Macronutrient intakes and cardio metabolic risk factors in high BMI African American children

<p>Abstract</p> <p>Background</p> <p>The aim of this study was to evaluate the relationship between intakes of energy-providing macronutrients, and markers of cardio metabolic risk factors in high BMI African American (AA) children.</p> <p>Methods</p> <p>A cross sectional analysis of a sample of 9-11 year old children (n = 80) with BMI greater then the 85^thpercentile. Fasting hematological and biochemical measurements, and blood pressure were measured as selected markers of cardio metabolic risk factors and their relationships to dietary intakes determined.</p> <p>Results</p> <p>After adjusting for gender, pubertal stage and waist circumference (WC), multivariate regression analysis showed that higher total energy intakes (when unadjusted for source of energy) were associated with higher plasma concentrations of intermediate density lipoprotein cholesterol (IDL-C) and very low density lipoprotein cholesterol (VLDL-C). Higher intakes of carbohydrate energy (fat and protein held constant) were associated with higher IDL-C, VLDL-C, triglycerides (TG) and homeostasis model assessment of insulin resistance (HOMA-IR). Higher intakes of fat (carbohydrate and protein held constant), however, were associated with lower IDL-C; and higher protein intakes (fat and carbohydrate held constant) were associated with lower HOMA-IR.</p> <p>Conclusion</p> <p>The specific macronutrients that contribute energy are significantly associated with a wide range of cardio metabolic risk factors in high BMI AA children. Increases in carbohydrate energy were associated with undesirable effects including increases in several classes of plasma lipids and HOMA-IR. Increases in protein energy were associated with the desirable effect of reduced HOMA-IR, and fat energy intakes were associated with the desirable effect of reduced IDL-C. This analysis suggests that the effect of increased energy on risk of developing cardio metabolic risk factors is influenced by the source of that energy.</p

Predictive factors for severe toxicity of sunitinib in unselected patients with advanced renal cell cancer

Sunitinib has been registered for the treatment of advanced renal cell cancer (RCC). As patient inclusion was highly selective in previous studies, experience with sunitinib in general oncological practice remains to be reported. We determined the efficacy and safety of sunitinib in patients with advanced RCC included in an expanded access programme. ECOG performance status >1, histology other than clear cell and presence of brain metastases were no exclusion criteria. Eighty-two patients were treated: 23% reached a partial response, 50% had stable disease, 20% progressed and six patients were not evaluable. Median progression-free survival (PFS) was 9 months and median overall survival (OS) was 15 months. Importantly, 47 patients (57%) needed a dose reduction, 35 (43%) because of treatment-related adverse events, 10 (12%) because of continuous dosing, and two because of both. Stomatitis, fatigue, hand–foot syndrome and a combination of grade 1–2 adverse events were the most frequent reasons for dose reduction. In 40 patients (49%), there was severe toxicity, defined as dose reduction or permanent discontinuation, which was highly correlated with low body surface area, high age and female gender. On the basis of age and gender, a model was developed that could predict the probability of severe toxicity

Use of radiolabelled choline as a pharmacodynamic marker for the signal transduction inhibitor geldanamycin

There is an urgent need to develop non-invasive pharmacodynamic endpoints for the evaluation of new molecular therapeutics that inhibit signal transduction. We hypothesised that, when labelled appropriately, changes in choline kinetics could be used to assess geldanamycin pharmacodynamics, which involves inhibition of the HSP90 molecular chaperone→Raf1→Mitogenic Extracellular Kinase→Extracellular Signal-Regulated Kinase 1 and 2 signal transduction pathway. Towards identifying a potential pharmacodynamic marker response, we have studied radiolabelled choline metabolism in HT29 human colon carcinoma cells following treatment with geldanamycin. We studied the effects of geldanamycin, on net cellular accumulation of (methyl-14C)choline and (methyl-14C)phosphocholine production. In parallel experiments, the effects of geldanamycin on extracellular signal-regulated kinase 1 and 2 phosphorylation and cell viability were also assessed. Additional validation studies were carried out with the mitogenic extracellular kinase inhibitor U0126 as a positive control; a cyclin-dependent kinase-2 inhibitor roscovitine and the phosphatidylinositol 3-kinase inhibitor LY294002 as negative controls. Hemicholinium-3, an inhibitor of choline transport and choline kinase activity was included as an additional control. In exponentially growing HT29 cells, geldanamycin inhibited extracellular signal-regulated kinase 1 and 2 phosphorylation in a concentration- and time-dependent manner. These changes were associated with a reduction in (methyl-14C)choline uptake, (methyl-14C) phosphocholine production and cell viability. Brief exposure to U0126, suppressed phosphocholine production to the same extent as Hemicholinium-3. In contrast to geldanamycin and U0126, which act upstream of extracellular signal-regulated kinase 1 and 2, roscovitine and LY294002 failed to suppress phosphocholine production. Our results suggest that when labelled with carbon-11 isotope, (methyl-11C)choline may be a useful pharmacodynamic marker for the non-invasive evaluation of geldanamycin analogues

