tbuckley/cabot-search huggingface dataset:
Dystrophic cardiomyopathy: amplification of cellular damage by Ca2+ signalling and reactive oxygen species-generating pathways
Authors: Carole Jung, Adriano S. Martins, Ernst Niggli, Natalia Shirokova
Journal: Cardiovascular Research (2007)

Cardiac myopathies are the second leading cause of death in patients with Duchenne and Becker muscular dystrophy, the two most common and severe forms of a disabling striated muscle disease. Although the genetic defect has been identified as mutations of the dystrophin gene, very little is known about the molecular and cellular events leading to progressive cardiac muscle damage. Dystrophin is a protein linking the cytoskeleton to a complex of transmembrane proteins that interact with the extracellular matrix. The fragility of the cell membrane resulting from the lack of dystrophin is thought to cause an excessive susceptibility to mechanical stress. Here, we examined cellular mechanisms linking the initial membrane damage to the dysfunction of dystrophic heart.Cardiac ventricular myocytes were enzymatically isolated from 5- to 9-month-old dystrophic mdx and wild-type (WT) mice. Cells were exposed to mechanical stress, applied as osmotic shock. Stress-induced cytosolic and mitochondrial Ca(2+) signals, production of reactive oxygen species (ROS), and mitochondrial membrane potential were monitored with confocal microscopy and fluorescent indicators. Pharmacological tools were used to scavenge ROS and to identify their possible sources. Osmotic shock triggered excessive cytosolic Ca(2+) signals, often lasting for several minutes, in 82% of mdx cells. In contrast, only 47% of the WT cardiomyocytes responded with transient and moderate intracellular Ca(2+) signals. On average, the reaction was 6-fold larger in mdx cells. Removal of extracellular Ca(2+) abolished these responses, implicating Ca(2+) influx as a trigger for abnormal Ca(2+) signalling. Our further experiments revealed that osmotic stress in mdx cells produced an increase in ROS production and mitochondrial Ca(2+) overload. The latter was followed by collapse of the mitochondrial membrane potential, an early sign of cell death.Overall, our findings reveal that excessive intracellular Ca(2+) signals and ROS generation link the initial sarcolemmal injury to mitochondrial dysfunctions. The latter possibly contribute to the loss of functional cardiac myocytes and heart failure in dystrophy. Understanding the sequence of events of dystrophic cell damage and the deleterious amplification systems involved, including several positive feed-back loops, may allow for a rational development of novel therapeutic strategies.
Phosphorylation-dependent translocation of sphingosine kinase to the plasma membrane drives its oncogenic signalling
Authors: Stuart M. Pitson, Pu Xia, Tamara M. Leclercq, Paul A.B. Moretti, Julia R. Zebol, Helen E. Lynn, Binks W. Wattenberg, Mathew A. Vadas
Journal: The Journal of Experimental Medicine (2004)

Sphingosine kinase (SK) 1 catalyzes the formation of the bioactive lipid sphingosine 1-phosphate, and has been implicated in several biological processes in mammalian cells, including enhanced proliferation, inhibition of apoptosis, and oncogenesis. Human SK (hSK) 1 possesses high instrinsic catalytic activity which can be further increased by a diverse array of cellular agonists. We have shown previously that this activation occurs as a direct consequence of extracellular signal-regulated kinase 1/2-mediated phosphorylation at Ser225, which not only increases catalytic activity, but is also necessary for agonist-induced translocation of hSK1 to the plasma membrane. In this study, we report that the oncogenic effects of overexpressed hSK1 are blocked by mutation of the phosphorylation site despite the phosphorylation-deficient form of the enzyme retaining full instrinsic catalytic activity. This indicates that oncogenic signaling by hSK1 relies on a phosphorylation-dependent function beyond increasing enzyme activity. We demonstrate, through constitutive localization of the phosphorylation-deficient form of hSK1 to the plasma membrane, that hSK1 translocation is the key effect of phosphorylation in oncogenic signaling by this enzyme. Thus, phosphorylation of hSK1 is essential for oncogenic signaling, and is brought about through phosphorylation-induced translocation of hSK1 to the plasma membrane, rather than from enhanced catalytic activity of this enzyme.
Outcome of Primary Tumor in Patients With Synchronous Stage IV Colorectal Cancer Receiving Combination Chemotherapy Without Surgery As Initial Treatment
Authors: George A. Poultsides, Elliot L. Servais, Leonard B. Saltz, Sujata Patil, Nancy E. Kemeny, Jose G. Guillem, Martin Weiser, Larissa K.F. Temple, W. Douglas Wong, Phillip B. Paty
Journal: Journal of Clinical Oncology (2009)

