tbuckley/cabot-search huggingface dataset:
Alternative Splicing of Caspase 9 Is Modulated by the Phosphoinositide 3-Kinase/Akt Pathway via Phosphorylation of SRp30a
Authors: Jacqueline C. Shultz, Rachel W. Goehe, D. Shanaka Wijesinghe, Charuta Murudkar, Amy J. Hawkins, Jerry W. Shay, John D. Minna, Charles E. Chalfant
Journal: Cancer Research (2010)

Increasing evidence points to the functional importance of alternative splice variations in cancer pathophysiology. Two splice variants are derived from the CASP9 gene via the inclusion (Casp9a) or exclusion (Casp9b) of a four-exon cassette. Here we show that alternative splicing of Casp9 is dysregulated in non-small cell lung cancers (NSCLC) regardless of their pathologic classification. Based on these findings we hypothesized that survival pathways activated by oncogenic mutation regulated this mechanism. In contrast to K-RasV12 expression, epidermal growth factor receptor (EGFR) overexpression or mutation dramatically lowered the Casp9a/9b splice isoform ratio. Moreover, Casp9b downregulation blocked the ability of EGFR mutations to induce anchorage-independent growth. Furthermore, Casp9b expression blocked inhibition of clonogenic colony formation by erlotinib. Interrogation of oncogenic signaling pathways showed that inhibition of phosphoinositide 3-kinase or Akt dramatically increased the Casp9a/9b ratio in NSCLC cells. Finally, Akt was found to mediate exclusion of the exon 3,4,5,6 cassette of Casp9 via the phosphorylation state of the RNA splicing factor SRp30a via serines 199, 201, 227, and 234. Taken together, our findings show that oncogenic factors activating the phosphoinositide 3-kinase/Akt pathway can regulate alternative splicing of Casp9 via a coordinated mechanism involving the phosphorylation of SRp30a.
A strategy for extracting and analyzing large-scale quantitative epistatic interaction data.
Authors: Sean R Collins, Maya Schuldiner, Nevan J Krogan, Jonathan S Weissman
Journal: Genome biology (2006)

Abstract Recently, approaches have been developed for high-throughput identification of synthetic sick/lethal gene pairs. However, these are only a specific example of the broader phenomenon of epistasis, wherein the presence of one mutation modulates the phenotype of another. We present analysis techniques for generating high-confidence quantitative epistasis scores from measurements made using synthetic genetic array and epistatic miniarray profile (E-MAP) technology, as well as several tools for higher-level analysis of the resulting data that are greatly enhanced by the quantitative score and detection of alleviating interactions.
Differential Metabolism of Arachidonic Acid in Nasal Polyp Epithelial Cells Cultured from Aspirin-sensitive and Aspirin-tolerant Patients
Authors: MAREK L. KOWALSKI, RAFAL PAWLICZAK, JANINA WOZNIAK, KATARZYNA SIUDA, MARITA PONIATOWSKA, JOLANTA IWASZKIEWICZ, TOMASZ KORNATOWSKI, MICHAEL A. KALINER
Journal: American Journal of Respiratory and Critical Care Medicine (2000)

The mechanism of aspirin (acetylsalicylic acid [ASA]) sensitivity associated with severe asthma and chronic rhinosinusitis with nasal polyps ("aspirin triad") has been attributed to arachidonic metabolism alternations, although the putative biochemical defects have not been elucidated. The aim of this study was assessment of the hypothesis that local production of eicosanoids in the respiratory epithelium in patients with ASA-sensitive asthma/rhinosinusitis (ASARS) differs from that of ASA-tolerant patients with rhinosinusitis (ATRS). Nasal polyps were obtained from 10 patients with ASARS and 15 with ATRS during routine polypectomies, and epithelial cells (ECs) were cultured on bovine collagen type I matrix (Vitrogen 100), in medium supplemented with growth factors. The generation of eicosanoids in supernatants of confluent ECs (6 to 8 d of culture; purity > 98%) was quantified by immunoassays. Unstimulated ECs from ASARS patients generated significantly less prostaglandin E2(PGE2) compared with ATRS (0.8 ± 0.3 versus 2.4 ± 0.5 ng/ μ g double-stranded deoxyribonucleic acid [dsDNA], respectively), although a similar relative increase in response to calcium ionophore and inhibition with ASA was observed in both groups. Basal levels of 15-hydroxyeicosatetraenoic acid (15-HETE) were not different between groups, and calcium ionophore enhanced its production to a similar extent. However, cells incubation with 200 μ M ASA for 60 min resulted in a significant increase (mean + 359%) in 15-HETE generation only in ASARS patients, whereas no effect of ASA on 15-HETE generation in ATRS patients was observed. PGF2 α generation was similar in both groups, and no significant generation of PGD2 or leukotriene C4 (LTC4) was observed in epithelial cell cultures from either group. Our results indicate that nasal polyps ECs from ASA-sensitive patients have significant abnormality in basal and ASA-induced generation of eicosanoids which may be causally related to the mechanism of ASA sensitivity. Kowalski ML, Pawliczak R, Wozniak J, Siuda K, Poniatowska M, Iwaszkiewicz J, Kornatowski T, Kaliner MA. Differential metabolism of arachidonic acid in nasal polyp epithelial cells cultured from aspirin-sensitive and aspirin-tolerant patients.
A Close Look at Therapeutic Touch
Authors: Linda Rosa
Journal: JAMA (1998)

