Predictive value of the SLC22A18 protein expression in glioblastoma patients receiving temozolomide therapy

BACKGROUND: Our previous study showed that SLC22A18 downregulation and promoter methylation were associated with the development and progression of glioma and the elevated expression of SLC22A18 was found to increase the sensitivity of glioma U251 cells to the anticancer drug 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). In this study, we investigated the predictive value of SLC22A18 promoter methylation and protein expression in glioblastoma multiforme (GBM) patients receiving temozolomide (TMZ) therapy. PATIENTS AND METHODS: SLC22A18 promoter methylation and protein expression were examined by methylation-specific polymerase chain reaction (MSP) and Western blotting respectively, then we compared SLC22A18 promoter methylation and protein expression in tumor cell explants in regard to prediction of TMZ response and survival time of 86 GBM patients. RESULTS: SLC22A18 promoter methylation was detected in 61 of 86 (71%) samples, whereas 36 of 86 (42%) cases were scored positive for SLC22A18 protein expression. Overall SLC22A18 promoter methylation was significantly related to SLC22A18 protein expression, but a subgroup of cases did not follow this association. Multivariate Cox regression analysis indicated that SLC22A18 protein expression, but not promoter methylation, was significantly correlated with TMZ therapy. SLC22A18 protein expression predicted a significantly shorter overall survival in 51 patients receiving TMZ therapy, whereas no differences in overall survival were observed in 35 patients without TMZ therapy. CONCLUSIONS: These results show that lack of SLC22A18 protein expression is superior to promoter methylation as a predictive tumor biomarker in GBM patients receiving temozolomide therapy

Promoter methylation and downregulation of SLC22A18 are associated with the development and progression of human glioma

<p>Abstract</p> <p>Background</p> <p>Downregulation of the putative tumor suppressor gene <it>SLC22A18 </it>has been reported in a number of human cancers. The aim of this study was to investigate the relationship between <it>SLC22A18 </it>downregulation, promoter methylation and the development and progression of human glioma.</p> <p>Method</p> <p><it>SLC22A18 </it>expression and promoter methylation was examined in human gliomas and the adjacent normal tissues. U251 glioma cells stably overexpressing <it>SLC22A18 </it>were generated to investigate the effect of <it>SLC22A18 </it>on cell growth and adherence <it>in vitro </it>using the methyl thiazole tetrazolium assay. Apoptosis was quantified using flow cytometry and the growth of <it>SLC22A18 </it>overexpressing U251 cells was measured in an <it>in viv</it>o xenograft model.</p> <p>Results</p> <p><it>SLC22A18 </it>protein expression is significantly decreased in human gliomas compared to the adjacent normal brain tissues. <it>SLC22A18 </it>protein expression is significantly lower in gliomas which recurred within six months after surgery than gliomas which did not recur within six months. <it>SLC22A18 </it>promoter methylation was detected in 50% of the gliomas, but not in the adjacent normal tissues of any patient. SLC22A18 expression was significantly decreased in gliomas with <it>SLC22A18 </it>promoter methylation, compared to gliomas without methylation. The <it>SLC22A18 </it>promoter is methylated in U251 cells and treatment with the demethylating agent 5-aza-2-deoxycytidine increased <it>SLC22A18 </it>expression and reduced cell proliferation. Stable overexpression of <it>SLC22A18 </it>inhibited growth and adherence, induced apoptosis <it>in vitro </it>and reduced <it>in vivo </it>tumor growth of U251 cells.</p> <p>Conclusion</p> <p><it>SLC22A18 </it>downregulation via promoter methylation is associated with the development and progression of glioma, suggesting that <it>SLC22A18 </it>is an important tumor suppressor in glioma.</p

Improved representation of the diurnal variation of warm season precipitation by an atmospheric general circulation model at a 10 km horizontal resolution