The purpose of this study was to describe the frequency of interventions necessary to palliate the intact primary tumor in patients who present with synchronous, stage IV colorectal cancer (CRC) and who receive up-front modern combination chemotherapy without prophylactic surgery.
Microvesicles as Cell–Cell Messengers in Cardiovascular Diseases
Authors: Xavier Loyer, Anne-Clémence Vion, Alain Tedgui, Chantal M. Boulanger
Journal: Circulation Research (2014)

Cell–cell communication has proven to be even more complex than previously thought since the discovery that extracellular vesicles serve as containers of biological information on various pathophysiological settings. Extracellular vesicles are classified into exosomes, microvesicles/microparticles, or apoptotic bodies, originating from different subcellular compartments. The cellular machinery controlling their formation and composition, as well as the mechanisms regulating their extracellular release, remain unfortunately much unknown. Extracellular vesicles have been found in plasma, urine, saliva, and inflammatory tissues. Their biomarker potential has raised significant interest in the cardiovascular field because the vesicle composition and microRNA content are specific signatures of cellular activation and injury. More than simply cell dust, extracellular vesicles are capable of transferring biological information to neighboring cells and play an active role in inflammatory diseases, including atherosclerosis and angiogenesis. The molecular interactions regulating these effects involve specific receptor activation, proteolytic enzymes, reactive oxygen species, or delivery of genetic information to target cells. Unraveling their mechanisms of action will likely open new therapeutic avenues.
Point: If It Is Important to Prevent Type 2 Diabetes, It Is Important to Consider All Proven Therapies Within a Comprehensive Approach
Authors: Hertzel C. Gerstein
Journal: Diabetes Care (2007)

Type 2 diabetes is a common metabolic disease that is defined on the basis of glucose levels above specific thresholds. Individuals with type 2 diabetes are at high risk of blindness, renal failure, amputation, cardiovascular disease, premature death, dementia, and a variety of other chronic diseases and life-threatening events. However, unlike other risk factors for future events (e.g., hyperlipidemia or hypertension), type 2 diabetes is often associated with symptoms and discomfort related to elevated glucose levels that range from fatigue, nocturia, polyuria, and nonspecific aches and pains to dehydration and coma. Moreover, once diabetes is diagnosed, affected individuals incur additional cost and inconvenience related to disease labeling, dietary and lifestyle modification, glucose monitoring, eye assessments, and higher health and life insurance premiums.

Several trials have shown that aggressive management of type 2 diabetes can reduce the risk of microvascular disease (1–3), and that multifactorial risk factor interventions can reduce the risk of these and other consequences (4–6). These considerations and epidemiologic evidence that the risk of eye and kidney disease is well below the diagnostic thresholds for diabetes suggest that if glucose levels are prevented from rising past these thresholds, or the rise is delayed, these consequences will also be prevented or delayed. Moreover, evidence that the glucose level is a progressive risk factor for cardiovascular events (i.e., that the risk rises with the glucose level) (7–11) supports the hypothesis that preventing or delaying any rise within the nondiabetic range may reduce the risk of cardiovascular events. Finally, if ongoing clinical trials (12 …
Systematic Review: The Comparative Effectiveness of Percutaneous Coronary Interventions and Coronary Artery Bypass Graft Surgery
Authors: Dena M. Bravata, Allison L. Gienger, Kathryn M. McDonald, Vandana Sundaram, Marco V. Perez, Robin Varghese, John R. Kapoor, Reza Ardehali, Douglas K. Owens, Mark A. Hlatky
Journal: Annals of Internal Medicine (2007)