Therapeutic Touch (TT) is a widely used nursing practice rooted in mysticism but alleged to have a scientific basis. Practitioners of TT claim to treat many medical conditions by using their hands to manipulate a "human energy field" perceptible above the patient's skin.To investigate whether TT practitioners can actually perceive a "human energy field."Twenty-one practitioners with TT experience for from 1 to 27 years were tested under blinded conditions to determine whether they could correctly identify which of their hands was closest to the investigator's hand. Placement of the investigator's hand was determined by flipping a coin. Fourteen practitioners were tested 10 times each, and 7 practitioners were tested 20 times each.Practitioners of TT were asked to state whether the investigator's unseen hand hovered above their right hand or their left hand. To show the validity of TT theory, the practitioners should have been able to locate the investigator's hand 100% of the time. A score of 50% would be expected through chance alone.Practitioners of TT identified the correct hand in only 123 (44%) of 280 trials, which is close to what would be expected for random chance. There was no significant correlation between the practitioner's score and length of experience (r=0.23). The statistical power of this experiment was sufficient to conclude that if TT practitioners could reliably detect a human energy field, the study would have demonstrated this.Twenty-one experienced TT practitioners were unable to detect the investigator's "energy field." Their failure to substantiate TT's most fundamental claim is unrefuted evidence that the claims of TT are groundless and that further professional use is unjustified.
bilbo, a non-LTR retrotransposon of Drosophila subobscura: a clue to the evolution of LINE-like elements in Drosophila
Authors: D. Blesa, M. J. Martinez-Sebastian
Journal: Molecular Biology and Evolution (1997)

We used the repetitive character of transposable elements to isolate a non-LTR retrotransposon in Drosophila subobscura. bilbo, as we have called it, has homology to TRIM and LOA elements. Sequence analysis showed a 5' untranslated region (UTR), an open reading frame (ORF) with no RNA-binding domains, a downstream ORF that had structural homology to that of the I factor, and, finally, a 3' UTR which ended in several 5-nt repeats. The results of our phylogenetic and structural analyses shed light on the evolution of Drosophila non-LTR retrotransposons and support the hypothesis that an ancestor of these elements was structurally complex.
Prevention of Diabetes Mellitus in Subjects with Impaired Glucose Tolerance in the Finnish Diabetes Prevention Study
Authors: Jaana Lindström, Johan G. Eriksson, Timo T. Valle, Sirkka Aunola, Zygimantas Cepaitis, Martti Hakumäki, Helena Hämäläinen, Pirjo Ilanne-Parikka, Sirkka Keinänen-Kiukaanniemi, Mauri Laakso, Anne Louheranta, Marjo Mannelin, Vesa Martikkala, Vladislav Moltchanov, Merja Rastas, Virpi Salminen, Jouko Sundvall, Matti Uusitupa, Jaakko Tuomilehto
Journal: Journal of the American Society of Nephrology (2003)