This study investigates the diurnal variation of the warm season precipitation simulated by the Goddard Earth Observing System version 5 atmospheric general circulation model for 2??years (2005???2006) at a horizontal resolution of 10??km. The simulation was validated with the satellite-derived Tropical Rainfall Measuring Mission (TRMM) 3B42 precipitation data and the Modern-Era Retrospective analysis for Research and Applications atmospheric reanalysis for atmospheric winds and moisture. The simulation is compared with the coarse-resolution run in 50??km to examine the impacts driven by resolution change. Overall, the 10??km model tends to reproduce the important features of the observed diurnal variation, such as the amplitude and phase at which precipitation peaks in the evening on land and in the morning over the ocean, despite an excessive amplitude bias over land. The model also reproduces the realistic propagation patterns of precipitation in the vicinity of ocean coasts and major mountains. The regional characteristics of the diurnal precipitation over two regions, the Bay of Bengal and the Great Plains in North America, are examined in detail, where the observed diurnal cycle exhibits a systematic transition in the peak phase due to the development and propagation of regional-scale convective systems. The model is able to reproduce this pattern as well as the diurnal variation of low-level wind and moisture convergence; however, it is less effective at representing the nocturnal peak of precipitation over the Great Plains. The model results suggest that increasing the horizontal resolution of the model to 10??km substantially improves the representation of the diurnal precipitation cycle. However, intrinsic model deficiencies in topographical precipitation and the accurate representation of mesoscale convective systems remain a challenge

Multidrug efflux pumps:structure, function and regulation

Infections arising from multidrug-resistant pathogenic bacteria are spreading rapidly throughout the world and threaten to become untreatable. The origins of resistance are numerous and complex, but one underlying factor is the capacity of bacteria to rapidly export drugs through the intrinsic activity of efflux pumps. In this Review, we describe recent advances that have increased our understanding of the structures and molecular mechanisms of multidrug efflux pumps in bacteria. Clinical and laboratory data indicate that efflux pumps function not only in the drug extrusion process but also in virulence and the adaptive responses that contribute to antimicrobial resistance during infection. The emerging picture of the structure, function and regulation of efflux pumps suggests opportunities for countering their activities

Comparing recombinant human rabies monoclonal antibody (ormutivimab) with human rabies immunoglobulin (HRIG) for postexposure prophylaxis: A phase III, randomized, double-blind, non-inferiority trial

Objectives: To evaluate the immunogenicity and safety of an anti-rabies monoclonal antibody (mAb), ormutivimab, compared with human rabies immunoglobulin (HRIG). Methods: This phase III trial was designed as a randomized, double-blind, non-inferiority clinical trial in patients aged ≥18 years with suspected World Health Organization category Ⅲ rabies exposure. The participants were randomized 1:1 to ormutivimab and HRIG groups. After thorough wound washing and injection of ormutivimab/HRIG on day 0, the vaccination was administered on days 0, 3, 7, 14, and 28. The primary endpoint was the adjusted geometric mean concentration (GMC) of rabies virus-neutralizing activity (RVNA) on day 7. The endpoint of safety included the occurrence of adverse reactions and serious adverse events. Results: A total of 720 participants were recruited. The adjusted-GMC of RVNA (0.41 IU/ml) on day 7 in ormutivimab group was not inferior to that in the HRIG group (0.41 IU/ml), with ratio of adjusted-GMC of 1.01 (95% confidence interval: 0.91, 1.14). The seroconversion rate of the ormutivimab group was higher than that of the HRIG group on days 7, 14, and 42. Most local injection sites and systemic adverse reactions reported from both groups were mild to moderate in severity. Conclusion: ormutivimab + vaccine can protect victims aged ≥18 years with category Ⅲ suspected rabies exposure as a component of postexposure prophylaxis. ormutivimab has a weaker influence on the immunity response of rabies vaccines. Clinical trials registration: ChiCTR1900021478 (the Chinese Clinical Trial Registry of World Health Organization)