Differential involvement of glutathione S‐transferase mu 1 and multidrug resistance protein 1 in melanoma acquired resistance to vinca alkaloids

On account of its extreme intrinsic resistance to apoptosis and of its strong ability to become chemoresistant after a primary response to drugs, malignant melanoma (MM) is still a therapeutic challenge. We previously showed that glutathione S‐transferase mu 1 (GSTM1) acts in synergy with multidrug resistance protein 1 (MRP1) to protect GSTM1‐transfected human CAL1 melanoma cells from toxic effects of vincristine (VCR). Herein, we investigated the role of these proteins in the acquired resistance of CAL1 cells to vinca alkaloids (VAs). Resistant lines were established by continuous exposure (>1 year) of parental CAL1‐wt cells to VCR, vindesine (VDS), or vinorelbine (VRB): CAL1R‐VCR, CAL1R‐VDS, CAL1R‐VRB, respectively. All resistant lines displayed more than 10‐fold increase in resistance to their selection VA, and specifically expressed GSTM1. Suggesting a direct interaction between this protein and VAs, each VA specifically decreased the GSTM1‐mediated glutathione conjugation activity in cell lysates. Curcumin (GSTM1 inhibitor), BSO (glutathione synthesis inhibitor), and MK571 (MRP1 inhibitor) considerably reversed the acquired resistance to VCR and VDS, but not to VRB. Microarray data analysis revealed similar gene expression patterns of CAL1R‐VCR and CAL1R‐VDS, and a distinct one for CAL1R‐VRB. These data suggest a differential involvement of GSTM1 and MRP1 in acquired resistance to VAs. A coordinated expression and activity of GSTM1 and MRP1 is required to protect CAL1 cells from VCR and VDS, while the simple expression of GSTM1 is sufficient, possibly by a direct drug/protein interaction, to confer resistance against VRB.     

miRNA失控表达在乳腺癌耐药中研究进展

近年来，乳腺癌耐药的研究取得了显著的进步。microRNA ( miRNA)作为乳腺癌耐药相关的分子标志物及治疗靶点，可能通过药物转运、DNA修复、细胞凋亡、上皮间质转化、乳腺癌干细胞等方面调控乳腺癌耐药。靶向调节miRNA的异常表达，恢复miRNA正常的调控功能，可能为治疗乳腺癌的提供新方向。     

Corrosion Behavior of Detonation Gun Sprayed Fe-Al Type Intermetallic Coating

The detonation gun sprayed Fe-Al type coatings as an alternative for austenitic valve steel, were investigated using two different methods of testing corrosion resistance. High temperature, 10-hour isothermal oxidation experiments at 550, 750, 950 and 1100 °C show differences in the oxidation behavior of Fe-Al type coatings under air atmosphere. The oxide layer ensures satisfying oxidation resistance, even at 950 and 1100 °C. Hematite, α-Al₂O₃ and metastable alumina phases were noticed on the coatings top surface, which preserves its initial thickness providing protection to the underlying substrate. In general, only negligible changes of the phase composition of the coatings were noticed with simultaneous strengthening controlled in the micro-hardness measurements, even after 10-hours of heating at 1100 °C. On the other hand, the electrochemical corrosion tests, which were carried out in 200 ppm Cl⁻ (NaCl) and pH ~4 (H₂SO₄) solution to simulate the acid-rain environment, reveal higher values of the breakdown potential for D-gun sprayed Fe-Al type coatings than the ones for the bulk Fe-Al type alloy and Cr21Mn9Ni4 austenitic valve steel. This enables these materials to be used in structural and multifunctional applications in aggressive environments, including acidic ones.     

Inhibitors of the Hepatitis C Virus Polymerase; Mode of Action and Resistance

The hepatitis C virus (HCV) is a pandemic human pathogen posing a substantial health and economic burden in both developing and developed countries. Controlling the spread of HCV through behavioural prevention strategies has met with limited success and vaccine development remains slow. The development of antiviral therapeutic agents has also been challenging, primarily due to the lack of efficient cell culture and animal models for all HCV genotypes, as well as the large genetic diversity between HCV strains. On the other hand, the use of interferon-α-based treatments in combination with the guanosine analogue, ribavirin, achieved limited success, and widespread use of these therapies has been hampered by prevalent side effects. For more than a decade, the HCV RNA-dependent RNA polymerase (RdRp) has been targeted for antiviral development. Direct acting antivirals (DAA) have been identified which bind to one of at least six RdRp inhibitor-binding sites, and are now becoming a mainstay of highly effective and well tolerated antiviral treatment for HCV infection. Here we review the different classes of RdRp inhibitors and their mode of action against HCV. Furthermore, the mechanism of antiviral resistance to each class is described, including naturally occurring resistance-associated variants (RAVs) in different viral strains and genotypes. Finally, we review the impact of these RAVs on treatment outcomes with the newly developed regimens.     

多囊卵巢综合征与相关微小RNA的研究进展

微小RNA(mi RNAs)是一组小分子非编码RNA,在转录后水平调控基因的表达。mi RNAs水平与糖尿病、胰岛素抵抗相关;多囊卵巢综合征(PCOS)患者外周血以及卵泡液中存在某些mi RNAs,提示mi RNAs可能作为PCOS相关的潜在生物标志物。研究发现,PCOS肥胖患者血清mi R-21、mi R-27b、mi R-103和mi R-155这4种mi RNAs的表达明显增加;而mi R-222、mi R-146a和mi R-30c这3种mi RNAs具有作为PCOS的血清生物标志物的某种可能性。卵泡液表达丰富的成熟mi RNAs,PCOS患者卵泡液中mi R-132和mi R-320表达显著低水平;mi R-224、mi R-376a和mi R-143这3种mi RNAs也可能作为PCOS病理生理机制研究的靶标。由于PCOS的异质性,不同研究得到的mi RNAs表达谱也不完全相同,所以对与PCOS相关的mi RNAs尚需进一步研究。     

RAW TROPICAL OYSTERS AS VEHICLES FOR MULTIDRUG-RESISTANT Vibrio parahaemolyticus

The following study aimed to determine the antimicrobial susceptibility profile of Vibrio parahaemolyticus strains from fresh and frozen oysters Crassostrea rhizophorae sold in Fortaleza-Brazil. An antibiogram was performed on 87 isolates using nine antibiotics: gentamicin (Gen 10 µg), ampicillin (Amp 10 µg), penicillin G (Pen 10U), ciprofloxacin (Cip 5 µg), chloramphenicol (Chl 30 µg), nalidixic acid (Nal 30 µg), tetracycline (Tet 30 µg), vancomycin (Van 30 µg) and erythromycin (Ery 15 µg). All strains were resistant to at least one antibiotic, and 85 (97.7%) were multi-resistant, with predominance of the Van+ Pen+Amp resistance profile (n = 46). Plasmid resistance to Pen, Amp and Ery was detected. Thus, the risk that raw oyster consumption poses to the health of consumers is highlighted, due to the fact that these bivalves may host antibacterial-resistant microorganisms.