Purpose:The rationale for developing an alternative paclitaxel formulation concerns Cremophor EL-related side effects, and a novel paclitaxel delivery system might augment its therapeutic efficacy. Genexol-PM is a polymeric micelle formulated paclitaxel free of Cremophor EL. A phase I study was performed to determine the maximum tolerated dosage, dose-limiting toxicities, and the pharmacokinetic profile of Genexol-PM in patients with advanced, refractory malignancies.Experimental Design: Twenty-one patients were entered into the study. Genexol-PM was i.v. administered over 3 h every 3 weeks without premedication. The Genexol-PM dose was escalated from 135 mg/m 2 to 390 mg/m 2 . Results: All of the patients were evaluable for toxicity and response. Acute hypersensitivity reactions were not observed. Neuropathy and myalgia were the most common toxicities. During cycle 1, grade 3 myalgia occurred in 1 patient at 230 and 300 mg/m 2 , respectively. At 390 mg/m 2 , 2 of 3 patients developed grade 4 neutropenia or grade 3 polyneuropathy. Therefore, the maximum tolerated dosage was determined to be 390 mg/m 2 . There were 3 partial responses (14%) among the 21 patients. Of the 3 responders, 2 were refractory to prior taxane therapy. The paclitaxel area under the curve from time 0 to infinity and peak or maximum paclitaxel concentration seemed to increase with escalating dose, except at 230 mg/m 2 , which suggests that Genexol-PM has linear pharmacokinetics. Conclusion:The main dose-limiting toxicities were neuropathy, myalgia, and neutropenia, and the recommended dosage for a phase II study is 300 mg/m 2 . Genexol-PM is believed to be superior to conventional paclitaxel in terms of the obviation of premedication and the delivery of higher paclitaxel doses without additional toxicity.

The HIV-1 restriction factor SAMHD11,2 is proposed to inhibit HIV-1 replication by depleting the intracellular dNTP pool3-5. However, the phosphorylation of SAMHD1 regulates its ability to restrict HIV-1 without decreasing cellular dNTP levels6-8, which is not consistent with a role for SAMHD1 dNTPase activity in HIV-1 restriction. Here, we show that SAMHD1 possesses RNase activity and that the RNase but not the dNTPase function is essential for HIV-1 restriction. By enzymatically characterizing Aicardi-Goutières syndrome (AGS)-associated SAMHD1 mutations and mutations in the allosteric dGTP-binding site of SAMHD1, we identify SAMHD1 mutants that are RNase-positive but dNTPase-negative (SAMHD1D137N) or RNase-negative but dNTPase-positive (SAMHD1Q548A). The allosteric mutant SAMHD1D137N is able to restrict HIV-1 infection, whereas the AGS mutant SAMHD1Q548A is defective for HIV-1 restriction. SAMHD1 associates with HIV-1 RNA and degrades it during the early phases of infection. SAMHD1 silencing in macrophages and CD4+ T cells from healthy donors increases HIV-1 RNA stability, rendering the cells permissive for HIV-1 infection. Furthermore, the phosphorylation of SAMHD1 at T592 negatively regulates its RNase activity in vivo and impedes HIV-1 restriction. Our results reveal that the RNase activity of SAMHD1 is responsible for preventing HIV-1 infection by directly degrading the HIV-1 RNA.

The occurrence of 15 antibiotics belonging to three different groups, tetracyclines (TCs), sulfonamides (SAs), and macrolides (MLs), mainly used to prevent or treat illness for humans and also to control disease or to promote the growth for animals was studied in aqueous and sediment matrices. The result of spatial and temporal statistical analysis revealed that measured concentrations of individual antibiotics were significantly different depending on sampling location and time periods for aqueous and sediment samples. High concentrations of human-used antibiotics were detected downstream of a wastewater treatment plant, and animal-used antibiotics were mainly found in a region with significant agricultural activity. Generally, the highest concentrations of antibiotics for both water and sediment samples were measured in winter indicating that low flow conditions and cold-water temperatures might enhance the persistence of these compounds. Furthermore, a pseudo-partitioning coefficient(P-PC) was introduced to provide a better understanding of the partitioning of antibiotics into the sediment. Different P-PC values were found depending on the sorption characteristics of the individual antibiotics. Sediment samples showed a greater detection frequency and a much higher concentration compared to aqueous samples taken at the same site. Since microorganism antibiotic resistance can develop in sediments, the importance of analyzing this matrix is underscored.

No abstract

No abstract