tbuckley/cabot-search huggingface dataset:
Uptake and transport of B 12 -conjugated nanoparticles in airway epithelium
Authors: Robyn Fowler, Driton Vllasaliu, Franco H. Falcone, Martin Garnett, Bryan Smith, Helen Horsley, Cameron Alexander, Snow Stolnik
Journal: Journal of Controlled Release (2013)

Non-invasive delivery of biotherapeutics, as an attractive alternative to injections, could potentially be achieved through the mucosal surfaces, utilizing nanoscale therapeutic carriers. However, nanoparticles do not readily cross the mucosal barriers, with the epithelium presenting a major barrier to their translocation. The transcytotic pathway of vitamin B12 has previously been shown to 'ferry' B12-decorated nanoparticles across intestinal epithelial (Caco-2) cells. However, such studies have not been reported for the airway epithelium. Furthermore, the presence in the airways of the cell machinery responsible for transepithelial trafficking of B12 is not widely reported. Using a combination of molecular biology and immunostaining techniques, our work demonstrates that the bronchial cell line, Calu-3, expresses the B12-intrinsic factor receptor, the transcobalamin II receptor and the transcobalamin II carrier protein. Importantly, the work showed that sub-200 nm model nanoparticles chemically conjugated to B12 were internalised and transported across the Calu-3 cell layers, with B12 conjugation not only enhancing cell uptake and transepithelial transport, but also influencing intracellular trafficking. Our work therefore demonstrates that the B12 endocytotic apparatus is not only present in this airway model, but also transports ligand-conjugated nanoparticles across polarised epithelial cells, indicating potential for B12-mediated delivery of nanoscale carriers of biotherapeutics across the airways.
Hemodynamic and Neurohumoral Effects of Selective Endothelin A (ET <sub>A</sub> ) Receptor Blockade in Chronic Heart Failure
Authors: Thomas F. Lüscher, Frank Enseleit, Richard Pacher, Veselin Mitrovic, Matthias R. Schulze, Roland Willenbrock, Rainer Dietz, Valentin Rousson, David Hürlimann, Sebastian Philipp, Thomas Notter, Georg Noll, Frank Ruschitzka
Journal: Circulation (2002)

Background— The endothelin (ET-1) system is activated in chronic heart failure (CHF). Whether, what type, and what degree of selective ET blockade is clinically beneficial is unknown. We investigated hemodynamic and neurohumoral effects of 3 weeks of treatment with various dosages of the orally available ET A antagonist darusentan in addition to modern standard therapy in patients with CHF. Methods and Results— A total of 157 patients with CHF (present or recent NYHA class III of at least 3 months duration), pulmonary capillary wedge pressure ≥12 mm Hg, and a cardiac index ≤2.6 L · min −1 · m −2 were randomly assigned to double-blind treatment with placebo or darusentan (30, 100, or 300 mg/d) in addition to standard therapy. Short-term administration of darusentan increased the cardiac index, but this did not reach statistical significance compared with placebo. The increase in cardiac index was significantly more pronounced after 3 weeks of treatment ( P &lt;0.0001 versus placebo). Pulmonary capillary wedge pressure, pulmonary arterial pressure, pulmonary vascular resistance, and right atrial pressure remained unchanged. Heart rate, mean artery pressure, and plasma catecholamines remained unaltered, but systemic vascular resistance decreased significantly ( P =0.0001). Higher dosages were associated with a trend to more adverse events (including death), particularly early exacerbation of CHF without further benefit on hemodynamics compared with moderate dosages. Conclusions— This study demonstrates for the first time in a large patient population that 3 weeks of selective ET A receptor blockade improves cardiac index in patients with CHF. However, long-term studies are needed to determine whether ET A blockade is beneficial in CHF.
An annotation infrastructure for the analysis and interpretation of Affymetrix exon array data
Authors: Michał J Okoniewski, Tim Yates, Siân Dibben, Crispin J Miller
Journal: Genome biology (2007)

Abstract Affymetrix exon arrays contain probesets intended to target every known and predicted exon in the entire genome, posing significant challenges for high-throughput genome-wide data analysis. X:MAP http://xmap.picr.man.ac.uk , an annotation database, and exonmap http://www.bioconductor.org/packages/2.0/bioc/html/exonmap.html , a BioConductor/R package, are designed to support fine-grained analysis of exon array data. The system supports the application of standard statistical techniques, prior to the use of genome scale annotation to provide gene-, transcript- and exon-level summaries and visualization tools.
Mediterranean diet intervention in rheumatoid arthritis
Authors: J Kjeldsen-Kragh
Journal: Annals of the Rheumatic Diseases (2003)

Is the controlled clinical trial the only tool for testing the efficacy of dietary treatment?

