6-amine (SQ 22,536), and it was increased by tissue incubation with the phosphodiesterase inhibitor, rolipram. On tissue without endothelium, PAR2-AP did not cause vasorelaxation, up to a concentration of 10(-4) M. However, after tissue incubation with sodium nitroprusside (SNP, 3 x 10(-9) M), the vasorelaxant effect of PAR2-AP was restored. Following tissue incubation with PAR2-AP, cAMP levels were significantly increased compared to control values.Our results suggest that vasorelaxation induced by PAR2-AP is modulated by basal nitric oxide with an involvement of both cyclic nucleotides, cGMP and cAMP.
A pharmacist-led information technology intervention for medication errors (PINCER): a multicentre, cluster randomised, controlled trial and cost-effectiveness analysis
Authors: Anthony J Avery, Sarah Rodgers, Judith A Cantrill, Sarah Armstrong, Kathrin Cresswell, Martin Eden, Rachel A Elliott, Rachel Howard, Denise Kendrick, Caroline J Morris, Robin J Prescott, Glen Swanwick, Matthew Franklin, Koen Putman, Matthew Boyd, Aziz Sheikh
Journal: The Lancet (2012)
Randomized Phase II Study of Cilengitide, an Integrin-Targeting Arginine-Glycine-Aspartic Acid Peptide, in Recurrent Glioblastoma Multiforme
Authors: David A. Reardon, Karen L. Fink, Tom Mikkelsen, Timothy F. Cloughesy, Alison O'Neill, Scott Plotkin, Michael Glantz, Paula Ravin, Jeffrey J. Raizer, Keith M. Rich, David Schiff, William R. Shapiro, Susan Burdette-Radoux, Edward J. Dropcho, Sabine M. Wittemer, Johannes Nippgen, Martin Picard, L. Burt Nabors
Journal: Journal of Clinical Oncology (2008)

Cilengitide, an inhibitor of alphavbeta3 and alphavbeta5 integrin receptors, demonstrated minimal toxicity and durable activity across a wide range of doses administered to adults with recurrent glioblastoma multiforme (GBM) in a prior phase I study. The current multicenter phase II study was conducted to evaluate the activity and safety of cilengitide in GBM patients at first recurrence.Eligible patients were randomly assigned to receive either 500 or 2,000 mg of cilengitide twice weekly on a continuous basis. Patients were assessed every 4 weeks. The primary end point was 6-month progression-free survival (PFS) rate. Secondary end points included PFS, overall survival (OS), and radiographic response, as well as quality-of-life and pharmacokinetic assessments.Eighty-one patients were enrolled, including 41 on the 500-mg arm and 40 on the 2,000-mg arm. The safety profile of cilengitide was excellent, with no significant reproducible toxicities observed on either arm. Antitumor activity was observed in both treatment cohorts but trended more favorably among patients treated with 2,000 mg, including a 6-month PFS of 15% and a median OS of 9.9 months.Cilengitide monotherapy is well tolerated and exhibits modest antitumor activity among recurrent GBM patients. Additional studies integrating cilengitide into combinatorial regimens for GBM are warranted.
Early Occurrence of <b> <i>RASSF1A</i> </b> Hypermethylation and Its Mutual Exclusion with <b> <i>BRAF</i> </b> Mutation in Thyroid Tumorigenesis
Authors: Mingzhao Xing, Yoram Cohen, Elizabeth Mambo, Giovanni Tallini, Robert Udelsman, Paul W. Ladenson, David Sidransky
Journal: Cancer Research (2004)