The comparative effectiveness of coronary artery bypass graft (CABG) surgery and percutaneous coronary intervention (PCI) for patients in whom both procedures are feasible remains poorly understood.To compare the effectiveness of PCI and CABG in patients for whom coronary revascularization is clinically indicated.MEDLINE, EMBASE, and Cochrane databases (1966-2006); conference proceedings; and bibliographies of retrieved articles.Randomized, controlled trials (RCTs) reported in any language that compared clinical outcomes of PCI with those of CABG, and selected observational studies.Information was extracted on study design, sample characteristics, interventions, and clinical outcomes.The authors identified 23 RCTs in which 5019 patients were randomly assigned to PCI and 4944 patients were randomly assigned to CABG. The difference in survival after PCI or CABG was less than 1% over 10 years of follow-up. Survival did not differ between PCI and CABG for patients with diabetes in the 6 trials that reported on this subgroup. Procedure-related strokes were more common after CABG than after PCI (1.2% vs. 0.6%; risk difference, 0.6%; P = 0.002). Angina relief was greater after CABG than after PCI, with risk differences ranging from 5% to 8% at 1 to 5 years (P < 0.001). The absolute rates of angina relief at 5 years were 79% after PCI and 84% after CABG. Repeated revascularization was more common after PCI than after CABG (risk difference, 24% at 1 year and 33% at 5 years; P < 0.001); the absolute rates at 5 years were 46.1% after balloon angioplasty, 40.1% after PCI with stents, and 9.8% after CABG. In the observational studies, the CABG-PCI hazard ratio for death favored PCI among patients with the least severe disease and CABG among those with the most severe disease.The RCTs were conducted in leading centers in selected patients. The authors could not assess whether comparative outcomes vary according to clinical factors, such as extent of coronary disease, ejection fraction, or previous procedures. Only 1 small trial used drug-eluting stents.Compared with PCI, CABG was more effective in relieving angina and led to fewer repeated revascularizations but had a higher risk for procedural stroke. Survival to 10 years was similar for both procedures.
Increased MCP-1 and MIP-1β in bronchoalveolar lavage fluid of chronic bronchitics
Authors: A. Capelli, A. Di Stefano, I. Gnemmi, P Balbo, C.G. Cerutti, B. Balbi, M. Lusuardi, C.F. Donner
Journal: European Respiratory Journal (1999)

CC-chemokines are chemotactic factors expressed in a wide range of cell types and tissues. The aim of this study was to evaluate the involvement of CC-chemokines in the airways inflammation of patients affected by chronic bronchitis. The study evaluated, with an immunoassay, the concentrations of monocyte chemotactic protein-1 (MCP-1), macrophage inflammatory protein-1alpha (MIP-1alpha) and macrophage inflammatory protein-1beta (MIP-1beta), in the bronchoalveolar lavage fluid (BALF) of 12 smokers affected by chronic bronchitis and 14 smoking, 15 nonsmoking and six exsmoking healthy subjects. MCP-1 was significantly increased in patients with chronic bronchitis ((mean+/-SD) 10.75+/-4.04 pg x mL(-1)) and in the smoker control group (12.39+/-5.87 pg x mL(-1)) compared with healthy exsmokers: (7.12+/-1.60 pg x mL(-1), p=0.035 and p=0.045, respectively) and nonsmokers (6.41+/-3.87 pg x mL(-1), p=0.003 and p=0.006, respectively). MIP-1alpha concentrations were undetectable. A significant difference was observed in MIP-1-beta levels in BALF of chronic bronchitics (8.11+/-5.97 pg x mL(-1)) compared to smoker (3.57+/-2.90 pg x mL(-1), p=0.018), exsmoker (3.43+/-0.68 pg x mL(-1), p=0.025) and nonsmoker (3.39+/-3.73 pg x mL(-1), p=0.008) control groups. A negative correlation was observed between MIP-1beta levels and forced expiratory volume in one second values (p=-0.64, p=0.035) in chronic bronchitics. An increase of monocyte chemotactic protein-1 is related to smoking habit and seems consistent with a lung inflammatory reaction. On the contrary, an increase in macrophage inflammatory protein-1beta levels is restricted to smokers developing chronic obstructive pulmonary disease. These data suggest a role of CC-chemokines in the pathogenesis of chronic bronchitis.
Reproductive Hormone-Induced, STAT3-Mediated Interleukin 6 Action in Normal and Malignant Human Ovarian Surface Epithelial Cells
Authors: V. Syed
Journal: JNCI Journal of the National Cancer Institute (2002)

