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Bobigny, France

Looyenga B.D.,Van Andel Research Institute | Hutchings D.,Van Andel Research Institute | Cherni I.,The Translational Genomics Research Institute TGEN | Kingsley C.,Diabetes | And 3 more authors.
PLoS ONE | Year: 2012

Constitutive activation of STAT3 is a common feature in many solid tumors including non-small cell lung carcinoma (NSCLC). While activation of STAT3 is commonly achieved by somatic mutations to JAK2 in hematologic malignancies, similar mutations are not often found in solid tumors. Previous work has instead suggested that STAT3 activation in solid tumors is more commonly induced by hyperactive growth factor receptors or autocrine cytokine signaling. The interplay between STAT3 activation and other well-characterized oncogenic "driver" mutations in NSCLC has not been fully characterized, though constitutive STAT3 activation has been proposed to play an important role in resistance to various small-molecule therapies that target these oncogenes. In this study we demonstrate that STAT3 is constitutively activated in human NSCLC samples and in a variety of NSCLC lines independent of activating KRAS or tyrosine kinase mutations. We further show that genetic or pharmacologic inhibition of the gp130/JAK2 signaling pathway disrupts activation of STAT3. Interestingly, treatment of NSCLC cells with the JAK1/2 inhibitor ruxolitinib has no effect on cell proliferation and viability in two-dimensional culture, but inhibits growth in soft agar and xenograft assays. These data demonstrate that JAK2/STAT3 signaling operates independent of known driver mutations in NSCLC and plays critical roles in tumor cell behavior that may not be effectively inhibited by drugs that selectively target these driver mutations. © 2012 Looyenga et al. Source

This prospective study described the trajectory of sexual well-being from before hematopoietic cell transplantation (HCT) to 3 years after in 131 allogeneic and 146 autologous HCT recipients using Derogatis Interview for Sexual Function and Derogatis Global Sexual Satisfaction Index. Sixty-one percent of men and 37% of women were sexually active pre-HCT; the prevalence declined to 51%(P 5.01) in men and increased to 48% (P 5 .02) in women at 3 years post-HCT. After HCT, sexual satisfaction declined in both sexes (P < .001). All sexual function domains were worse in women compared with men (P ≤ .001). Orgasm (P 5 .002) and drive/relationship (P < .001) declined inmen, but sexual cognition/fantasy (P 5.01) and sexual behavior/ experience (P 5 .01) improved in women. Older age negatively impacted sexual function post-HCT in both sexes (P < .01). Chronic graft-versus-host disease was associated with lower sexual cognition/fantasy (P 5 .003) and orgasm (P 5 .006) in men and sexual arousal (P 5.05) and sexual satisfaction (P 5.005) in women. Allmale sexual function domains declined after total body irradiation (P < .05). This study identifies vulnerable subpopulations that could benefit from interventional strategies to improve sexual well-being. © 2013 by The American Society of Hematology. Source

Kruger D.F.,Diabetes | Boucher J.L.,Minneapolis Heart Institute Foundation | Banerji M.A.,SUNY Downstate Medical Center
Postgraduate Medicine | Year: 2011

Within the past 2 years, the American Diabetes Association (ADA)/European Association for the Study of Diabetes (EASD) and the American Association of Clinical Endocrinologists (AACE)/American College of Endocrinology (ACE) have revised their guidelines for the diagnosis and treatment of type 2 diabetes mellitus (T2DM). Both organizations recommend a diagnostic glycated hemoglobin (HbA1c) of > 6.5% (based on a new appreciation of the relationship between glycemia and complications) and fasting plasma glucose levels or an oral glucose tolerance test. Findings from major trials of glucose control in patients with T2DM and the approval of novel medications have prompted revised treatment algorithms from both organizations. While both treatment guidelines recommend starting metformin in most patients on diagnosis of T2DM, they differ in terms of the "trigger" for treatment intensification (HbA1c ≥ 7% and > 6.5%, respectively) and which agents are preferred as second-line therapies. The ADA/EASD recommends a tiered approach to treatment, starting with well-validated second-line agents, such as sulfonylureas and basal insulin for patients unable to achieve target glucose levels with metformin. The AACE/ACE recommendations are based on the patient's HbA1c level and include a broader range of firstand second-line therapies and combinations. In addition to metformin, the ACCE/ACE treatment algorithm includes dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 agonists, thiazolidinediones, α-glucosidase inhibitors, sulfonylureas, and glinides. Both organizations advocate individualizing therapy to meet patient needs. This review highlights recent changes in the guidelines and uses a case-based format to illustrate how the current guidelines may be tailored to fit individual patient characteristics and circumstances. © Postgraduate Medicine. Source

Singh M.,Mayo Medical School | Rihal C.S.,Mayo Medical School | Spertus J.A.,Mayo Medical School | Nair K.S.,Diabetes | Roger V.L.,Mayo Medical School
Circulation: Cardiovascular Quality and Outcomes | Year: 2011

Background-Although older patients frequently undergo percutaneous coronary interventions (PCI), frailty, comorbidity, and quality of life are seldom part of risk prediction approaches. We assessed their incremental prognostic value over and above the risk factors in the Mayo Clinic risk score. Methods and Results-Patients ≥ 65 years who underwent PCI were assessed for frailty (Fried criteria), comorbidity (Charlson index), and quality of life [SF-36]. Of the 628 discharged [median follow-up of 35.0 months (interquartile range, 22.7 to 42.9)], 78 died and 72 had a myocardial infarction (MI) . Three-year mortality was 28% for frail patients, 6% for nonfrail patients. The respective 3-year rates of death or MI were 41% and 17%. After adjustment, frailty [hazard ratio (HR), 4.19 [95% confidence interval (CI), 1.85, 9.51], physical component score of the SF-36 (HR, 1.59; 95% CI, 1.24 to 2.02), and comorbidity, (HR, 1.10; 95% CI, 1.05, 1.16) were associated with mortality. Frailty was associated with mortality/MI (HR, 2.61, 1.52, 4.50). Models with conventional Mayo Clinic risk score had C-statistics of 0.628, 0.573 for mortality and mortality/MI, respectively. Adding frailty, quality of life, and comorbidity, the C-statistic was (0.675, 0.694, 0.671) for mortality and (0.607, 0.587, 0.576) for mortality/MI, respectively. Including frailty, comorbidities and SF-36, conferred a discernible improvement to predict death and death/MI (integrated discrimination improvement, 0.027 and 0.016, and net reclassification improvement of 43% and 18%, respectively). Conclusions-After PCI, frailty, comorbidity and poor quality of life are prevalent and are associated with adverse long-term outcomes. Their inclusion improves the discriminatory ability of the Mayo Clinic risk score derived from the routine cardiovascular risk factors. © 2011 American Heart Association, Inc. Source

Conte-Devolx B.,Diabetes | Vialettes B.,Metabolic Diseases
Annales d'Endocrinologie | Year: 2013

Hyperthyroidism due to Graves' disease is autoimmune in origin. The initiation of dysimmunity responsible for the disease is still poorly understood. Numerous population studies show that genetic factors have a major role, but the environment and any kind of stress also contribute to the onset of the disease. There remains the recurring question for medical experts of the accountability of stress in the onset of Graves' disease. To date, it is impossible to establish a direct link between this disease and a specific stress. The relationship can only be hypothetical, indirect and partial. © 2013 Elsevier Masson SAS. Source

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