Follicular epithelial cell-derived thyroid tumors are common neoplasms comprised mainly of benign thyroid adenomas, follicular thyroid cancers, and papillary thyroid cancers (PTCs). Hypermethylation of the tumor suppressor gene RASSF1A and activating mutation of BRAF gene have been reported recently in thyroid cancers. To additionally investigate the roles of these two epigenetic/genetic alterations in thyroid tumor progression, we examined their occurrences and relationship in both benign and malignant thyroid neoplasms. With real-time quantitative methylation-specific PCR, we found that 4 of 9 (44%) benign adenomas, 9 of 12 (75%) follicular thyroid cancers tumors, and 6 of 30 (20%) of PTC tumors harbored promoter methylation in > or = 25% of RASSF1A alleles. Additional quantitative analysis revealed RASSF1A methylation only in BRAF mutation-negative PTCs. A similar inverse correlation of RASSF1A methylation with BRAF mutation was seen in thyroid tumor cell lines. Our results, therefore, suggest that epigenetic inactivation of RASSF1A through aberrant methylation is an early step in thyroid tumorigenesis. Like the previously reported mutually exclusive relationship between BRAF mutation and other Ras pathway components such as RET/PTC rearrangement, a mutually exclusive relationship also exists between BRAF mutation and RASSF1A methylation in thyroid tumorigenesis.
Individualized Systems Medicine Strategy to Tailor Treatments for Patients with Chemorefractory Acute Myeloid Leukemia
Authors: Tea Pemovska, Mika Kontro, Bhagwan Yadav, Henrik Edgren, Samuli Eldfors, Agnieszka Szwajda, Henrikki Almusa, Maxim M. Bespalov, Pekka Ellonen, Erkki Elonen, Bjørn T. Gjertsen, Riikka Karjalainen, Evgeny Kulesskiy, Sonja Lagström, Anna Lehto, Maija Lepistö, Tuija Lundán, Muntasir Mamun Majumder, Jesus M. Lopez Marti, Pirkko Mattila, Astrid Murumägi, Satu Mustjoki, Aino Palva, Alun Parsons, Tero Pirttinen, Maria E. Rämet, Minna Suvela, Laura Turunen, Imre Västrik, Maija Wolf, Jonathan Knowles, Tero Aittokallio, Caroline A. Heckman, Kimmo Porkka, Olli Kallioniemi, Krister Wennerberg
Journal: Cancer Discovery (2013)

We present an individualized systems medicine (ISM) approach to optimize cancer drug therapies one patient at a time. ISM is based on (i) molecular profiling and ex vivo drug sensitivity and resistance testing (DSRT) of patients' cancer cells to 187 oncology drugs, (ii) clinical implementation of therapies predicted to be effective, and (iii) studying consecutive samples from the treated patients to understand the basis of resistance. Here, application of ISM to 28 samples from patients with acute myeloid leukemia (AML) uncovered five major taxonomic drug-response subtypes based on DSRT profiles, some with distinct genomic features (e.g., MLL gene fusions in subgroup IV and FLT3-ITD mutations in subgroup V). Therapy based on DSRT resulted in several clinical responses. After progression under DSRT-guided therapies, AML cells displayed significant clonal evolution and novel genomic changes potentially explaining resistance, whereas ex vivo DSRT data showed resistance to the clinically applied drugs and new vulnerabilities to previously ineffective drugs.Here, we demonstrate an ISM strategy to optimize safe and effective personalized cancer therapies for individual patients as well as to understand and predict disease evolution and the next line of therapy. This approach could facilitate systematic drug repositioning of approved targeted drugs as well as help to prioritize and de-risk emerging drugs for clinical testing.
Noninvasive Radiofrequency Field Destruction of Pancreatic Adenocarcinoma Xenografts Treated with Targeted Gold Nanoparticles
Authors: Evan S. Glazer, Cihui Zhu, Katheryn L. Massey, C. Shea Thompson, Warna D. Kaluarachchi, Amir N. Hamir, Steven A. Curley
Journal: Clinical Cancer Research (2010)