Reproductive hormones are associated with risk for epithelial ovarian cancer. To determine the effect of such hormones on the activation of interleukin 6 (IL-6)/STAT3 (signal transducer and activator of transcription-3) signaling, which may be involved in ovarian cancer, we investigated the status of STAT3, IL-6, and its receptor in immortalized human ovarian surface epithelial (HOSE) and ovarian cancer (OVCA) cell lines.Two immortalized HOSE cell lines and two OVCA cell lines were cultured with gonadotropins, sex steroid hormones, and/or IL-6, alone or with specific inhibitors or IL-6-neutralizing antibodies. Expression of IL-6, the IL-6 receptor alpha chain (IL-6Ralpha), and phosphorylated and unphosphorylated STAT3 messenger RNAs (mRNAs) and proteins in all cells was determined. Cell proliferation and soft-agar colony formation were assessed. STAT3 activity was investigated in OVCA cells transfected with a dominant negative STAT3 (Dn-STAT3), wild-type STAT3, or an empty control vector. All statistical tests were two-sided.Levels of IL-6 mRNA and protein increased in all cells treated with follicle-stimulating hormone (FSH), luteinizing hormone (LH), 17beta-estradiol, or estrone but increased only in OVCA cells treated with testosterone and 5alpha-dihydrotestosterone. For all lines, IL-6 antibodies partially inhibited hormone-stimulated cell proliferation but completely inhibited IL-6-enhanced cell proliferation. IL-6 induced STAT3 phosphorylation and activation in HOSE cells; STAT3 was constitutively activated in OVCA cells. Higher levels of IL-6Ralpha and STAT3 transcription factors were observed in OVCA cells than in HOSE cells. After transfection, Dn-STAT3 suppressed endogenous STAT3 and inhibited all forms of IL-6-stimulated OVCA cell proliferation (OVCA 429 cells, P<.001; OVCA 432 cells, P<.006), whereas wild-type STAT3 enhanced HOSE cell proliferation (wild-type STAT3 at 0.5 microg/mL in HOSE 306 cells, P<.002; STAT3 at 1.0 microg/mL in HOSE 306 or both concentrations of wild-type STAT3 in HOSE 642 cells, P<.001).The IL-6/STAT3 signaling pathway may mediate FSH-, LH-, and estrogen-stimulated HOSE cell proliferation. Increased IL-6Ralpha expression and constitutive STAT3 activation may be associated with ovarian cancer.
Effect of 1-Year Treatment with Roflumilast in Severe Chronic Obstructive Pulmonary Disease
Authors: Peter M A Calverley, Fernando Sanchez-Toril, Andrew McIvor, Peter Teichmann, Dirk Bredenbroeker, Leonardo M Fabbri
Journal: American Journal of Respiratory and Critical Care Medicine (2007)