The belief that diet may influence the severity of rheumatoid arthritis (RA) is part of the folklore of the disease, and dietary treatment has been one of many unconventional remedies that have been widely used at health farms in northern Europe. Over the years, several stories about arthritic patients who improved dramatically after changing diet have appeared, not only in the lay press but also in scientific journals. Although the possible benefits of specific diets for patients with RA have been tested in a number of trials, many of the studies that showed positive results of dietary treatment have not been published as full papers in peer reviewed journals, probably because these studies lacked controls or were poorly designed and/or inadequately described.

A scientific investigation of the efficacy of dietary treatment of RA was pioneered by Swedish doctors. More than two decades ago Skoldstam et al conducted the first controlled randomised trial, in which they tested the effect of fasting and lactovegetarian diet in patients with RA.1 They reported that fasting resulted in a striking reduction in disease activity but, unfortunately, the patients deteriorated again when they started eating. Since then only a few randomised controlled trials on dietary treatment of patients with RA have been carried out.2–8 These trials are not directly comparable because of differences in the diets, and accordingly the results varied from no effect2 to good clinical response to the experimental diet.4

There has been much speculation about why some patients with RA improve by changing diet. Allergy or other adverse antibody mediated reactions towards certain foods have been suggested,3,9–13 but seem to have a role in only a few patients with RA. …
Tree of Life Reveals Clock-Like Speciation and Diversification
Authors: S. Blair Hedges, Julie Marin, Michael Suleski, Madeline Paymer, Sudhir Kumar
Journal: Molecular Biology and Evolution (2015)

Genomic data are rapidly resolving the tree of living species calibrated to time, the timetree of life, which will provide a framework for research in diverse fields of science. Previous analyses of taxonomically restricted timetrees have found a decline in the rate of diversification in many groups of organisms, often attributed to ecological interactions among species. Here, we have synthesized a global timetree of life from 2,274 studies representing 50,632 species and examined the pattern and rate of diversification as well as the timing of speciation. We found that species diversity has been mostly expanding overall and in many smaller groups of species, and that the rate of diversification in eukaryotes has been mostly constant. We also identified, and avoided, potential biases that may have influenced previous analyses of diversification including low levels of taxon sampling, small clade size, and the inclusion of stem branches in clade analyses. We found consistency in time-to-speciation among plants and animals, ∼2 My, as measured by intervals of crown and stem species times. Together, this clock-like change at different levels suggests that speciation and diversification are processes dominated by random events and that adaptive change is largely a separate process.
Automated external defibrillator use at NCAA Division II and III universities
Authors: J A Drezner, K J Rogers, J G Horneff
Journal: British Journal of Sports Medicine (2010)

The placement of automated external defibrillators (AEDs) at collegiate sporting venues is a growing trend. The purpose of this study was to investigate the prevalence, location and past utilisation of AEDs at National Collegiate Athletic Association (NCAA) Division II and III universities.Cross-sectional survey.NCAA Division II and III universities.Questionnaires were mailed to the head athletic trainer at NCAA Division II and III (N=711) colleges and universities in the fall of 2003. Findings were compared to previously published results at Division I institutions.Prevalence, location and past utilisation of AEDs.Completed surveys were returned by 254 NCAA Division II and III institutions for a 35.7% response rate (254/711). 205 (81%) institutions had at least one AED in the university athletic setting, with a median of 2 AEDs per institution (range 1-9). Athletic training rooms (75%) were the most likely location to place an AED. Twelve cases of AED use for sudden cardiac arrest were reported with 67% (8/12) occurring in older non-students, 16% (2/12) in intercollegiate athletes and 16% (2/12) in students (non-intercollegiate athletes). The AED deployed a shock in eight cases. 8 of 12 (66%) victims were immediately resuscitated, but only 4 survived to hospital discharge (overall survival 33%). None of the intercollegiate athletes or students survived.Most NCAA Division II and III institutions that responded to the survey have implemented AEDs in their athletic programs, although they have a lower prevalence of AEDs than previously reported at Division I universities. Although no benefit was demonstrated in a small number of intercollegiate athletes, AEDs were successfully used in older individuals on campus with cardiac arrest.
Differences in utilization of asthma drugs between two neighbouring Swedish provinces: relation to symptom reporting
Authors: L Larsson, G Boethius, M Uddenfeldt
Journal: European Respiratory Journal (1993)