ABSTRACT. Type 2 diabetes mellitus is increasing worldwide largely as a result from increasing obesity and sedentary lifestyle. The Finnish Diabetes Prevention Study (DPS) is the first individually randomized controlled clinical trial to test the feasibility and efficacy of lifestyle modification in high-risk subjects. We randomly assigned 522 (172 men, 350 women) middle-aged (mean age 55 yr), overweight (mean body mass index 31 kg/m2) subjects with impaired glucose tolerance either to the lifestyle intervention or control group. Each subject in the intervention group received individualized counseling aimed at reducing weight and intake of total and saturated fat, and increasing intake of fiber and physical activity. An oral glucose tolerance test was performed annually to detect incident cases of diabetes and to measure changes in metabolic parameters. The mean (± SD) weight reduction from baseline to year 1 and to year 2, respectively, was 4.2 ± 5.1 kg and 3.5 ± 5.5 in the intervention group and 0.8 ± 3.7 kg and 0.8 ± 4.4 in the control group (P < 0.001 between the groups). At the time of first analysis of the outcome data the mean duration of follow-up was 3.2 yr. The risk of diabetes was reduced by 58% (P < 0.001) in the intervention group compared with the control group. The reduction in the incidence of diabetes was directly associated with number and magnitude of lifestyle changes made. In conclusion, the DPS is the first controlled trial demonstrating that type 2 diabetes can be prevented by changes in lifestyle in high-risk subjects. E-mail: [email protected]
An Alignment Confidence Score Capturing Robustness to Guide Tree Uncertainty
Authors: O. Penn, E. Privman, G. Landan, D. Graur, T. Pupko
Journal: Molecular Biology and Evolution (2010)

Multiple sequence alignment (MSA) is the basis for a wide range of comparative sequence analyses from molecular phylogenetics to 3D structure prediction. Sophisticated algorithms have been developed for sequence alignment, but in practice, many errors can be expected and extensive portions of the MSA are unreliable. Hence, it is imperative to understand and characterize the various sources of errors in MSAs and to quantify site-specific alignment confidence. In this paper, we show that uncertainties in the guide tree used by progressive alignment methods are a major source of alignment uncertainty. We use this insight to develop a novel method for quantifying the robustness of each alignment column to guide tree uncertainty. We build on the widely used bootstrap method for perturbing the phylogenetic tree. Specifically, we generate a collection of trees and use each as a guide tree in the alignment algorithm, thus producing a set of MSAs. We next test the consistency of every column of the MSA obtained from the unperturbed guide tree with respect to the set of MSAs. We name this measure the "GUIDe tree based AligNment ConfidencE" (GUIDANCE) score. Using the Benchmark Alignment data BASE benchmark as well as simulation studies, we show that GUIDANCE scores accurately identify errors in MSAs. Additionally, we compare our results with the previously published Heads-or-Tails score and show that the GUIDANCE score is a better predictor of unreliably aligned regions.
Plasma phospholipase A2 activity in patients with asthma: association with body mass index and cholesterol concentration
Authors: N L A Misso, N Petrovic, C Grove, A Celenza, J Brooks-Wildhaber, P J Thompson
Journal: Thorax (2007)

<h3>Background:</h3> Secretory phospholipases A<sub>2 </sub>(sPLA<sub>2</sub>) have functions relevant to asthmatic inflammation, including eicosanoid synthesis and effects on dendritic cells and T cells. The aim of this study was to measure sPLA<sub>2</sub> activity in patients with stable and acute asthma and to assess potential associations with body mass index (BMI), and plasma cholesterol and vitamin C concentrations. <h3>Methods:</h3> Plasma sPLA<sub>2 </sub>activity and concentrations of cholesterol and vitamin C were measured in 23 control subjects and 61 subjects with stable asthma (42 mild to moderate, 19 severe). In addition, sPLA<sub>2 </sub>activity was measured in 36 patients experiencing acute asthma and in 22 of these patients after recovery from the acute attack. <h3>Results:</h3> sPLA<sub>2 </sub>activity was not significantly greater in severe (499.9 U; 95% confidence interval (CI) 439.4 to 560.4) compared with mild to moderate asthmatic subjects (464.8; 95% CI 425.3 to 504.3) or control subjects (445.7; 95% CI 392.1 to 499.4), although it was higher in patients with acute asthma (581.6; 95% CI 541.2 to 622.0; p&lt;0.001). Male gender, high plasma cholesterol, increased BMI and atopy were associated with increased sPLA<sub>2 </sub>activity, while plasma vitamin C was inversely correlated with sPLA<sub>2 </sub>activity in patients with stable asthma and in control subjects. There were significant interactions between gender and plasma cholesterol and between gender and vitamin C in relation to sPLA<sub>2 </sub>activity. <h3>Conclusions:</h3> Plasma sPLA<sub>2 </sub>may provide a biological link between asthma, inflammation, increased BMI, lipid metabolism and antioxidants. Interactions among these factors may be pertinent to the pathophysiology and increasing prevalence of both asthma and obesity.
CPAP and measures of cardiovascular risks in patients with OSAS
Authors: M. Enoz, H. M. Inancli
Journal: European Respiratory Journal (2009)