Abstract Purpose: Pancreatic carcinoma is one of the deadliest cancers with few effective treatments. Gold nanoparticles (AuNP) are potentially therapeutic because of the safety demonstrated thus far and their physiochemical characteristics. We used the astounding heating rates of AuNPs in nonionizing radiofrequency (RF) radiation to investigate human pancreatic xenograft destruction in a murine model. Experimental Design: Weekly, Panc-1 and Capan-1 human pancreatic carcinoma xenografts in immunocompromised mice were exposed to an RF field 36 hours after treatment (intraperitoneal) with cetuximab- or PAM4 antibody–conjugated AuNPs, respectively. Tumor sizes were measured weekly, whereas necrosis and cleaved caspase-3 were investigated with hematoxylin–eosin staining and immunofluorescence, respectively. In addition, AuNP internalization and cytotoxicity were investigated in vitro with confocal microscopy and flow cytometry, respectively. Results: Panc-1 cells demonstrated increased apoptosis with decreased viability after treatment with cetuximab-conjugated AuNPs and RF field exposure (P = 0.00005). Differences in xenograft volumes were observed within 2 weeks of initiating therapy. Cetuximab- and PAM4-conjugated AuNPs demonstrated RF field–induced destruction of Panc-1 and Capan-1 pancreatic carcinoma xenografts after 6 weeks of weekly treatment (P = 0.004 and P = 0.035, respectively). There was no evidence of injury to murine organs. Cleaved caspase-3 and necrosis were both increased in treated tumors. Conclusions: This study demonstrates a potentially novel cancer therapy by noninvasively inducing intracellular hyperthermia with targeted AuNPs in an RF field. While the therapy is dependent on the specificity of the targeting antibody, normal tissues were without toxicity despite systemic therapy and whole-body RF field exposure. Clin Cancer Res; 16(23); 5712–21. ©2010 AACR.
Randomized Evaluation of the Effects of Filter-Based Distal Protection on Myocardial Perfusion and Infarct Size After Primary Percutaneous Catheter Intervention in Myocardial Infarction With and Without ST-Segment Elevation
Authors: Michael Gick, Nikolaus Jander, Hans-Peter Bestehorn, Rolf-Peter Kienzle, Miroslaw Ferenc, Klaus Werner, Thomas Comberg, Kristhild Peitz, Dietlind Zohlnhöfer, Valerio Bassignana, Heinz Joachim Buettner, Franz-Josef Neumann
Journal: Circulation (2005)

In acute myocardial infarction, distal embolization of debris during primary percutaneous catheter intervention may curtail microvascular reperfusion of the infarct region. Our randomized trial investigated whether distal protection with a filter device can improve microvascular perfusion and reduce infarct size after primary percutaneous catheter intervention.We enrolled 200 patients who had angina within 48 hours after onset of pain plus at least 1 of 3 additional criteria: ST-segment elevation, elevated myocardial marker proteins, and angiographic evidence of thrombotic occlusion. Among the patients included (83% men; mean age, 62+/-12 years), 100 were randomly assigned to the filter-wire group and 100 to the control group. The primary end point was the maximal adenosine-induced Doppler flow velocity in the recanalized infarct artery; the secondary end point was infarct size estimated by the volume of delayed enhancement on nuclear MRI. ST-segment elevation myocardial infarction was present in 68.5% of the patients; the median time from onset of pain was 6.9 hours. In the filter-wire group, maximal adenosine-induced flow velocity was 34+/-17 compared with 36+/-20 cm/s in the control group (P=0.46). Infarct sizes, assessed in 82 patients in the filter-wire group and 78 patients in the control group, were 11.8+/-9.3% of the left ventricular mass in the filter-wire group and 10.4+/-9.4% in the control group (P=0.33). Thirty-day mortality was 2% in filter-wire group and 3% in the control group.The filter wire as an adjunct to primary percutaneous catheter intervention in myocardial infarction with and without ST-segment elevation did not improve reperfusion or reduce infarct size.
Association of Lifecourse Socioeconomic Status with Chronic Inflammation and Type 2 Diabetes Risk: The Whitehall II Prospective Cohort Study
Authors: Silvia Stringhini, G. David Batty, Pascal Bovet, Martin J. Shipley, Michael G. Marmot, Meena Kumari, Adam G. Tabak, Mika Kivimäki
Journal: PLoS Medicine (2013)

Silvia Stringhini and colleagues followed a group of British civil servants over 18 years to look for links between socioeconomic status and health. Please see later in the article for the Editors' Summary
The distinctive germinal center phase of IgE+ B lymphocytes limits their contribution to the classical memory response
Authors: Jin-Shu He, Michael Meyer-Hermann, Deng Xiangying, Lim Yok Zuan, Leigh Ann Jones, Lakshmi Ramakrishna, Victor C. de Vries, Jayashree Dolpady, Hoi Aina, Sabrina Joseph, Sriram Narayanan, Sharrada Subramaniam, Manoj Puthia, Glenn Wong, Huizhong Xiong, Michael Poidinger, Joseph F. Urban, Juan J. Lafaille, Maria A. Curotto de Lafaille
Journal: The Journal of Experimental Medicine (2013)