Utilization of anti-asthma drugs is rapidly increasing and varies markedly between counties in Sweden. In 1989, the sales in the county of Gävleborg were less than 60% of those in neighbouring Jämtland. In order to study the possible reasons for--and effects of--this difference, an epidemiological survey was started in 1989, the first part of which is reported here. A questionnaire was sent to all 16 yr olds, and to a random sample of 30-39 and 60-69 yr olds, in the two counties. A total of 12,500 questionnaires were distributed. Overall response rate was 90%. A total of 7.2% in Jämtland and 5.8% in Gävleborg (p < 0.01) reported that they had had asthma at some time. A similar significant difference between the counties was also present in response to questions on attacks of shortness of breath, wheezing and self-reported diagnosis of asthma, as well as on use of anti-asthma drugs. There were no statistically significant differences between the counties in positive answers to questions concerning history and symptoms of chronic bronchitis; approximately 5% in the oldest age group. The findings support earlier results indicating a high asthma prevalence in northern Sweden. Contrary to reports from other countries, the prevalence was higher in the colder and less urbanised of the two provinces. We conclude that the differences in drug sales between the counties reflect a difference in prevalence of asthmatic symptoms.
NADPH Oxidases, Reactive Oxygen Species, and the Kidney
Authors: Mona Sedeek, Rania Nasrallah, Rhian M. Touyz, Richard L. Hébert
Journal: Journal of the American Society of Nephrology (2013)

Reactive oxygen species (ROS) play an important role in normal cellular physiology. They regulate different biologic processes such as cell defense, hormone synthesis and signaling, activation of G protein-coupled receptors, and ion channels and kinases/phosphatases. ROS are also important regulators of transcription factors and gene expression. On the other hand, in pathologic conditions, a surplus of ROS in tissue results in oxidative stress with various injurious consequences such as inflammation and fibrosis. NADPH oxidases are one of the many sources of ROS in biologic systems, and there are seven isoforms (Nox1-5, Duox1, Duox2). Nox4 is the predominant form in the kidney, although Nox2 is also expressed. Nox4 has been implicated in the basal production of ROS in the kidney and in pathologic conditions such as diabetic nephropathy and CKD; upregulation of Nox4 may be important in renal oxidative stress and kidney injury. Although there is growing evidence indicating the involvement of NADPH oxidase in renal pathology, there is a paucity of information on the role of NADPH oxidase in the regulation of normal renal function. Here we provide an update on the role of NADPH oxidases and ROS in renal physiology and pathology.
Dietary Magnesium Intake in Relation to Plasma Insulin Levels and Risk of Type 2 Diabetes in Women
Authors: Yiqing Song, JoAnn E. Manson, Julie E. Buring, Simin Liu
Journal: Diabetes Care (2004)