CPAP and measures of cardiovascular risks in patients with OSASTo the Editors:We read with great interest the article by KOHLER et al. [1], which was published in a previous issue of the European Respiratory Journal.In their study, the authors emphasized that continuous positive airway pressure (CPAP) treatment can reduce the cardiovascular risks by reducing sympathetic nerve activity, ambulatory blood pressure and arterial stiffness, and increasing sensitivity of the arterial baroreflex in sleep apnoea patients.
Palliative cancer care in Middle Eastern countries: accomplishments and challenges
Authors: M. Silbermann, M. Arnaout, M. Daher, S. Nestoros, B. Pitsillides, H. Charalambous, M. Gultekin, R. Fahmi, K.A.H. Mostafa, A.D. Khleif, N. Manasrah, A. Oberman
Journal: Annals of Oncology (2012)
What's Behind the Health Expenditure Trends?
Authors: Ateev Mehrotra, R. Adams Dudley, Harold S. Luft
Journal: Annual Review of Public Health (2003)

▪ Abstract In this paper, we review the literature on a number of the potential explanations for the rise in health care expenditures in the United States: the aging population, the costs of dying, technology, physician incomes, administrative costs, prescription drugs, managed care, and the underfunding of public health. Our goal is not to pass definitive judgment on the force(s) driving health care costs, but rather to make the reader a more educated consumer of these widely cited data. We place special emphasis on how health expenditures are measured and the inherent weaknesses in the methodology. We find that frequently it is difficult to accurately estimate how individual forces influence total health care expenditures. Moreover, we conclude that interpreting the causes of the rise in expenditures goes beyond simple observations of trends and depends on how we value various segments and aspects of health and health care.
Words Matter: Distinguishing "Personalized Medicine" and "Biologically Personalized Therapeutics"
Authors: N. I. Cherny, E. G. E. de Vries, L. Emanuel, L. Fallowfield, P. A. Francis, A. Gabizon, M. J. Piccart, D. Sidransky, L. Soussan-Gutman, C. Tziraki
Journal: JNCI Journal of the National Cancer Institute (2014)

"Personalized medicine" has become a generic term referring to techniques that evaluate either the host or the disease to enhance the likelihood of beneficial patient outcomes from treatment interventions. There is, however, much more to personalization of care than just identifying the biotherapeutic strategy with the highest likelihood of benefit. In its new meaning, "personalized medicine" could overshadow the individually tailored, whole-person care that is at the bedrock of what people need and want when they are ill. Since names and definitional terms set the scope of the discourse, they have the power to define what personalized medicine includes or does not include, thus influencing the scope of the professional purview regarding the delivery of personalized care. Taxonomic accuracy is important in understanding the differences between therapeutic interventions that are distinguishable in their aims, indications, scope, benefits, and risks. In order to restore the due emphasis to the patient and his or her needs, we assert that it is necessary, albeit belated, to deconflate the contemporary term "personalized medicine" by taxonomizing this therapeutic strategy more accurately as "biologically personalized therapeutics" (BPT). The scope of truly personalized medicine and its relationship to biologically personalized therapeutics is described, emphasizing that the best of care must give due recognition and emphasis to both BPT and truly personalized medicine.
Development and validation of a consensus methodology for the classification of the ANCA-associated vasculitides and polyarteritis nodosa for epidemiological studies
Authors: R. Watts, S. Lane, T. Hanslik, T. Hauser, B. Hellmich, W. Koldingsnes, A. Mahr, M. Segelmark, J. W Cohen-Tervaert, D. Scott
Journal: Annals of the Rheumatic Diseases (2006)

