tbuckley/cabot-search huggingface dataset:
<i>KIT</i> Mutations Induce Intracellular Retention and Activation of an Immature Form of the KIT Protein in Gastrointestinal Stromal Tumors
Authors: Séverine Tabone-Eglinger, Frédéric Subra, Hiba El Sayadi, Laurent Alberti, Eric Tabone, Jean-Philippe Michot, Nathalie Théou-Anton, Antoinette Lemoine, Jean-Yves Blay, Jean-François Emile
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Gastrointestinal stromal tumors (GIST) are frequently associated with gain-of-function mutations of KIT, which can be inhibited by imatinib both in vitro and in vivo. The survival of patients with GIST, following imatinib therapy, has been correlated with the nature of mutations but not with KIT expression. Experimental Design: Subcellular localization, activation, and trafficking of the mature and the immature forms of KIT were investigated in GIST samples and in NIH3T3 cells infected with two different GIST-type exon 11–mutated human KIT cDNA. Results: Paranuclear dot expression of KIT was more frequent in GISTs with homozygous KIT mutations than in those with heterozygous (P = 0.01) or no mutations (P &amp;lt; 0.01). Activation of the immature 125 kDa form of KIT was detected in most GISTs with KIT mutations but not in GISTs without KIT mutations. In NIH3T3 cells, mutant KIT was mainly retained within endoplasmic reticulum and Golgi compartments in an immature constitutively phosphorylated form, whereas the wild-type KIT was expressed at the plasma membrane, in a mature nonphosphorylated form. Imatinib-induced inhibition of the phosphorylation of immature and mature mutant KIT proteins resulted in the restoration of KIT expression at the cell surface. Conclusions: These results show that GIST-type KIT mutations induce an activation-dependent alteration of normal maturation and trafficking, resulting in the intracellular retention of the activated kinase within the cell. These observations likely account for the absence of correlation between response to imatinib and KIT expression using immunohistochemistry and may deserve to be investigated in other tyrosine kinase–activated tumors.
Aspirin and Mortality in Patients With Diabetes Sustaining Acute Coronary Syndrome
Authors: Richard M. Cubbon, Christopher P. Gale, Adil Rajwani, Afroze Abbas, Christine Morrell, Raj Das, Julian H. Barth, Peter J. Grant, Mark T. Kearney, Alistair S. Hall
Journal: Diabetes Care (2008)

OBJECTIVE—We sought to compare mortality reduction associated with secondary prevention in patients with and without diabetes after acute coronary syndrome (ACS). RESEARCH DESIGN AND METHODS—We conducted a cohort study involving 2,499 patients with ACS recruited from 11 U.K. hospitals. Multivariable analysis comparing all-cause mortality risk reduction associated with pharmacologic agents in patients with and without diabetes. RESULTS—Aspirin was not associated with significant mortality benefit in diabetes sufferers (95% CI 0.50–1.08); nondiabetic patients derived a 48% mortality reduction (P &amp;lt; 0.001). The interaction between diabetes and aspirin use was statistically significant (P = 0.037), indicating that patients with diabetes experience less effective mortality reduction from aspirin use. CONCLUSIONS—Aspirin, but not other secondary prevention agents, is associated with less effective mortality reduction in patients with diabetes and unstable coronary artery disease.
The Histone Demethylase KDM1A Sustains the Oncogenic Potential of MLL-AF9 Leukemia Stem Cells
Authors: William J. Harris, Xu Huang, James T. Lynch, Gary J. Spencer, James R. Hitchin, Yaoyong Li, Filippo Ciceri, Julian G. Blaser, Brigit F. Greystoke, Allan M. Jordan, Crispin J. Miller, Donald J. Ogilvie, Tim C.P. Somervaille
Journal: Cancer Cell (2012)
Matrix Metalloproteinase Polymorphisms and Bladder Cancer Risk
Authors: A. Karim Kader, Lina Shao, Colin P. Dinney, Matthew B. Schabath, Yunfei Wang, Jun Liu, Jian Gu, H. Barton Grossman, Xifeng Wu
Journal: Cancer Research (2006)

