tbuckley/cabot-search huggingface dataset:
Isoform-Specific Phosphoinositide 3-Kinase Inhibitors Exert Distinct Effects in Solid Tumors
Authors: Kyle A. Edgar, Jeffrey J. Wallin, Megan Berry, Leslie B. Lee, Wei Wei Prior, Deepak Sampath, Lori S. Friedman, Marcia Belvin
Journal: Cancer Research (2010)

Therapeutic inhibitors are being developed against the phosphoinositide 3-kinase (PI3K) pathway, the deregulation of which drives tumor growth and survival in many cancers. There are eight PI3Ks in mammals divided into three classes. Class IA PI3Ks (p110alpha, p110beta, and p110delta) are critical for cell growth and survival, with the p110alpha isoform implicated as the most important in carcinomas. In this study, we examined the effects of small-molecule inhibitors of class IA PI3Ks to explore the contributions of different isoforms in cancer cells. Similar responses were seen in cancer cells with wild-type or activated mutant PI3K genes treated with p110alpha/delta or p110alpha/beta/delta inhibitors in cell viability assays. In contrast, PTEN-negative cell lines tended to be less responsive (4-fold overall) to an inhibitor of p110alpha/delta versus p110alpha/beta/delta. Combining a p110alpha/delta inhibitor with a p110beta inhibitor resulted in comparable potency to the p110alpha/beta/delta inhibitor. The disparity in efficacy was confirmed in vivo. Pharmacodynamic biomarker analysis revealed that an inhibitor with insufficient potency against the p110beta isoform was less effective at inhibiting the PI3K pathway in PTEN-negative tumor xenografts. Our results imply that patients with PTEN-negative tumors may preferentially benefit from treatment with a class I PI3K inhibitor that is capable of inhibiting the p110beta isoform.
Susceptibility variants for rheumatoid arthritis in the <i>TRAF1-C5</i> and 6q23 loci: a meta-analysis
Authors: Nikolaos A Patsopoulos, John P A Ioannidis
Journal: Annals of the Rheumatic Diseases (2009)

Background Genome-wide association studies have proposed susceptibility variants for rheumatoid arthritis in the TRAF1-C5 locus and 6q23 region. Furthermore, additional independent studies have investigated the same or highly linked polymorphisms in the same regions. Objective To carry out a meta-analysis of the available evidence for the association of polymorphisms in the TRAF1-C5 locus and 6q23 region with rheumatoid arthritis. Methods Data were synthesised for four polymorphisms: rs3761847 (n=13 datasets) and rs2900180 (n=9 datasets) in the TRAF1-C5 locus, and rs10499194 (n=5 datasets) and rs6920220 (n=7 datasets) in the 6q23 region. Meta-analyses for subgroups defined by anti-cyclic citrullinated peptide (anti-CCP) and rheumatoid factor (RF) status were also performed. Results The polymorphism rs6920220 reached genome-wide statistical significance with p=7.9×10 −17 and an allelic odds ratio of 1.24 (95% CI 1.18 to 1.30) and no between-study heterogeneity (I 2 =0%). The risk was significantly stronger in patients with anti-CCP antibodies and in patients with RF. The other three variants showed large between-study heterogeneity across datasets (I 2 range 74–82%); rs10499194 was nominally statistically significant after exclusion of the discovery data. Two variants had genome-wide statistical significance in subgroups defined by the presence of RF (rs3761847 and rs6920220) or anti-CCP (rs6920220). Conclusions Genetic markers in the 6q23 region and TRAF1-C5 are associated with rheumatoid arthritis, in particular with positive anti-CCP and RF profile. With the exception of rs6920220, which shows highly consistent results, other proposed markers have high between-study heterogeneity that may reflect unrecognised phenotypic or genetic variability (eg, gene environment interactions) within rheumatoid arthritis. Furthermore, these markers may not be the true causative loci but rather be in linkage disequilibrium with the true ones.
Short term variability in FEV1 and bronchodilator responsiveness in patients with obstructive ventilatory defects.
Authors: P M Tweeddale, F Alexander, G J McHardy
Journal: Thorax (1987)