OBJECTIVE—Higher intake of magnesium appears to improve glucose and insulin homeostasis; however, there are sparse prospective data on the association between magnesium intake and incidence of type 2 diabetes. RESEARCH DESIGN AND METHODS—In the Women’s Health Study, a cohort of 39,345 U.S. women aged ≥45 years with no previous history of cardiovascular disease, cancer, or type 2 diabetes completed validated semiquantitative food frequency questionnaires in 1993 and were followed for an average of 6 years. We used Cox proportional hazard models to estimate multivariate relative risks (RRs) of type 2 diabetes across quintiles of magnesium intake compared with the lowest quintile. In a sample of 349 apparently healthy women from this study, we measured plasma fasting insulin levels to examine their relation to magnesium intake. RESULTS—During 222,523 person-years of follow-up, we documented 918 confirmed incident cases of type 2 diabetes. There was a significant inverse association between magnesium intake and risk of type 2 diabetes, independent of age and BMI (P = 0.007 for trend). After further adjustment for physical activity, alcohol intake, smoking, family history of diabetes, and total calorie intake, the multivariate-adjusted RRs of diabetes from the lowest to highest quintiles of magnesium intake were attenuated at 1.0, 1.06, 0.81, 0.86, and 0.89 (P = 0.05 for trend). Among women with BMI ≥25 kg/m2, the inverse trend was significant; multivariate-adjusted RRs were 1.0, 0.96, 0.76, 0.84, and 0.78 (P = 0.02 for trend). Multivariate-adjusted geometric mean insulin levels for overweight women in the lowest quartile of magnesium intake was 53.5 compared with 41.5 pmol/l among those at the highest quartile (P = 0.03 for trend). CONCLUSIONS—These findings support a protective role of higher intake of magnesium in reducing the risk of developing type 2 diabetes, especially in overweight women.
A Pilot Study of Medical Student 'Abuse'
Authors: K. Harnett Sheehan
Journal: JAMA (1990)

A pilot survey of one third-year medical school class was carried out to explore student perceptions of mistreatment and professional misconduct in medical school training. Students were asked to rate the frequency and cite sources of mistreatment and misconduct among classmates, faculty, residents, and interns. They were also asked to assess the effects of such episodes on their physical health, emotional well-being, social and family life, and attitudes toward becoming a physician. The results indicate that students perceive mistreatment (particularly verbal abuse and unfair tactics) to be pervasive and professional misconduct all too common. As many as three fourths of the students report having become more cynical about academic life and the medical profession as a result of these episodes. Two thirds feel they are worse off than their peers in other professions. More than a third have considered dropping out of medical school and one fourth report they would have chosen a different profession had they known in advance about the extent of mistreatment they would experience. Rather than dismiss these problems as isolated events, we need to examine this issue more closely. (<i>JAMA</i>. 1990;263:533-537)
Depression in terminally ill patients with cancer
Authors: A. Huang, D. Fuchs
Journal: Journal of the Royal Society of Medicine (2002)

Dr Tiernan and his colleagues (August 2002 JRSM1) found a significant correlation between the desire for death and depressive scores on the Hospital Anxiety and Depression Scale (HADS) in patients with terminal cancer, and concluded that treatment with antidepressants such as selective serotonin reuptake inhibitors (SSRIs) might improve their quality of life (QoL). Previous work with the HADS and other QoL questionnaires in patients with advanced colorectal cancer has shown that QoL impairment correlates more with immune activation than with serum tumour markers and tumour volume2. Furthermore, this immune response was associated with a reduction in serum tryptophan that correlated with worse QoL scores3. Therefore, impairment of QoL in advanced cancer may be due to immune-mediated depletion in tryptophan concentrations4. Since tryptophan is a precursor for serotonin in the brain and reduction in the latter may be associated with depression, treatment with SSRIs might be effective by raising cerebral serotonin concentrations5.
S100A2 Induces Metastasis in Non–Small Cell Lung Cancer
Authors: Etmar Bulk, Bülent Sargin, Utz Krug, Antje Hascher, Yu Jun, Markus Knop, Claus Kerkhoff, Volker Gerke, Ruediger Liersch, Rolf M. Mesters, Marc Hotfilder, Alessandro Marra, Steffen Koschmieder, Martin Dugas, Wolfgang E. Berdel, Hubert Serve, Carsten Müller-Tidow
Journal: Clinical Cancer Research (2008)