Abstract Matrix metalloproteinases (MMP) contribute to tumor microenvironment and are associated with bladder cancer. A study examining the association between MMP polymorphisms and bladder cancer risk has never been published. We analyzed the association of 11 single nucleotide polymorphisms (SNPs) and one microsatellite polymorphism in MMP genes MMP-1, MMP-2, MMP-3, MMP-8, MMP-9, and MMP-12 with bladder cancer risk in 560 Caucasian patients and 560 controls matched on age, gender, and ethnicity. Individual, combination, haplotype, and diplotype analyses were done. No associations between individual MMP polymorphisms and overall bladder cancer risk were seen. The MMP-9 microsatellite ≥24 CA repeat allele and the MMP-12-82 GG polymorphisms were associated with invasive bladder cancer risk [odds ratio (OR), 2.60; 95% confidence interval (95% CI), 1.07–6.26; and OR, 4.59; 95% CI, 1.21–17.32, respectively]. Smoke-stratified analyses revealed several associations between MMP polymorphisms, alone and in combination, with bladder cancer risk, particularly in light smokers. Linkage disequilibrium was seen in all of the MMP-1, MMP-3, MMP-8, and MMP-12 SNPs and in four of five MMP-9 polymorphisms tested. Several MMP-9 haplotype and diplotypes were associated with overall and invasive bladder cancer risk. Our study suggests that genetic variations in the MMP family are associated with bladder cancer risk. Heavy carcinogen exposure may overwhelm some of the genetic effects of MMP polymorphisms. Our study confirms the importance of taking a multigenic pathway–based approach to risk assessment. (Cancer Res 2006; 66(24): 11644-8)
<i>Chlamydia</i> Inhibit Host Cell Apoptosis by Degradation of Proapoptotic BH3-only Proteins
Authors: Silke F. Fischer, Juliane Vier, Susanne Kirschnek, Andreas Klos, Simone Hess, Songmin Ying, Georg Häcker
Journal: The Journal of Experimental Medicine (2004)

Chlamydia are obligate intracellular bacteria that replicate in a vacuole inside a host cell. Chlamydial infection has been shown to protect the host cell against apoptotic stimuli. This is likely important for the ability of Chlamydia to reproduce in human cells. Here we show that resistance to apoptosis is conveyed by the destruction of the proapoptotic BH3-only proteins Bim/Bod, Puma, and Bad during infection. Apoptotic stimuli were blocked upstream of the mitochondrial activation of Bax/Bak. During infection with both species, Chlamydia trachomatis and Chlamydia pneumoniae, Bim protein gradually disappeared without noticeable changes in Bim mRNA. The disappearance was blocked by inhibitors of the proteasome. Infected cells retained sensitivity to Bim expressed by transfection, indicating functional relevance of the Bim disappearance. Fusion to Bim targeted the green fluorescent protein for destruction during infection. Analysis of truncation mutants showed that a short region of Bim containing the BH3 domain was sufficient for destruction during chlamydial infection. Like Bim, Puma and Bad proteins disappeared during infection. These results reveal a novel way by which microbes can interfere with the host cell's apoptotic machinery, and provide a molecular explanation of the cellular resistance to apoptosis during infection with Chlamydia.
RGS4 Regulates Parasympathetic Signaling and Heart Rate Control in the Sinoatrial Node
Authors: Carlo Cifelli, Robert A. Rose, Hangjun Zhang, Julia Voigtlaender-Bolz, Steffen-Sebastian Bolz, Peter H. Backx, Scott P. Heximer
Journal: Circulation Research (2008)

Heart rate is controlled by the opposing activities of sympathetic and parasympathetic inputs to pacemaker myocytes in the sinoatrial node (SAN). Parasympathetic activity on nodal myocytes is mediated by acetylcholine-dependent stimulation of M 2 muscarinic receptors and activation of Gα i/o signaling. Although regulators of G protein signaling (RGS) proteins are potent inhibitors of Gα i/o signaling in many tissues, the RGS protein(s) that regulate parasympathetic tone in the SAN are unknown. Our results demonstrate that RGS4 mRNA levels are higher in the SAN compared to right atrium. Conscious freely moving RGS4-null mice showed increased bradycardic responses to parasympathetic agonists compared to wild-type animals. Moreover, anesthetized RGS4-null mice had lower baseline heart rates and greater heart rate increases following atropine administration. Retrograde-perfused hearts from RGS4-null mice showed enhanced negative chronotropic responses to carbachol, whereas SAN myocytes showed greater sensitivity to carbachol-mediated reduction in the action potential firing rate. Finally, RGS4-null SAN cells showed decreased levels of G protein–coupled inward rectifying potassium (GIRK) channel desensitization and altered modulation of acetylcholine-sensitive potassium current ( I KACh ) kinetics following carbachol stimulation. Taken together, our studies establish that RGS4 plays an important role in regulating sinus rhythm by inhibiting parasympathetic signaling and I KACh activity.
Duration of Humoral Immunity to Common Viral and Vaccine Antigens
Authors: Ian J. Amanna, Nichole E. Carlson, Mark K. Slifka
Journal: New England Journal of Medicine (2007)