A phase I/II study of siltuximab (CNTO 328), an anti-interleukin-6 monoclonal antibody, in metastatic renal cell cancer

Background: Serum interleukin (IL)-6 levels correlate with disease outcomes in renal cell carcinoma (RCC) patients. Siltuximab, a chimeric, murine-human mAb against IL-6, was evaluated in a three-part phase I/II study in patients with progressive metastatic RCC. Methods: In part 1, 11 patients received 1, 3, 6, or 12 mg kg–1 at weeks 1, 4 and q2w × 2 thereafter; in part 2, 37 patients randomly received 3 or 6 mg kg–1 q3w × 4; in part 3, 20 low-risk patients received 6 mg kg–1 q2w × 6. Modified WHO response criteria were assessed at weeks 7, 11, the 6-week follow-up, and when clinically indicated. Results: Siltuximab was well tolerated overall, with no maximum tolerated dose or immune response observed. In all, 5 out of 11, 17 out of 37, and 9 out of 20 patients in parts 1, 2, and 3, respectively, received extended treatment beyond 4–6 initial infusions. In part 2, stable disease (SD) (greater than or equal to11weeks) or better was achieved by 11 out of 17 (65%) 3 mg kg–1 treated patients (one partial response (PR) ~8 months, 10 SD) and 10 out of 20 (50%) 6 mg kg–1 treated patients (10 SD). In part 3, documented complete or PR was not observed, but 13 out of 20 (65%) patients achieved SD. Conclusion: Siltuximab stabilised disease in >50% of progressive metastatic RCC patients. One PR was observed. Given the favourable safety profile of siltuximab and poor correlation of tumour shrinkage with clinical benefit demonstrated for other non-cytotoxic therapies, further evaluation of dose-escalation strategies and/or combination therapy may be considered for patients with RCC

Taking Action Together: A YMCA-based protocol to prevent Type-2 Diabetes in high-BMI inner-city African American children

<p>Abstract</p> <p>Background</p> <p>Associated with a tripling in obesity since 1970, type 2 diabetes mellitus (T2DM) in children has risen 9-10 fold. There is a critical need of protocols for trials to prevent T2DM in children.</p> <p>Methods/Design</p> <p>This protocol includes the theory, development, evaluation components and lessons learned from a novel YMCA-based T2DM prevention intervention designed specifically for high-BMI African American children from disadvantaged, inner-city neighborhoods of Oakland, California. The intervention was developed on the basis of: review of epidemiological and intervention studies of pediatric T2DM; a conceptual theory (social cognitive); a comprehensive examination of health promotion curricula designed for children; consultation with research, clinical experts and practitioners and; input from community partners. The intervention, <it>Taking Action Together</it>, included culturally sensitive and age-appropriate programming on: healthy eating; increasing physical activity and, improving self esteem.</p> <p>Discussion</p> <p>Evaluations completed to date suggest that <it>Taking Action Together </it>may be an effective intervention, and results warrant an expanded evaluation effort. This protocol could be used in other community settings to reduce the risk of children developing T2DM and related health consequences.</p> <p>Trial registration</p> <p>ClinicalTrials.gov NCT01039116.</p

Sunitinib and other targeted therapies for renal cell carcinoma

Targeted therapy has radically altered the way metastatic renal cancer is treated. Six drugs are now licensed in this setting, with several other agents under evaluation. Sunitinib is currently the most widely used in the first line setting with impressive efficacy and an established toxicity profile. However, as further randomised studies report and as newer drugs become available this may change. In this review, we address our current understanding of targeted therapy in renal cancer. We also discuss areas in which our knowledge is incomplete, including the identification of correlative biomarkers and mechanisms of drug resistance. Finally, we will describe the major areas of clinical research that will report over the next few years