The mechanisms involved in the maintenance of memory IgE responses are poorly understood, and the role played by germinal center (GC) IgE+ cells in memory responses is particularly unclear. IgE+ B cell differentiation is characterized by a transient GC phase, a bias toward the plasma cell (PC) fate, and dependence on sequential switching for the production of high-affinity IgE. We show here that IgE+ GC B cells are unfit to undergo the conventional GC differentiation program due to impaired B cell receptor function and increased apoptosis. IgE+ GC cells fail to populate the GC light zone and are unable to contribute to the memory and long-lived PC compartments. Furthermore, we demonstrate that direct and sequential switching are linked to distinct B cell differentiation fates: direct switching generates IgE+ GC cells, whereas sequential switching gives rise to IgE+ PCs. We propose a comprehensive model for the generation and memory of IgE responses.
Contemporary Occupational Carcinogen Exposure and Bladder Cancer
Authors: Marcus G. K. Cumberbatch, Angela Cox, Dawn Teare, James W. F. Catto
Journal: JAMA Oncology (2015)

Bladder cancer (BC) is a common disease. Despite manufacturing and legislative changes to workplace hygiene, many BCs still arise through occupational carcinogen exposure.To profile contemporary risks of occupational BC.A systematic review using PubMed, Medline, Embase, and Web of Science was performed in October 2012 (initial review) and May 2014 (final review) and was updated in June 2015.We identified 263 eligible articles. We excluded reports in which BC or occupation were not the main focus, and those with insufficient case, risk, or confidence interval data. We selected the most recent data from populations with multiple reports.Reports were selected by 2 of us independently. We combined odds ratios and risk ratios (RRs) to provide pooled RRs, using maximally adjusted RRs in a random effects model. Heterogeneity and publication bias were assessed using I2 and Begg and Egger tests. Risk estimates were annotated by occupational class using Nordisk Yrkesklassificering, or Nordic Occupational Classification, and International Standard Classifications of Occupations (NYK and ISCO-1958) Codes.Occupations were profiled by BC incidence and mortality risk over time. After data collection, we detected a sex difference in these profiles and recorded this as a secondary outcome.Meta-analysis revealed increased BC incidence in 42 of 61 occupational classes and increased BC-specific mortality in 16 of 40 occupational classes. Reduced incidence and mortality were seen in 6 of 61 and 2 of 40 classes, respectively. Risk varied with sex and was greatest in men (standardized incidence ratio, 1.03 [95% CI, 1.02-1.03]; P < .001]). From the 1960s to the 1980s, there was a steady decline in standarized incidence ratio (SIR) for both sexes. This trend reversed from the 1980s, as in the decade 2000 to 2010 the SIR increased to 1.13 (95% CI, 1.07-1.19) for men and 1.27 (95% CI, 1.12-1.43) for women. In contrast, mortality risk declined for both sexes from the 1960s to the 1990s. The overall risk of BC mortality was also greater for men (standardized mortality ratio [SMR], 1.32 [95% CI, 1.18-1.48]) than for women (SMR, 1.14 [95% CI, 0.80-1.63]). Limitations include possible publication bias, that reports stratify workers mostly by job title not task, that not all studies adjusted for smoking, and that the population was mostly derived from Western nations.The profile of contemporary occupations with increased BC risk is broad and differs for incidence and mortality. Currently the incidence seems to be increasing, and this increase is occurring faster in women than men. Improved detection mechanisms and screening are possible reasons for this. Workers with aromatic amine exposure have the highest incidence, while those exposed to polycyclic aromatic hydrocarbons and heavy metals have the greatest mortality.
Disparate Patterns of Left Ventricular Mechanics Differentiate Constrictive Pericarditis From Restrictive Cardiomyopathy
Authors: Partho P. Sengupta, Vijay K. Krishnamoorthy, Walter P. Abhayaratna, Josef Korinek, Marek Belohlavek, Thoralf M. Sundt, Krishnaswamy Chandrasekaran, Farouk Mookadam, James B. Seward, A. Jamil Tajik, Bijoy K. Khandheria
Journal: JACC. Cardiovascular imaging (2008)
Failed phlebotomy? Think William Harvey
Authors: K. L. Dorrington, J. K. Aronson
Journal: BMJ (2014)

Why do health professionals take blood in the wrong direction? Shortly before his death in 1657, William Harvey told the young Robert Boyle that the main thing that convinced him of the circulation of the blood was that the valves in arm veins prevent flow down the arm.1 This is a truth universally acknowledged, but ignored, given that it is the retrograde direction in which all hopeful phlebotomists expect blood to flow into their needles. We sometimes get away with it, when the blood, travelling headwards up a vein, struggles past the occluding needle, does an about turn, and ends up in the right place. Sometimes. The headwards …