Maintenance of long-term antibody responses is critical for protective immunity against many pathogens. However, the duration of humoral immunity and the role played by memory B cells remain poorly defined.We performed a longitudinal analysis of antibody titers specific for viral antigens (vaccinia, measles, mumps, rubella, varicella-zoster virus, and Epstein-Barr virus) and nonreplicating antigens (tetanus and diphtheria) in 45 subjects for a period of up to 26 years. In addition, we measured antigen-specific memory B cells by means of limiting-dilution analysis, and we compared memory B-cell frequencies to their corresponding serum antibody levels.Antiviral antibody responses were remarkably stable, with half-lives ranging from an estimated 50 years for varicella-zoster virus to more than 200 years for other viruses such as measles and mumps. Antibody responses against tetanus and diphtheria antigens waned more quickly, with estimated half-lives of 11 years and 19 years, respectively. B-cell memory was long-lived, but there was no significant correlation between peripheral memory B-cell numbers and antibody levels for five of the eight antigens tested.These studies provide quantitative analysis of serologic memory for multiple antigens in subjects followed longitudinally over the course of more than one decade. In cases in which multiple exposures or repeated vaccinations were common, memory B-cell numbers did not correlate with antibody titers. This finding suggests that peripheral memory B cells and antibody-secreting plasma cells may represent independently regulated cell populations and may play different roles in the maintenance of protective immunity.
Rampant Purifying Selection Conserves Positions with Posttranslational Modifications in Human Proteins
Authors: V. E. Gray, S. Kumar
Journal: Molecular Biology and Evolution (2011)

Posttranslational modifications (PTMs) are chemical alterations that are critical to protein conformation and activation states. Despite their functional importance and reported involvement in many diseases, evolutionary analyses have produced enigmatic results because only weak or no selective pressures have been attributed to many types of PTMs. In a large-scale analysis of 16,836 PTM positions from 4,484 human proteins, we find that positions harboring PTMs show evidence of higher purifying selection in 70% of the phosphorylated and N-linked glycosylated proteins. The purifying selection is up to 42% more severe at PTM residues as compared with the corresponding unmodified amino acids. These results establish extensive selective pressures in the long-term history of positions that experience PTMs in the human proteins. Our findings will enhance our understanding of the historical function of PTMs over time and help in predicting PTM positions by using evolutionary comparisons.
NCI–RTOG Translational Program Strategic Guidelines for the Early-Stage Development of Radiosensitizers
Authors: Yaacov Richard Lawrence, Bhadrasain Vikram, James J. Dignam, Arnab Chakravarti, Mitchell Machtay, Boris Freidlin, Naoko Takebe, Walter J. Curran, Soren M. Bentzen, Paul Okunieff, C. Norman Coleman, Adam P. Dicker
Journal: JNCI Journal of the National Cancer Institute (2012)

The addition of chemotherapeutic agents to ionizing radiation has improved survival in many malignancies. Cure rates may be further improved by adding novel targeted agents to current radiotherapy or radiochemotherapy regimens. Despite promising laboratory data, progress in the clinical development of new drugs with radiation has been limited. To define and address the problems involved, a collaborative effort between individuals within the translational research program of the Radiation Oncology Therapy Group and the National Cancer Institute was established. We discerned challenges to drug development with radiation including: 1) the limited relevance of preclinical work, 2) the pharmaceutical industry's diminished interest, and 3) the important individual skills and institutional commitments required to ensure a successful program. The differences between early-phase trial designs with and without radiation are noted as substantial. The traditional endpoints for early-phase clinical trials-acute toxicity and maximum-tolerated dose-are of limited value when combining targeted agents with radiation. Furthermore, response rate is not a useful surrogate marker of activity in radiation combination trials.Consequently, a risk-stratified model for drug-dose escalation with radiation is proposed, based upon the known and estimated adverse effects. The guidelines discuss new clinical trial designs, such as the time-to-event continual reassessment method design for phase I trials, randomized phase II "screening" trials, and the use of surrogate endpoints, such as pathological response. It is hoped that by providing a clear pathway, this article will accelerate the rate of drug development with radiation.
Generation of chemiluminescence by a particulate fraction isolated from human neutrophils. Analysis of molecular events.
Authors: L C McPhail, L R DeChatelet, R B Johnston
Journal: Journal of Clinical Investigation (1979)

