A phase 1b/pharmacokinetic trial of PTC299, a novel post-transcriptional VEGF inhibitor, for AIDS-related Kaposi’s sarcoma: AIDS Malignancy Consortium trial 059

Vascular endothelial growth factor (VEGF) plays an important role in Kaposi’s sarcoma (KS). We administered PTC299, a post-transcriptional inhibitor of pathogenic VEGF, to persons with HIV-related KS. Seventeen participants received three different doses of PTC299. Adverse events typically observed with VEGF-inhibition were absent. Three participants had partial tumor responses and 11 had stable disease. There were no differences in exposure to PTC299 by antiretroviral regimen. Serum VEGF, but not KSHV DNA, decreased on treatment. Given redundancies in the VEGF feedback loop, future trials should consider combining PTC299 with agents that inhibit different pathways implicated in KS and KSHV proliferation

Заболевание тазобедренного сустава у детей с наследственной предрасположенностью: концептуальная модель

На основе принципов интегративной медицины, системного подхода с использованием концептуально−логического моделирования разработана единая система представлений о заболеваниях тазобедренного сустава у детей с наследственной предрасположенностью. Показано, что предлагаемый интегративный подход может служить основой для разработки диагностических и прогностических критериев развития суставов и проведения патогенетического хирургического лечения, направленного на ликвидацию или существенное снижение частоты формирования диспластического коксартроза.Based on the principles of integrative medicine, systemic approach with the use of concept of logical modelling, a uniform system of concepts about the diseases of the hip joint in children with hereditary susceptibility was worked out. It was shown that the suggested integrative approach can be used for working out diagnostic and prognostic criteria of joint development and performing pathogenetic surgery aimed at elimination or reduction in the frequency of forming dysplastic coxarthrosis

The PI3K/Akt1 pathway enhances steady-state levels of FANCL

Fanconi anemia hematopoietic stem cells display poor self-renewal capacity when subjected to a variety of cellular stress. This phenotype raises the question of whether the Fanconi anemia proteins are stabilized or recruited as part of a stress response and protect against stem cell loss. Here we provide evidence that FANCL, the E3 ubiquitin ligase of the Fanconi anemia pathway, is constitutively targeted for degradation by the proteasome. We confirm biochemically that FANCL is polyubiquitinated with Lys-48-linked chains. Evaluation of a series of N-terminal-deletion mutants showed that FANCL's E2-like fold may direct ubiquitination. In addition, our studies showed that FANCL is stabilized in a complex with axin1 when glycogen synthase kinase-3β is overexpressed. This result leads us to investigate the potential regulation of FANCL by upstream signaling pathways known to regulate glycogen synthase kinase-3β. We report that constitutively active, myristoylated-Akt increases FANCL protein level by reducing polyubiquitination of FANCL. Two-dimensional PAGE analysis shows that acidic forms of FANCL, some of which are phospho-FANCL, are not subject to polyubiquitination. These results indicate that a signal transduction pathway involved in self-renewal and survival of hematopoietic stem cells also functions to stabilize FANCL and suggests that FANCL participates directly in support of stem cell function

Effect of food on bioavailability of chloroquine

The bioavailability of chloroquine in 7 healthy adult male volunteers was assessed with and without a standard breakfast. Chloroquine (600 mg base) was administered orally and timed blood samples were obtained for determination of plasma concentrations. The results suggest that the AUC and peak plasma levels were significantly higher when chloroquine was administered together with food, although the rate of absorption was not different. It appears, therefore, that food facilitates chloroquine absorption and the extent of absorption is significantly modified. Hence administration of chloroquine together with food appears to be an advisable clinical practice

Indocyanine green clearance in the undernourished adults

1. Indocyanine green clearance was studied in eight undernourished subjects. 2. The data showed that in mild to moderately, undernourished adult males, the plasma concentration of ICG were low, the t 0.5 tended to prolong, as a result of increased volume of distribution. 3. However, the ICG clearance was not found to be affected indicating that the clearance of drugs with a high hepatic extraction ratio is unlikely to be altered in these subjects

Chloroquine kinetics in the undernourished

The plasma and whole blood kinetics of chloroquine was studied in 7 normal and 8 undernourished subjects following a single oral dose of 600 mg. The terminal half-lives were similar in both groups. The AUC was also similar in the 2 groups, even though a higher dose per kg body weight was administered to the undernourished. This was probably because of faster clearance in this group. Chloroquine uptake by erythrocytes, its main site of action in malaria, was also comparable in the two groups. The plasma concentration of chloroquine over a period of time was found to be similar in 4 normal and 4 undernourished subjects following administration of 1.5 g of the drug in divided doses. The undernourished appear, therefore, to handle chloroquine in such a way that they do not suffer a greater risk of toxicity than normals

Monte Carlo simulation: Remanufacturing or not -A newsvendor perspective

The concept of random yields or uncertain supply is not new in inventory management. While this aspect has been extensively studied in the literature over several decades, the factors impacting uncertain supply have been largely been limited to quality defects, uncertain capacity and sourcing issues. The concept of random yields is very much applicable to the reverse logistics and remanufacturing activities that has received increased attention in recent years. The purpose of this paper is to demonstrate the modeling of the newsvendor problem with uncertain supply via spreadsheet based simulation as a managerial tool for optimizing the performance of a remanufacturing operation