Substances from the medicinal mushroom Daedalea gibbosa inhibit kinase activity of native and T315I mutated Bcr-Abl

Human chronic myelogenous leukemia (CML) is a malignancy of pluripotent hematopoietic cells characterized by a distinctive cytogenetic abnormality resulting in the creation of a p210 Bcr-Abl fusion protein with abnormal tyrosine kinase activity. Recently, a selective Abl kinase inhibitor, Imatinib mesylate, was introduced as a first line therapy for CML. Despite the initial response, CML patients develop a resistantance to Imatinib, which is mediated mainly by point mutations within the Abl protein. Herein, we describe the identification of mycelium organic extracts of Daedalea gibbosa with selective anti-proliferating and apoptosis-inducing activities against K562 cells and other laboratory model of CML. Using activity-guided purification, we isolated an active fraction, F6, which inhibits in vitro kinase activity of recombinant Abl. The active fraction significantly inhibits the autophosphorylation of native and mutated Bcr-Abl, which are resistant to Imatinib treatment including the T315I mutation. Using a colony-forming assay, we demonstrated that the active fraction is effective in inhibiting the colony formation of the Ba/F3 cell line harboring either native Bcr-Abl or its mutations, including the T315I mutation. Our data illustrated the potential of natural products in cancer therapeutics.     

Is obesity an independent prognosis factor in woman breast cancer?

Background Breast cancer and obesity represent important public health issues in most western countries. A number of studies found a negative prognosis effect of obesity or excess of weight in woman breast cancer. However, to date, this issue remains controversial. The objectives of this study were to confirm the prognosis role of obesity on a large cohort of patients and to investigate a potential independent effect. Materials and methods We constituted a cohort of 14,709 patients who were recruited and treated at the Curie Institute (Paris) from 1981 to 1999. These patients were followed prospectively for a first unilateral invasive breast cancer without distant metastasis. Obesity was defined by a Body Mass Index (BMI) above 30 kg/m(2) according to the World Health Organization recommendations. Results Obese patients (8%) presented more extended tumors at diagnosis time suggesting a delayed breast cancer diagnosis. However, obesity appeared as a negative prognosis factor for several events in respectively univariate and multivariate survival analysis: metastasis recurrence (HR = 1.32[1.19-1.48]; HR = 1.12[1.00-1.26]), disease free interval (1.20[1.08-1.32]; 1.10[0.99-1.22]), overall survival (1.43[1.28-1.60]; 1.12[0.99-1.25]) and second primary cancer outcome (1.57[1.19-2.07]; 1.43[1.09-1.89]). Even if obese patients presented more advanced tumors at diagnosis time, multivariate analysis showed that there was a relevant independent effect. Other BMI codings, distinguishing overweight patients or using BMI as a continuous variable, showed a consistent correlation between BMI's value and prognosis effect. Interaction analysis revealed a more important obesity effect in the presence of tumor estrogen receptors and among limited extent tumors. Conclusions This survey confirms the prognosis role of obesity on one of the largest cohort by investigating several prognosis events. While independent obesity effect linked to hormonal disorders appeared consistent as obesity's mechanism, we stress that obesity prognosis effect was also related to breast cancer presentation at diagnosis time.     

Ocular motility problems associated with sumatriptan administration

In a 55-year-old woman with classic migraine, paresis of the superior division of the right oculomotor nerve occurred twice after subcutaneous injections of sumatriptan. Each paresis disappeared within 2 weeks. Magnetic resonance imaging of the head was normal. Sumatriptan injections were discontinued, and ocular motility problems ceased. Use of sumatriptan for migraine should be considered in the diagnosis of transient, pupil-sparing, oculomotor nerve palsies in the absence of other microvascular risk factors.     

Network meta-analysis of nine large cardiovascular outcome trials of new antidiabetic drugs

The aim of this network meta-analysis (NMA) was to indirectly compare the cardiovascular (CV) safety of new antidiabetic medications in patients with type 2 diabetes mellitus (T2DM).Data synthesisA search of the Embase and MEDLINE databases was conducted systematically to identify cardiovascular outcome trials (CVOTs) of new antidiabetic medications (DPP-4 inhibitors, GLP-1 agonists and SGLT-2 inhibitors) in patients with T2DM. The primary outcomes were the composite endpoint of CV death, nonfatal MI, and nonfatal stroke (MACE), death from CV causes, nonfatal MI, nonfatal stroke and death from any cause. Hospitalization for HF and unstable angina were evaluated as secondary endpoints. A total of 9 trials, including 87,162 patients, met the eligibility criteria and were retained for the analysis.The NMA results showed no significant differences among the DPP-4 inhibitors (sitagliptin, alogliptin, and saxagliptin) in any of the CV endpoints. Similarly, no significant changes were seen in the NMA among the GLP-1 receptor agonists nor the SGLT-2 inhibitors. The pairwise meta-analysis showed that DPP-4 inhibitors have a CV safety profiled comparable to placebo. GLP-1 agonists on the other hand, showed significant reduction in MACE (RR 0.92; 95% CI 0.87–0.97), death from CV causes (RR = 0.88; 95% CI 0.80–0.97), and death from any cause (RR = 0.89; 95% CI 0.82–0.96). SGLT-2 inhibitors showed significant reduction in hospitalization for heart failure events (RR 0.72; 95% CI 0.6–0.86) compared to placebo.ConclusionThis meta-analysis has shown that new antidiabetic medications do not impose any additional CV risk. The indirect comparison among the medications of each class resulted in no significant changes regarding CV endpoints and death from any cause.     

Safety and effectiveness of thromboprophylaxis use in hospitalized elderly medical patients at a Saudi tertiary care center

IntroductionAppropriate prescribing of thromboprophylaxis according to guidelines’ recommendations can heighten over- or underutilization risk. The study intended to evaluate the safety and effectiveness of appropriate/inappropriate thromboprophylaxis use among hospitalized elderly medical patients.MethodsA retrospective observational cohort study was conducted, including patients who were ≥60 years old, hospitalized for an acute medical illness that required hospitalization in a medical ward for >48 h, and received thromboprophylaxis. Against the American College of Chest Physicians guidelines, the thromboprophylaxis use appropriateness was assessed.ResultsA total of 370 patients met the inclusion criteria, in 71.9% of whom thromboprophylaxis use was appropriate. The mean age of the included patients was 75 years (±9.1), and 72.4% of them were at high risk of venous thromboembolism (VTE), and almost all these patients received appropriate thromboprophylaxis. The occurrence of bleeding was significantly higher in the appropriate use group during hospitalization than the inappropriate use group (11.7% vs. 2.9%, p = 0.009); the majority of these bleeding events were classified as major. There were no differences in VTE events during hospitalization or 90 days all-cause mortality between the two groups.ConclusionThe study demonstrates high prescribers’ compliance with recommendations in high-risk patients. In patients at low risk for VTE, the overutilization of thromboprophylaxis did not increase their bleeding risk. This study suggests that the benefits of thromboprophylaxis in elderly patients, regardless of their VTE risk, may outweigh the risk of bleeding.     

Bibliometric analysis of cancer care operations management: current status,developments, and future directions

Health Care Management Science - Around the world, cancer care services are facing many operational challenges. Operations management research can provide important solutions to these challenges,...