A particulate fraction isolated from human neutrophils by homogenization, then centrifugation at 27,000 g, was demonstrated to generate chemiluminescence. This luminescence required the addition of reduced pyridine nucleotide and was very low in fractions from resting normal cells. Stimulation of neutrophils with opsonized zymosan, phorbol myristate acetate, or ionophore A23187 resulted in marked enhancement of the chemiluminescence measured in subsequently isolated particulate fractions. Stimulation did not boost the luminescence produced by fractions from cells of patients with chronic granulomatous disease. The chemiluminescence of particulate fractions from stimulated neutrophils was linear with increasing protein concentration, had a pH optimum of 7.0, and was higher with NADPH as substrate than with NADH. These results confirm previous studies suggesting that the enzyme system responsible for the respiratory burst in neutrophils is present in this fraction. The particulate fraction was used to examine the nature and origin of neutrophil luminescence by investigating the effect on this phenomenon of certain chemical and enzymatic scavengers of oxygen metabolites. Results suggest that the energy responsible for the luminescence of particulate fractions and, presumably, the intact cell, is derived from more than one oxygen species and that luminescence is a product of the interaction of these species and excitable substrates within the cell.
Barrel Bandage for Fractures
Authors: W. K. Fry
Journal: BMJ (1939)

OBJECTIVE: To evaluate the association between median episiotomy and severe (third- and fourth-degree) perineal lacerations in primiparous women. DESIGN: Retrospective cohort study. SETTING: University-affiliated hospital providing secondary obstetric care in Quebec City. PATIENTS: A total of 6522 primiparous women who gave birth vaginally to a single live baby in cephalic position between 1985 and 1993. OUTCOME MEASURE: Incidence of third- and fourth-degree perineal lacerations. RESULTS: Median episiotomy was performed in 4390 women (67.3%). A total of 1002 women (15.4%) had a third- or fourth-degree laceration. The frequency of severe perineal lacerations was 20.6% with episiotomy and 4.5% without episiotomy (relative risk [RR] 4.58, 95% confidence interval [CI] 3.74-5.62). This association persisted after adjustment by stratified analysis for type of delivery and birth weight (RR 3.03, 95% CI 2.52-3.63) and by logistic regression for type of delivery, birth weight, epidural analgesia, shoulder dystocia, baby9s head circumference, experience of the physician and year of delivery (odds ratio 3.58, 95% CI 2.84-4.50). CONCLUSION: Median episiotomy is strongly associated with third- and fourth-degree perineal lacerations in primiparous women. Reducing the use of this procedure could decrease the occurrence of severe perineal tears.
Evidence for a conformational change in a class II major histocompatibility complex molecule occurring in the same pH range where antigen binding is enhanced.
Authors: J J Boniface, D S Lyons, D A Wettstein, N L Allbritton, M M Davis
Journal: The Journal of Experimental Medicine (1996)

Many class II histocompatibility complex molecules bind antigenic peptides optimally at low pH, consistent with their exposure to antigen in acidic endosomal compartments. While it has been suggested that a partially unfolded state serves as an intermediate involved in peptide binding, very little evidence for such a state has been obtained. In this report, we show that the murine class II molecule IE becomes increasingly less stable to sodium dodecyl sulfate-induced dissociation since the pH is decreased in the same range that enhances antigenic peptide binding. Furthermore, at mildly acidic pH levels, IEk binds the fluorescent dye 1-anilino-naphthalene-8-sulfonic acid (ANS), a probe for exposed nonpolar sites in proteins, suggesting that protonation produces a molten globule-like state. The association of IEk with a single high-affinity peptide had only a small effect in these two assays, indicating that the changes that occur are distal to the peptide-binding groove. Circular dichroism analysis shows that a pH shift from neutral to mildly acidic pH causes subtle changes in the environment of aromatic residues but does not grossly disrupt the secondary structure of IEk. We propose a model in which perturbations in interdomain contacts outside the peptide-binding domain of IEk occur at acidic pH, producing a partially unfolded state that facilitates optimal antigen binding.
LSC 2011 Abstract: Evaluation of morpho-functional changes in airways of young cigarette smokers
Authors: Agnese Kislina, Gunta Strazda, Liga Balode, Marina Beinare, Normunds Jurka, Immanuels Taivans
Journal: European Respiratory Journal (2011)