Short term variability in FEV1 and responsiveness to inhaled bronchodilator were measured in 150 patients with obstructive ventilatory defects. The range of initial FEV1 was 0.5-4.71 and the natural variability over a 20 minute period when expressed in absolute terms was similar over the entire range, and differed insignificantly from that found in normal subjects. The increase in FEV1 and vital capacity (VC) required to exclude natural variability with 95% confidence in these patients was 160 ml and 330 ml respectively. Natural variability when expressed in percentage terms was negatively correlated with the level of FEV1 recorded. The analysis of changes in FEV1 and VC after administration of bronchodilator used absolute and percentage criteria for response. The number of responders differed considerably according to the criterion used. In those defined by the absolute criterion as responders there was no evidence that size of response was related to level of FEV1. Percentage criteria have traditionally been used to identify responses to bronchodilator that may be clinically useful, while absolute criteria, although statistically valid, have not been favoured. Reappraisal of the criteria used and their limitations and implications is required.
Depth Asymmetries of the Pore-Lining Segments of the Na+ Channel Revealed by Cysteine Mutagenesis
Authors: Nipavan Chiamvimonvat, M.Teresa Pé]\\|rez-Garc\ía, Ravi Ranjan, Eduardo Marban, Gordon F Tomaselli
Journal: Neuron (1996)

We used serial cysteine mutagenesis to study the structure of the outer vestibule and selectivity region of the voltage-gated Na+ channel. The voltage dependence of Cd2+ block enabled us to determine the locations within the electrical field of cysteine-substituted mutants in the P segments of all four domains. The fractional electrical distances of the substituted cysteines were compared with the differential sensitivity to modification by sulfhydryl-specific modifying reagents. These experiments indicate that the P segment of domain II is external, while the domain IV P segment is displaced internally, compared with the first and third domain P segments. Sulfhydryls with a steep voltage dependence for Cd2+ block produced changes in monovalent cation selectivity; these included substitutions at the presumed selectivity filter, as well as residues in the domain IV P segment not previously recognized as determinants of selectivity. A new structural model is presented in which each of the P segments contribute unique loops that penetrate the membrane to varying depths to form the channel pore.
Reply to L.H. de Lima Araújo et al
Authors: Egbert F. Smit, Harry J.M. Groen, Nico van Zandwijk
Journal: Journal of Clinical Oncology (2009)

We thank Dr de Lima Araújo and colleagues for their thoughtful comment to the NVALT7 study 1 and for succinctly framing the relevant clinical question of platinum sensitivity in second-line treatment of non-small-cell lung cancer (NSCLC).As pointed out by de Lima Araújo et al platinum sensitivity in the second-line setting of NSCLC has been ill defined.The NVALT 7 study was designed to address the question whether treatment with a platinum doublet (carboplatin and pemetrexed) in this setting would prolong progression-free survival as compared to a standard of therapy (single-agent pemetrexed).Although the study met its primary end point for the population studied, there was no overall survival benefit.This may well be the result of the design of the study (ie, sample size), which prohibited the detection of a clinically relevant prolongation of survival.An identical Italian study-referred to by de Lima et al-was initiated during the course of the NVALT7 study and the results will be pooled in order to gain sufficient statistical power to detect overall survival differences.Until the results of this analysis are available, single-agent therapy remains the standard of care for patients with relapsed NSCLC. 3he multivariate analyses of NVALT 7 show that patients who were off first-line platinum (doublet) therapy for 6 months or more, had a significant superior overall survival when compared to those patients who started second line treatment after a shorter interval (9.5 months v 6.6 months; P ϭ .0009).For those patients who received carboplatin and pemetrexed in second line, the corresponding figures were 10.5 months versus 6.7 months (P ϭ .0003).Although from these figures one may be tempted to define platinum sensitivity as a treatment-free interval of 6 months or more after end of first-line platinum therapy, in fact the former is true for other agents as well.The finding that patients who have longer treatment-free intervals fare better on any second-line therapy, whether or not including platinum, is supported by a recent meta-analysis conducted by di Maio et al. 3 We agree with de Lima Araujo et al that trials investigating the efficacy of novel agents in the second-line management of NSCLC should take into account the time elapsed since first-line therapy.Our results and those of others support the view that a 6-month period is a reasonable choice for this purpose.Ideally, future trials should adopt a 6-month interval as a stratification factor, along with other known prognostic factors such as sex, histology, and response to firstline treatment.
Evaluation of brain tumor vessels specific contrast agents for glioblastoma imaging
Authors: Boguslaw Tomanek, Umar Iqbal, Barbara Blasiak, Abedelnasser Abulrob, Homam Albaghdadi, John R. Matyas, Dragana Ponjevic, Garnette R. Sutherland
Journal: Neuro-Oncology (2011)