Abstract Purpose: S100 proteins are implicated in metastasis development in several cancers. In this study, we analyzed the prognostic role of mRNA levels of all S100 proteins in early stage non–small cell lung cancer (NSCLC) patients as well as the pathogenetic of S100A2 in the development of metastasis in NSCLC. Experimental Design: Microarray data from a large NSCLC patient cohort was analyzed for the prognostic role of S100 proteins for survival in surgically resected NSCLC. Metastatic potential of the S100A2 gene was analyzed in vitro and in a lung cancer mouse model in vivo. Overexpression and RNAi approaches were used for analysis of the biological functions of S100A2. Results: High mRNA expression levels of several S100 proteins and especially S100A2 were associated with poor survival in surgically resected NSCLC patients. Upon stable transfection into NSCLC cell lines, S100A2 did not alter proliferation. However, S100A2 enhanced transwell migration as well as transendothelial migration in vitro. NOD/SCID mice injected s.c. with NSCLC cells overexpressing S100A2 developed significantly more distant metastasis (64%) than mice with control vector transfected tumor cells (17%; P &amp;lt; 0.05). When mice with S100A2 expressing tumors were treated i.v. with shRNA against S100A2, these mice developed significantly fewer lung metastasis than mice treated with control shRNA (P = 0.021). Conclusions: These findings identify S100A2 as a strong metastasis inducer in vivo. S100A2 might be a potential biomarker as well as a novel therapeutic target in NSCLC metastasis.
In search of the fibrotic epithelial cell: opportunities for a collaborative network
Authors: Gisli Jenkins, Andrew Blanchard, Zea Borok, Peter Bradding, Carsten Ehrhardt, Andrew Fisher, Nik Hirani, Simon Johnson, Melanie Königshoff, Toby M Maher, Ann Millar, Helen Parfrey, Chris Scotton, Terry Tetley, David Thickett, Paul Wolters
Journal: Thorax (2011)

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive disease of unknown aetiology. It has a very poor prognosis and no effective treatment. There are two major barriers to the development of novel treatments in IPF: an incomplete understanding of its pathogenesis and the fact that current models of the disease are poorly predictive of therapeutic response. Recent studies suggest an important role for the alveolar epithelium in the pathogenesis of IPF. However, practical limitations associated with isolation and culture of primary alveolar epithelial cells have hampered progress towards further elucidating their role in the pathogenesis of the disease or developing disease models that accurately reflect the epithelial contribution. The practical limitations of primary alveolar epithelial cell culture can be divided into technical, logistical and regulatory hurdles that need to be overcome to ensure rapid progress towards improved treatment for patients with IPF. To develop a strategy to facilitate alveolar epithelial cell harvest, retrieval and sharing between IPF research groups and to determine how these cells contribute to IPF, a workshop was organised to discuss the central issues surrounding epithelial cells in IPF (ECIPF). The central themes discussed in the workshop have been compiled as the proceedings of the ECIPF.
eIF4B Phosphorylation by Pim Kinases Plays a Critical Role in Cellular Transformation by<i>Abl</i>Oncogenes
Authors: Jianling Yang, Jun Wang, Ke Chen, Guijie Guo, Ruijiao Xi, Paul B. Rothman, Douglas Whitten, Lianfeng Zhang, Shile Huang, Ji-Long Chen
Journal: Cancer Research (2013)

Alterations in translation occur in cancer cells, but the precise pathogenic processes and mechanistic underpinnings are not well understood. In this study, we report that interactions between Pim family kinases and the translation initiation factor eIF4B are critical for Abl oncogenicity. Pim kinases, Pim-1 and Pim-2, both directly phosphorylated eIF4B on Ser406 and Ser422. Phosphorylation of eIF4B on Ser422 was highly sensitive to pharmacologic or RNA interference-mediated inhibition of Pim kinases. Expression and phosphorylation of eIF4B relied upon Abl kinase activity in both v-Abl- and Bcr-Abl-expressing leukemic cells based on their blockade by the Abl kinase inhibitor imatinib. Ectopic expression of phosphomimetic mutants of eIF4B conferred resistance to apoptosis by the Pim kinase inhibitor SMI-4a in Abl-transformed cells. In contrast, silencing eIF4B sensitized Abl-transformed cells to imatinib-induced apoptosis and also inhibited their growth as engrafted tumors in nude mice. Extending these observations, we found that primary bone marrow cells derived from eIF4B-knockdown transgenic mice were less susceptible to Abl transformation, relative to cells from wild-type mice. Taken together, our results identify eIF4B as a critical substrate of Pim kinases in mediating the activity of Abl oncogenes, and they highlight eIF4B as a candidate therapeutic target for treatment of Abl-induced cancers.