We assumed that even in asymptomatic young smokers, with relatively short smoking duration and normal lung function, induced sputum could be found some changes indicative for early inflammatory process.   Aim:  The aim of this study was to evaluate morpho-functional changes in airways of young cigarette smokers.   Method:  We enrolled 23±3 years old 12 non-allergic smokers (1.59±0.67 pack-years) and 7 healthy non-smoking volunteers. Lung function measurements, sputum induction (IS) and sputum cell analysis were performed.   Results:  Demographic data for both study groups did not differ significantly. Non-smokers and smokers had normal lung function indices. In smokers induced sputum contained statistically significantly (p=0.026) increased relative count of eosinophils 0.923 (0.355-1,753)% compared with non-smokers 0.069 (0.046 - 0.550)%. We also found significant reduction of absolute (r=0.482; p=0.037) and relative (r=0.682; p=0.004) count of bronchial epithelial cells in induced sputum that correlated to number of smoked pack-years. A trend towards statistical significance showed the correlation between smoked pack-years and the relative number of macrophages in induced sputum (r =0.402; p=0.0872). A trend towards statistical significance was also found in correlation between smoked pack-years and diminished FEV1% of predicted (r= - 0.463; p= 0.046).   Conclusion:  In this study we showed that even smokers with short duration of the smoking habit have already initial signs of inflammation with eosinophil involvement.
Influence of time of day on all-out swimming.
Authors: C. Baxter, T. Reilly
Journal: British Journal of Sports Medicine (1983)

The effect of time of day on all-out swim performances was examined. Fourteen subjects performed maximal front crawl swim tests on separate days over 100 m. and 400 m. at 5 different times of day between 06.30 h. and 22.00 h. Performance showed a significant linear trend with time of day in close though not exact association with the circadian rhythm in oral temperature: a goodness of fit test confirmed that the values predicted from linear trend analysis coincided with the measured values (p less than 0.05). The steady improvement throughout the day was 3.5% for 100 m. and 2.5% for 400 m. swims. Trunk flexibility displayed a time of day variation with a trough in the morning and a peak in the afternoon. No significant rhythm was observed in ankle and shoulder flexibility, grip strength or peak expiratory flow rate (p greater than 0.05). It was concluded that maximal swimming trials are best scheduled for the evening and worst in the early morning. Specific fitness factors cannot clearly account for the higher exercise capability in the evening which is strongly related to the circadian curve in body temperature.
Mutational Evidence for Control of Cell Adhesion Through Integrin Diffusion/Clustering, Independent of Ligand Binding
Authors: Robert L. Yauch, Dan P. Felsenfeld, Stine-Kathrein Kraeft, Lan Bo Chen, Michael P. Sheetz, Martin E. Hemler
Journal: The Journal of Experimental Medicine (1997)

Previous studies have shown that integrin α chain tails make strong positive contributions to integrin-mediated cell adhesion. We now show here that integrin α4 tail deletion markedly impairs static cell adhesion by a mechanism that does not involve altered binding of soluble vascular cell adhesion molecule 1 ligand. Instead, truncation of the α4 cytoplasmic domain caused a severe deficiency in integrin accumulation into cell surface clusters, as induced by ligand and/ or antibodies. Furthermore, α4 tail deletion also significantly decreased the membrane diffusivity of α4β1, as determined by a single particle tracking technique. Notably, low doses of cytochalasin D partially restored the deficiency in cell adhesion seen upon α4 tail deletion. Together, these results suggest that α4 tail deletion exposes the β1 cytoplasmic domain, leading to cytoskeletal associations that apparently restrict integrin lateral diffusion and accumulation into clusters, thus causing reduced static cell adhesion. Our demonstration of integrin adhesive activity regulated through receptor diffusion/clustering (rather than through altered ligand binding affinity) may be highly relevant towards the understanding of inside–out signaling mechanisms for β1 integrins.
6-Mercaptopurine metabolism in Crohn’s disease
Authors: A BALLINGER
Journal: Gut (1998)

Editor,—I have read with interest the article by Cuffari et al ( Gut 1996; 39 :401–6) and do not feel that the conclusions of their study are supported by the results. The major aim of their study was to determine whether erythrocyte 6 mercaptopurine metabolite (6-TG) concentrations correlated with disease activity in patients with Crohn’s disease. The authors state that their results show an inverse correlation ( r = −0.457, p < 0.05) between 6-mercaptopurine nucleotide concentrations and the Harvey-Bradshaw index of disease activity. They conclude that these results support the immunosuppressive role of 6-TG metabolites and …