A mouse model of glioblastoma multiforme was used to determine the accumulation of a targeted contrast agent in tumor vessels.The contrast agent, consisting of superparamagnetic iron oxide coated with dextran, was functionalized with an anti-insulin-like-growth-factor binding protein 7 (anti-IGFBP7) single domain antibody.The near infrared marker, Cy5.5, was also attached for an in vivo fluorescence study.A 9.4T magnetic resonance imaging (MRI) system was used for in vivo studies on days 10 and 11 following tumor inoculation.T 2 relaxation time was used to measure the accumulation of the contrast agent in the tumor.Changes in tumor to brain contrast because of active targeting were compared with a nontargeted contrast agent.Effective targeting was confirmed with near infrared measurements and fluorescent microscopic analysis.The results showed that there was a statistically significant (P < .01)difference in normalized T 2 between healthy brain and tumor tissue 10 min, 1 h, and 2 h point postinjection of the anti-IGFBP7 single domain antibody targeted and nontargeted iron oxide nanoparticles.A statistical difference remained in animals treated with targeted nanoparticles 24 h postinjection only.The MRI, near infrared imaging, and fluorescent microscopy studies showed corresponding spatial and temporal changes.We concluded that the developed anti-IGFBP7-iron oxide single domain antibody-targeted MRI contrast agent selectively binds to abnormal vessels within a glioblastoma.T 2 -weighted MRI and near infrared imaging are able to detect the targeting effects in brain tumors.
Phase I open study of the effects of ascending doses of the cytotoxic immunoconjugate CMB-401 (hCTMO1-calicheamicin) in patients with epithelial ovarian cancer
Authors: A.M. Gillespie, T.J. Broadhead, S.Y. Chan, J. Owen, A.P. Farnsworth, M. Sopwith, R.E. Coleman
Journal: Annals of Oncology (2000)
Red blood cell uridine sugar nucleotide levels in patients with classic galactosemia and other metabolic disorders
Authors: Gerard T. Berry, Michael J. Palmieri, Simon Heales, James V. Leonard, Stanton Segal
Journal: Metabolism (1992)

While dietary galactose restriction eliminates the life-threatening complications of classic galactosemia, central nervous system and ovarian disease are still evident in these patients, despite milk restriction. Because of the possibility that reduced tissue levels of uridine diphosphate galactose (UDPgalactose), the product of the deficient enzyme, galactose-1-phosphate uridyltransferase, are the cause of these unexplained complications, we have measured the concentration of red blood cell (RBC) uridine sugar nucleotides in these patients, comparing their values not only with those of normal subjects, but also with those of children who have other metabolic disorders. RBC UDPgalactose and uridine diphosphate glucose (UDPglucose) levels were measured by high-performance liquid chromatography (HPLC) in 35 control subjects, 24 galactosemic patients, and 19 patients with inborn errors of amino acid, organic acid, or ammonia metabolism. The last group of patients served as dietary controls, as they were all on special low-protein diets that restricted milk intake. The mean levels of UDPgalactose in galactosemic children and adults were 38% and 54% lower, respectively, than the levels in normal children and adults. While only six of 19 galactosemic children had levels below the 95% confidence limit for normals, four of five galactosemic adults had levels of UDPgalactose in the low range. The mean UDPgalactose level in children with other metabolic diseases who were on a low-milk diet was also reduced by 38%, with a mean not significantly different from galactosemics. Compared with normal adults, the level of UDPglucose in galactosemic adults was also reduced by 29%, with three of five affected adults having UDPglucose values below the 95% confidence limit.(ABSTRACT TRUNCATED AT 250 WORDS)
Sclerostin Is an Osteocyte-expressed Negative Regulator of Bone Formation, But Not a Classical BMP Antagonist
Authors: Rutger L. van Bezooijen, Bernard A.J. Roelen, Annemieke Visser, Lianne van der Wee-Pals, Edwin de Wilt, Marcel Karperien, Herman Hamersma, Socrates E. Papapoulos, Peter ten Dijke, Clemens W.G.M. Löwik
Journal: The Journal of Experimental Medicine (2004)