The oral phosphodiesterase-4 (PDE4) inhibitor, roflumilast, can improve lung function in moderate chronic obstructive pulmonary disease (COPD). Whether treatment is effective in more severe COPD (GOLD [Global Initiative for Chronic Obstructive Lung Disease] stages III and IV) over a longer period is unknown.To determine whether roflumilast improves lung function and decreases exacerbation frequency over 1 year in patients with stable COPD.We conducted a randomized, placebo-controlled, double-blind, parallel-group trial for 1 year. We recruited 1,513 patients (mean post-bronchodilator FEV1 41% predicted), 760 receiving oral 500 microg roflumilast and 753 receiving placebo once daily.We recorded post-bronchodilator FEV1, exacerbation rate, St. George's Respiratory Questionnaire total score at the study end point, and number and type of reported adverse events during treatment. Post-bronchodilator FEV1 increased by 39 ml with roflumilast compared with placebo by 52 weeks (p=0.001). The mean exacerbation rate was low and comparable in both treatment groups (0.86 vs. 0.92 exacerbations/patient/yr for roflumilast and placebo, respectively). In a retrospective analysis, the exacerbation rate in patients in GOLD stage IV disease was 36% lower in patients treated with roflumilast than in those treated with placebo (1.01 vs. 1.59 exacerbations/patient/year, respectively; p=0.024). The St. George's Respiratory Questionnaire total score did not differ between treatments. The commonest adverse events related to roflumilast treatment were diarrhea, nausea, and headache, which usually subsided during continued treatment. However, roflumilast resulted in more withdrawals within the first 3 to 4 weeks of administration.In severe, stable COPD, PDE4 inhibition with roflumilast produced a modest but significant improvement in lung function without changing the exacerbation rate or health status. However, patients with very severe disease experienced fewer exacerbations with roflumilast.
Effects of CYP2D6 and SULT1A1 genotypes including SULT1A1 gene copy number on tamoxifen metabolism
Authors: J. Gjerde, M. Hauglid, H. Breilid, S. Lundgren, J.E. Varhaug, E.R. Kisanga, G. Mellgren, V.M. Steen, E.A. Lien
Journal: Annals of Oncology (2007)
Identification of galactose‐α‐1,3‐galactose in the gastrointestinal tract of the tick <i><scp>I</scp>xodes ricinus</i>; possible relationship with red meat allergy
Authors: C. Hamsten, M. Starkhammar, T. A. T. Tran, M. Johansson, U. Bengtsson, G. Ahlén, M. Sällberg, H. Grönlund, M. van Hage
Journal: Allergy (2013)

Abstract Patients with I g E antibodies against the carbohydrate epitope galactose‐α‐1,3‐galactose (α‐ G al) have reported severe allergic reactions after consumption of red meat. Investigations have revealed associations between I g E to α‐ G al and tick bites. We provide the first direct evidence that α‐ G al is present within ticks thus potentially explaining the relationship between tick exposure and sensitization to α‐ G al, with development of red meat allergy as a secondary phenomena. Serum from S wedish patients with delayed severe reactions to red meat was included in the study. A dose‐dependent inhibition of I g E responses to α‐ G al by the tick I xodes ricinus is demonstrated. Furthermore, using cryostat‐cut sections of I . ricinus, we show that both a monoclonal and a polyclonal antibody against α‐ G al stains the gastrointestinal tract of the tick. The same pattern is seen when staining with patient sera IgE positive to α‐ G al. These results confirm that the α‐ G al epitope is present in I . ricinus and imply host exposure to α‐ G al during a tick bite. This provides further evidence that tick bites are associated with I g E responses to α‐ G al and red meat allergy.
Prevalence of Type 1 Diabetes Autoantibodies (GADA, IA2, and IAA) in Overweight and Obese Children
Authors: Valentina M. Cambuli, Michela Incani, Efisio Cossu, Tiziana Congiu, Francesca Scano, Sabrina Pilia, Federica Sentinelli, Claudio Tiberti, M. Gisella Cavallo, Sandro Loche, Marco G. Baroni
Journal: Diabetes Care (2009)

