Interplay of drug transporters P-glycoprotein (MDR1), MRP1, OATP1A2 and OATP1B3 in passage of maraviroc across human placenta

Special attention is required when pharmacological treatment is indicated for a pregnant woman. P-glycoprotein (MDR1) is a well-known transporter localized in the maternal blood-facing apical membrane of placental syncytiotrophoblast and is considered to play an important role in protecting the developing fetus. Maraviroc, a MDR1 substrate that is registered for treatment of HIV infection, shows a low toxicity profile, suggesting favorable tolerability also if administered to pregnant women. Nevertheless, there is only poor understanding to date regarding the extent to which it permeates across the placental barrier and what are the transport mechanisms involved. Endeavoring to clarify the passage of maraviroc across placenta, we used in this study the method of closed-circuit perfusion of maraviroc across human placental cotyledon. The data obtained confirmed slight involvement of MDR1, but they also suggest possible interaction with other transport system(s) working in the opposite direction from that of MDR1. Complementary in vitro studies, including cellular experiments on choriocarcinoma BeWo cells as well as transporter-overexpressing MDCKII and A431 cell lines and accumulation in placental fresh villous fragments, revealed maraviroc transport by MRP1, OATP1A2, and OATP1B3 transporters. Based on mRNA expression data in the placental tissue, isolated trophoblasts, and fetal endothelial cells, especially MRP1 and OATP1A2 seem to play a crucial role in cooperatively driving maraviroc into placental tissue. By the example of maraviroc, we show here the important interplay of transporters in placental drug handling and its possibility to overcome the MDR1-mediated efflux. © 2020 The Author

Адъювантная андрогенная блокада после дистанционной лучевой терапии при раке предстательной железы — отдаленные результаты III фазы исследования RTOG 85-31

The RTOG 85-31 study has indicated that adjuvant hormonotherapy is particularly effective in prostate cancer (PC) patients with a high Glisson score. Long-term adjuvant hormonotherapy is not warranted in patients with a total Glisson score of 2-6. Exception is patients with disseminated locally advanced tumors, in whom neoadjuvant androgenic suppression (RTOG 86-10 protocol) considerably improves the results of treatment. Long-term adjuvant hormonotherapy may be the method of choice in treating PC patients with a poor prognosis.

The Kremnica Au-Ag Epithermal Deposit: an Example of Laterally Outflowing Hydrothermal System?

The Neogene Kremnica low-sulphidation deposit is situated on marginal faults of a resurgent horst, associated with rhyolite magmatism. Wallrock alteration includes adularia, illite or I/S and kaolinite. South of the vein system extensive alteration continues with zones dominated by kaolinite, I/S and smectite replacing rhyolite. Fluid inclusion and stable isotope data indicate latral outflow of fluids from N to S, with major boiling and Au deposition in central part of the vein system. Large areas of steam-heated waters probably accompanied the veins at subsurface level, while their outflow to S could be responsible for the extensive alteration of rhyolites, sporadic low-grade quartz/chalcedony veinlets with stibnite and silicite deposits in local limnic/lacustrine basins

Mice lacking liver-specific β-catenin develop steatohepatitis and fibrosis after iron overload

Background & aimsIron overload disorders such as hereditary hemochromatosis and iron loading anemias are a common cause of morbidity from liver diseases and increase risk of hepatic fibrosis and hepatocellular carcinoma (HCC). Treatment options for iron-induced damage are limited, partly because there is lack of animal models of human disease. Therefore, we investigated the effect of iron overload in liver-specific β-catenin knockout mice (KO), which are susceptible to injury, fibrosis and tumorigenesis following chemical carcinogen exposure.MethodsIron overload diet was administered to KO and littermate control (CON) mice for various times. To ameliorate an oxidant-mediated component of tissue injury, N-Acetyl-L-(+)-cysteine (NAC) was added to drinking water of mice on iron overload diet.ResultsKO on iron diet (KO +Fe) exhibited remarkable inflammation, followed by steatosis, oxidative stress, fibrosis, regenerating nodules and occurrence of occasional HCC. Increased injury in KO +Fe was associated with activated protein kinase B (AKT), ERK, and NF-κB, along with reappearance of β-catenin and target gene Cyp2e1, which promoted lipid peroxidation and hepatic damage. Addition of NAC to drinking water protected KO +Fe from hepatic steatosis, injury and fibrosis, and prevented activation of AKT, ERK, NF-κB and reappearance of β-catenin.ConclusionsThe absence of hepatic β-catenin predisposes mice to hepatic injury and fibrosis following iron overload, which was reminiscent of hemochromatosis and associated with enhanced steatohepatitis and fibrosis. Disease progression was notably alleviated by antioxidant therapy, which supports its chemopreventive role in the management of chronic iron overload disorders.Lay summaryLack of animal models for iron overload disorders makes it hard to study the disease process for improving therapies. Feeding high iron diet to mice that lack the β-catenin gene in liver cells led to increased inflammation followed by fat accumulation, cell death and wound healing that mimicked human disease. Administration of an antioxidant prevented hepatic injury in this model

Adjuvant androgenic blockade after teleradiotherapy for prostate cancer: long-term results of phase III rtog 85-31 study

The RTOG 85-31 study has indicated that adjuvant hormonotherapy is particularly effective in prostate cancer (PC) patients with a high Glisson score. Long-term adjuvant hormonotherapy is not warranted in patients with a total Glisson score of 2-6. Exception is patients with disseminated locally advanced tumors, in whom neoadjuvant androgenic suppression (RTOG 86-10 protocol) considerably improves the results of treatment. Long-term adjuvant hormonotherapy may be the method of choice in treating PC patients with a poor prognosis

Modulational Instabilities in Passive Cavities: Theory and Experiment

Les Houches workshop, September 28-October 2, 1998.info:eu-repo/semantics/publishe