10 research outputs found
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The novel compound STK405759 is a microtubule-targeting agent with potent and selective cytotoxicity against multiple myeloma in vitro and in vivo
Despite advances in treatment, multiple myeloma (MM) remains incurable. Here we propose the use of STK405759, a novel microtubule targeting agent (MTA) and member of the furan metotica family for MM therapy. STK405759 inhibited tubulin polymerization in a cell-free system and in myeloma cells. This molecule had potent cytotoxic activity against several MM cell lines and patient-derived MM cells. Moreover, STK405759 demonstrated cytotoxicity against drug-resistant myeloma cells that overexpressed the P-glycoprotein drug-efflux pump. STK405759 was not cytotoxic to peripheral blood mononuclear cells, including activated B and T lymphocytes. This compound caused mitotic arrest and apoptosis of myeloma cells characterized by cleavage of poly (ADP-ribose) polymerase-1 and caspase-8, as well as decreased protein expression of mcl-1. The combination of STK405759 with bortezomib, lenalidomide or dexamethasone had synergistic cytotoxic activity. In in vivo studies, STK405759-treated mice had significantly decreased MM tumor burden and prolonged survival compared to vehicle treated- mice. These results provide a rationale for further evaluation of STK405759 as monotherapy or part of combination therapy for treating patients with MM
Israeli-born offspring of Jewish immigrants of Middle Eastern origin have a lower incidence of multiple myeloma than those of European origin: a cohort study of 746 200 Israeli men followed from late adolescence
Patients with CKD Secondary to Glomerular Disorders have Lower Arterial Stiffness, as Compared to Hypertensive and Diabetic CKD
Abstract Background Chronic kidney disease (CKD) manifested as reduced GFR and/or albuminuria, has been known to accelerate arterial stiffness and early vascular aging (EVA). Diabetes, hypertension, and glomerular disorders are the leading causes of CKD and renal failure. The question which etiology contributes more to this vascular phenomenon-hypertensive and diabetic CKD or CKD secondary to immune-mediated glomerulonephritis—remained unclear. Objective To compare pulse wave velocity (PWV), a marker of arterial stiffness, between CKD patients of different etiologies: hypertensive and diabetic nephrosclerosis. vs. CKD secondary to glomerular disorders. Methods Clinical data were collected on 56 patients followed at the Nephrology and Hypertension Institute in Samson Assuta Ashdod University Hospital. All patients had at least one visit at our Nephrology clinics prior to recruitment. All patients with a glomerular disorder had a clinical-pathological diagnosis based on a recent kidney biopsy. Pulse wave velocity (PWV) was measured using a validated Sphygmocor XCEL® device. Univariate and multivariate analyses were performed to compare PWV between hypertensive/diabetic CKD and CKD secondary to glomerular disorders. Results PWV was significantly higher in the hypertensive/diabetic CKD group, compared to the CKD-GN group, with an average of. 12.2 m/s vs 8.3 m/s, respectively (p < 0.001). In a multivariate linear regression model, having CKD secondary to glomerulonephritis was associated with a significantly lower PWV (B = − 3.262, p < 0.001), compared with CKD secondary to hypertension and diabetes, with adjustment of age, creatinine, and comorbidities. Conclusion CKD Patients secondary to glomerulonephritis, have lower PWV when compared to CKD patients with diabetes and/or hypertension, even after adjusting for age, renal function, and the presence of comorbidities. It is intriguing to further study the possible protective role of immunosuppression on the arterial properties of CKD patients
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Sex-specific associations between adolescent categories of BMI with cardiovascular and non-cardiovascular mortality in midlife
Context Most studies linking long-term consequences of adolescent underweight and obesity are limited to men. Objective: To assess the sex-specific association of adolescent BMI with cardiovascular- and non-cardiovascular-related mortality in young adulthood and midlife. Setting: A nationwide cohort. Participants: 927,868 women, 1,366,271 men. Interventions Medical examination data at age 17, including BMI, were linked to the national death registry. Main outcomes Death attributed to cardiovascular (CVD) and non-CVD causes. Results: During 17,346,230 women-years and 28,367,431 men-years of follow-up, there were 451 and 3208 CVD deaths, respectively, and 6235 and 22,223 non-CVD deaths, respectively. Compared to low-normal BMI (18.5–22.0 kg/m2), underweight women had a lower adjusted risk for CVD mortality (Cox hazard ratio (HR) = 0.68; 95% CI 0.46–0.98) in contrast to underweight men (HR = 0.99; 0.88–1.13). The latter were at higher risk for non-CVD mortality (HR = 1.04; 1.00–1.09), unlike underweight women (HR = 1.01; 0.93–1.10). Findings, which persisted when the study sample was limited to those with unimpaired health, were accentuated for the obese with ≥ 30 years follow-up. Both sexes exhibited similarly higher risk estimates already in the high-normal BMI range (22.0 ≤ BMI < 25.0 kg/m2) with overall no interaction between sex and BMI (p = 0.62). Adjusted spline models suggested lower BMI values for minimal mortality risk among women (16.8 and 18.2 kg/m2) than men (18.8 and 20.0 kg/m2), for CVD and non-CVD death, respectively. Conclusions: Underweight adolescent females have favorable cardiovascular outcomes in adulthood. Otherwise the risk patterns were similar between the sexes. The optimal BMI value for women and men with respect to future CVD outcomes is within or below the currently accepted low-normal BMI range. Electronic supplementary material The online version of this article (10.1186/s12933-018-0727-7) contains supplementary material, which is available to authorized users
BMI at Age 17 Years and Diabetes Mortality in Midlife: A Nationwide Cohort of 2.3 Million Adolescents
Exercise-induced hypertension among healthy firefighters—a comparison between two different definitions
MOESM1 of Sex-specific associations between adolescent categories of BMI with cardiovascular and non-cardiovascular mortality in midlife
Additional file 1. Additional tables