OBJECTIVE Little is known about the prevalence of β-cell autoantibodies in children with excess body weight. The prevalence of type 1 diabetes autoantibodies and its relation with hyperglycemia was analyzed in 686 overweight/obese children and adolescents. RESEARCH DESIGN AND METHODS All children underwent an oral glucose tolerance test, and anti-GAD, anti-IA2, and anti-IAA autoantibodies were measured. Autoantibody prevalence was evaluated in 107 normal-weight children for comparison. RESULTS A single autoantibody was present in 2.18% of overweight/obese subjects and 1.86% normal-weight subjects (P = NS). Postload glycemia was significantly higher in antibody-positive children (133 ± 69.9 vs. 105.4 ± 17.7 mg/dl, P &amp;lt; 0.0001) compared with autoantibody-negative subjects. No difference in autoantibody distribution was seen when our cohort was stratified by age, sex, SDS-BMI, pubertal stage, and homeostasis model assessment–insulin resistance (HOMA-IR). CONCLUSIONS The 2.18% prevalence of type 1 diabetes autoantibodies is similar to that reported in nonobese children. This study provided evidence that excess body weight and insulin resistance do not influence autoantibody frequency.
Body Iron Stores in Relation to Risk of Type 2 Diabetes in Apparently Healthy Women
Authors: Rui Jiang, JoAnn E Manson, James B Meigs, Jing Ma, Nader Rifai, Frank B Hu
Journal: JAMA (2004)

ContextType 2 diabetes is a common manifestation of hemochromatosis, a disease of iron overload. However, it is not clear whether higher iron stores predict the development of type 2 diabetes in a healthy population.ObjectiveTo examine plasma ferritin concentration and the ratio of the concentrations of transferrin receptors to ferritin in relation to risk of type 2 diabetes.Design, Setting, and ParticipantsProspective nested case-control study within the Nurses' Health Study cohort. Of the 32 826 women who provided blood samples during 1989-1990 and were free of diagnosed diabetes, cardiovascular disease, and cancer, 698 developed diabetes during 10 years of follow-up. The controls (n = 716) were matched to cases on age, race, and fasting status; and on body mass index (BMI) for cases in the top BMI decile.Main Outcome MeasureIncident cases of type 2 diabetes.ResultsAmong cases, the mean (SD) concentration of ferritin was significantly higher (109 [105] vs 71.5 [68.7] ng/mL for controls; P&lt;.001 for difference) and the mean (SD) ratio of transferrin receptors to ferritin was significantly lower (102 [205] vs 141 [340], respectively; P = .01). In conditional logistic regression stratified on the matching factors and controlled for BMI and other diabetes risk factors, the multivariate relative risks [RRs] of incident type 2 diabetes across increasing quintiles of ferritin were 1.00, 1.09 (95% confidence interval [CI], 0.70-1.70), 1.26 (95% CI, 0.82-1.95), 1.30 (95% CI, 0.83-2.04), and 2.68 (95% CI, 1.75-4.11) (P&lt;.001 for trend). The RRs across increasing quintiles of transferrin receptors to ferritin ratio were 2.44 (95% CI, 1.61-3.71), 1.00 (95% CI, 0.64-1.56), 1.13 (95% CI, 0.73-1.74), 0.99 (95% CI, 0.64-1.53), and 1.00 (P = .01 for trend). Further adjustment for an inflammatory marker (C-reactive protein) did not change the results appreciably. The associations persisted within strata defined by levels of BMI, menopausal status, alcohol consumption, and C-reactive protein.ConclusionHigher iron stores (reflected by an elevated ferritin concentration and a lower ratio of transferrin receptors to ferritin) are associated with an increased risk of type 2 diabetes in healthy women independent of known diabetes risk factors.