Sclerosteosis, a skeletal disorder characterized by high bone mass due to increased osteoblast activity, is caused by loss of the SOST gene product, sclerostin. The localization in bone and the mechanism of action of sclerostin are not yet known, but it has been hypothesized that it may act as a bone morphogenetic protein (BMP) antagonist. We show here that SOST/sclerostin is expressed exclusively by osteocytes in mouse and human bone and inhibits the differentiation and mineralization of murine preosteoblastic cells (KS483). Although sclerostin shares some of the actions of the BMP antagonist noggin, we show here that it also has actions distinctly different from it. In contrast to noggin, sclerostin did not inhibit basal alkaline phosphatase (ALP) activity in KS483 cells, nor did it antagonize BMP-stimulated ALP activity in mouse C2C12 cells. In addition, sclerostin had no effect on BMP-stimulated Smad phosphorylation and direct transcriptional activation of MSX-2 and BMP response element reporter constructs in KS483 cells. Its unique localization and action on osteoblasts suggest that sclerostin may be the previously proposed osteocyte-derived factor that is transported to osteoblasts at the bone surface and inhibits bone formation.
Differential Response to Risperidone in Schizophrenia Patients by <i>KCNH2</i> Genotype and Drug Metabolizer Status
Authors: Juliane Heide, Fengyu Zhang, Kristin L. Bigos, Stefan A. Mann, Vaughan J. Carr, Cynthia Shannon Weickert, Melissa J. Green, Daniel R. Weinberger, Jamie I. Vandenberg
Journal: American Journal of Psychiatry (2015)

Objective: Antipsychotic drugs target dopamine and serotonin receptors as well as Kv11.1 potassium channels encoded by KCNH2. Variable patient responses and a wide range of side effects, however, limit their efficacy. Slow metabolizer status and gene variants in KCNH2 associated with increased expression of Kv11.1-3.1, an alternatively spliced isoform of Kv11.1, are correlated with improved responses to antipsychotic medications. Here, the authors test the hypothesis that these effects may be influenced by differential drug binding to Kv11.1 channel isoforms. Method: Drug block of Kv11.1 isoforms was tested in cellular electrophysiology assays. The effects of drug metabolism and KCNH2 genotypes on clinical responses were assessed in patients enrolled in the multicenter Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE). Results: Risperidone caused greater in vitro block of the alternatively spliced Kv11.1-3.1 isoform than full-length Kv11.1-1A channels, whereas its metabolite paliperidone and other atypical antipsychotics have similar potencies for the two isoforms. In the CATIE study (N=362), patients with genotypes associated with increased Kv11.1-3.1 expression (N=52) showed a better treatment response to risperidone compared with other drugs, but this association was dependent on metabolism status. Patients with KCNH2 risk genotypes and slow metabolizer status (approximately 7% of patients) showed marked improvement in symptoms when treated with risperidone compared with patients with fast metabolizer status or without the KCNH2 risk genotypes. Conclusions: These data support the hypothesis that Kv11.1 channels play a role in the therapeutic action of antipsychotic drugs, particularly risperidone, and further highlight the promise of optimizing response with genotype-guided therapy for schizophrenia patients.
Measurement of the specific airway resistance by plethysmography in young children accompanied by an adult
Authors: B Klug, H Bisgaard
Journal: European Respiratory Journal (1997)

The purpose of this study was to evaluate a procedure for measurement of specific airway resistance (sRaw) by whole body plethysmography in young awake children accompanied by an adult. sRaw was measured by a single-step procedure, omitting the measurement of the thoracic gas volume. The frequency dependency of sRaw was investigated and the accuracy of simulating body temperature, atmospheric pressure and saturation with water vapour (BTPS) conditions by electronic compensation was assessed. One hundred and thirty one children with asthma were studied. In 57 children (mean (SD) age 5.6 (1.8) yrs) who performed measurements with and without an accompanying adult, the mean value of sRaw was 1.45 (0.36) and 1.44 (0.38) kPa x s, respectively, with a mean difference of 0.008 (0.152) kPa x s, and mean within-subject coefficients of variations (CV) of 8% and 10%, respectively. In 52 children (mean age 3.3 (0.8) yrs), for whom measurements made only in the presence of an accompanying adult, the CV was 8.5%. No measurements could be obtained in 22 children (17%) (mean age 2.8 (0.5) yrs). Measurements exhibited a significant frequency dependency, and electronic BTPS compensation substantially overestimated SRaw. In conclusion, the use of electronic compensation for simulating body temperature, atmospheric pressure and saturation with water vapour introduces a bias that affects the accuracy of the estimate of specific airway resistance. Nevertheless, plethysmographic measurements with and without an accompanying adult yielded comparable and equally repeatable estimates of specific airway resistance. The single-step plethysmographic procedure with an accompanying adult is a clinically useful method for evaluating airway function in children too young to perform plethysmographic measurements alone.
Updated National and International Hypertension Guidelines: A Review of Current Recommendations
Authors: Sverre Kjeldsen, Ross D. Feldman, Liu Lisheng, Jean-Jacques Mourad, Chern-En Chiang, Weizhong Zhang, Zhaosu Wu, Wei Li, Bryan Williams
Journal: Drugs (2014)