<b>Background:</b> The classification of antineutrophil cytoplasmic antibody-associated vasculitis (AAV) and polyarteritis nodosa (PAN) for epidemiology studies is confusing. The existing schemes such as American College of Rheumatology (ACR) criteria, Chapel Hill Consensus Conference (CHCC) definitions and Lanham criteria produce overlapping and conflicting classifications, making it difficult to compare incidence figures. <b>Aim:</b> To develop a consensus method of using these criteria and definitions for epidemiological studies to permit comparison without confounding by classification. <b>Methods:</b> A stepwise algorithm was developed by consensus between a group of doctors interested in the epidemiology of vasculitis. The aim was to categorise patients with Wegener's granulomatosis, microscopic polyangiitis (MPA), Churg–Strauss syndrome (CSS) and PAN into single clinically relevant categories. The ACR and Lanham criteria for CSS, and ACR criteria for Wegener's granulomatosis were applied first, as these were considered to be the most specific. Surrogate markers for Wegener's granulomatosis were included to distinguish Wegener's granulomatosis from MPA. MPA was classified using the CHCC definition and surrogate markers for renal vasculitis. Finally, PAN was classified using the CHCC definition. The algorithm was validated by application to 20 cases from each centre and 99 from a single centre, followed by a paper case exercise. <b>Results:</b> A four-step algorithm was devised. It successfully categorises patients into a single classification. There was good correlation between observers in the paper case exercise (91.5%; unweighted κ = 0.886). <b>Conclusion:</b> The algorithm achieves its aim of reliably classifying patients into a single category. The use of the algorithm in epidemiology studies should permit comparison between geographical areas.
The relation of localized myocardial warming to changes in cardiac surface electrograms in dogs.
Authors: M J Burgess, R L Lux, R F Wyatt, J A Abildskov
Journal: Circulation Research (1978)

We studied the relationship of the size and severity of alteration of recovery properties in localized areas to changes in cardiac surface electrograms in experiments on six open-chest dogs. Alterations in recovery properties were induced thermally because size and severity of the affected area could be controlled on the basis of physical principles which were modeled. We recorded unipolar electrograms from 75 cardiac surface sites simultaneously during stimulation of atria and pulmonary conus in control periods and in the presence of warmed areas of varying sizes and intensities. Size of the areas was controlled by the diameter of an aperture through which a light source was directed. Intensity was controlled by the light source excitation voltage. Myocardial temperature was monitored with a thermistor. The QRS, STT, and QRST deflection areas were determined by computer processing and displayed as isoarea maps. Difference maps also were determined by subtracting control QRST isoarea maps from those obtained in the presence of warmed areas. QRST area difference maps were related closely to the size and severity of the thermally induced changes in recovery properties. With areas of the same size and increasing myocardial temperatures, the magnitude of the change in QRST area increased, and the gradient of contour lines between the affected and unaffected areas increased. When myocardial temperature at the center of the warmed area was kept constant and the size of the warmed area was increased, the affected cardiac surface area increased, but the number of isoarea contours remained approximately the same. These findings suggest that the change in QRST isoarea maps may be a useful indicator of lesion size when combined with an index of lesion severity such as the QRST area change in the electrogram with the maximum change. QRST areas during both activation orders were similar, suggesting that the QRST area is independent of changes in activation sequence.
Prevention of Hip Fractures by External Hip Protectors
Authors: Natasja M. van Schoor, Johannes H. Smit, Jos W. R. Twisk, Lex M. Bouter, Paul Lips
Journal: JAMA (2003)

Context Several randomized controlled trials have been performed to examine the effectiveness of external hip protectors in reducing the incidence of hip fractures, but the results are controversial. Objective To examine the effectiveness of hip protectors in reducing the incidence of hip fractures in an elderly high-risk population. Design, Setting, and Participants Randomized controlled trial of elderly persons aged 70 years or older, who have low bone density, and are at high risk for falls. Participants lived in apartment houses for the elderly, homes for the elderly, and nursing homes in Amsterdam and surrounding areas in the Netherlands. They were enrolled in the study between March 1999 and March 2001; the mean follow-up was 69.6 weeks. Of the 830 persons who were screened, 561 persons were enrolled. Intervention External hip protector. Both groups received written information on bone health and risk factors for falls. Main Outcome Measure Time to first hip fracture. Survival analysis was used to include all participants for the time they participated. Results In the intervention group, 18 hip fractures occurred vs 20 in the control group. Four hip fractures in the intervention group occurred while an individual was wearing a hip protector. At least 4 hip fractures in the intervention group occurred late at night or early in the morning. Both in univariate analysis (log-rank P = .86) and in multivariate analysis (hazard ratio [HR], 1.05; 95% confidence interval [CI], 0.55-2.03), no statistically significant difference between the intervention group and control group was found with regard to time to first hip fracture. In addition, the per protocol analysis in compliant participants did not show a statistically significant difference between the groups (HR, 0.77; 95% CI, 0.25-2.38). Conclusion The hip protector studied was not effective in preventing hip fractures.