Despite the availability of effective pharmacological treatments to aid the control of blood pressure, the global rate of uncontrolled blood pressure remains high. As such, further measures are required to improve blood pressure control. Recently, several national and international guidelines for the management of hypertension have been published. These aim to provide easily accessible information for healthcare professionals and patients to aid the diagnosis and treatment of hypertension. In this review, we have compared new and current guidelines from the American and International Societies of Hypertension; the American Heart Association, American College of Cardiology and the US Center for Disease Control and Prevention; the panel appointed to the Eighth Joint National Committee; the European Societies of Hypertension and Cardiology; the French Society of Hypertension; the Canadian Hypertension Education Program; the National Institute for Health and Clinical Excellence (UK); the Taiwan Society of Cardiology and the Chinese Hypertension League. We have identified consensus opinion regarding best practises for the management of hypertension and have highlighted any discrepancies between the recommendations. In general there is good agreement between the guidelines, however, in some areas, such as target blood pressure ranges for the elderly, further trials are required to provide sufficient high-quality evidence to form the basis of recommendations.
Mechanism of phosphatidylserine inhibition of IgE/FcεRI-dependent anaphylactic human basophil degranulation via CD300a
Authors: Vito Sabato, Monica Boita, Saif Shubber, Chris H. Bridts, Akira Shibuya, Luc S. De Clerck, Franco H. Falcone, Didier G. Ebo
Journal: Journal of Allergy and Clinical Immunology (2014)
Growth in the Physiotherapy Evidence Database (PEDro) and use of the PEDro scale
Authors: Mark R Elkins, Anne M Moseley, Catherine Sherrington, Robert D Herbert, Christopher G Maher
Journal: British Journal of Sports Medicine (2012)

In 2010, the British Journal of Sports Medicine ( BJSM ) published an editorial1 about the Physiotherapy Evidence Database (PEDro, www.pedro.org.au). The editorial described how this freely available bibliographic database directs users to high-quality evidence about the effects of physiotherapy interventions. The growth of PEDro to that time was also described; it was shown that the number of records on the database had doubled every 3.5 years. This exponential growth has continued, and PEDro now indexes reports of over 18 000 randomised trials and 3500 systematic reviews. Since that editorial, growth has occurred in other aspects of PEDro as well.

For each article retrieved by a search of PEDro, users can access the title, abstract, citation details and, where available, a link to a full-text copy of the article. The range of links to full text has recently been expanded and PEDro now links to full-text versions of papers via PubMed Central, the Maastricht Centre for Evidence Based Physiotherapy, the digital object identifier, PubMed and the publisher. This expansion in the range of links to possible sources of the full-text article improves the likelihood that users can access the evidence they identify when searching PEDro. Access to full text through these links is often free of charge.

Anyone who wishes to keep abreast of new evidence can now elect to receive a monthly update of …
Effect of graded bicycle seat pressure on perineal compression: a magnetic resonance imaging analysis
Authors: Eadric Bressel, Dan Parker
Journal: British Journal of Sports Medicine (2008)

To identify a seat pressure threshold that corresponds to significant compression of the perineum.Quasiexperimental crossover.Hospital radiology department.Convenience sample of six male recreational cyclists.Compression of the corpus spongiosum and corpora cavernosa of the perineum without bicycle seat pressure (0%) and at 10%, 40% and 80% of the mean bicycling pressure was assessed using magnetic resonance imaging. Seat pressure was applied using a custom loading device.Measure Diameter measurements of the cavernous spaces at the point of peak compression.The mean diameter values for the corpus spongiosum in the unloaded and 10% of load conditions were 105% and 172% greater than the 40% and 80% loaded conditions, respectively (p=0.002-0.004). The corpora cavernosa values displayed a similar trend.Substantial compression of the perineal cavernous spaces may occur with total seat pressure values of less than 40% of typical seat loads.