GARNL3 identified as a crucial target for overcoming temozolomide resistance in EGFRvIII-positive glioblastoma.

OBJECT: Amplification of the epidermal growth factor receptor (EGFR) and its active mutant type III (EGFRvIII), frequently occurr in glioblastoma (GBM), contributing to chemotherapy and radiation resistance in GBM. Elucidating the underlying molecular mechanism of temozolomide (TMZ) resistance in EGFRvIII GBM could offer valuable insights for cancer treatment. METHODS: To elucidate the molecular mechanisms underlying EGFRvIII-mediated resistance to TMZ in GBM, we conducted a comprehensive analysis using Gene Expression Omnibus and The cancer genome atlas (TCGA) databases. Initially, we identified common significantly differentially expressed genes (DEGs) and prioritized those correlating significantly with patient prognosis as potential downstream targets of EGFRvIII and candidates for drug resistance. Additionally, we analyzed transcription factor expression changes and their correlation with candidate genes to elucidate transcriptional regulatory mechanisms. Using estimate method and databases such as Tumor IMmune Estimation Resource (TIMER) and CellMarker, we assessed immune cell infiltration in TMZ-resistant GBM and its relationship with candidate gene expression. In this study, we examined the expression differences of candidate genes in GBM cell lines following EGFRvIII intervention and in TMZ-resistant GBM cell lines. This preliminary investigation aimed to verify the regulatory impact of EGFRvIII on candidate targets and its potential involvement in TMZ resistance in GBM. RESULTS: Notably, GTPase Activating Rap/RanGAP Domain Like 3 (GARNL3) emerged as a key DEG associated with TMZ resistance and poor prognosis, with reduced expression correlating with altered immune cell profiles. Transcription factor analysis suggested Epiregulin (EREG) as a putative upstream regulator of GARNL3, linking it to EGFRvIII-mediated TMZ resistance. In vitro experiments confirmed EGFRvIII-mediated downregulation of GARNL3 and decreased TMZ sensitivity in GBM cell lines, further supported by reduced GARNL3 levels in TMZ-resistant GBM cells. CONCLUSION: GARNL3 downregulation in EGFRvIII-positive and TMZ-resistant GBM implicates its role in TMZ resistance, suggesting modulation of EREG/GARNL3 signaling as a potential therapeutic strategy.

[Responses of soil erosion to changes in landscape pattern and its evolution in watershed in the loess hilly region under characteristic management and development]. / é»„ä¸˜åŒºç‰¹è‰²æ²»ç†å¼€å‘å°æµåŸŸåœŸå£¤ä¾µèš€å˜åŒ–å¯¹æ™¯è§‚æ ¼å±€æ¼”å˜çš„å“åº”.

Understanding the relationship between soil erosion and the changes in landscape patterns is important for guiding the management and development of watersheds. The Nangou watershed in Ansai County, Shaanxi on the Loess Plateau, is an area with the implement of "Grain for Green", ecological agriculture, ecological tourism and the demonstration of science and technology for landscape management. We quantified the spatial and temporal variations of landscape pattern and soil erosion from 1981 to 2018 using the GIS and the universal soil loss equation (USLE). The relationship between the soil erosion modulus and nine landscape pattern indices in three categories was analyzed using the principal component analysis at both plot and landscape levels. The results showed that, among the five landscape types, the spatial and temporal changes of cultivated land and woodland dominated the evolution of landscape patterns, which affected the concentration and distribution degree of the whole watershed. Soil erosion in the Nangou watershed decreased annually, with erosion area, erosion modulus and soil erosion intensity decreasing by 29.7%, 61.2%, and 73.4% from 1981 to 2018, respectively. The variation of cultivated land and forest land areas determined the changes of soil erosion modulus of the whole watershed. The change trend of landscape pattern index was consistent with that of soil erosion. "Grain for Green" Project was the major dri-ving force for the changes in the landscape pattern and for the reduction of soil erosion. The characteristic development and management could weaken soil erosion intensity in parts of the study area. The rational configuration of landscape types could effectively control soil erosion in a watershed. The combination of rational configuration and characteristic management could help achieve the goals for sustainable and high quality development of the watershed.

Safety and effectiveness of SARS-CoV-2 vaccines: A systematic review and meta-analysis.

OBJECTIVE: To systematically evaluate the effectiveness and safety of the SARS-CoV-2 vaccines currently undergoing clinical trials. METHODS: PubMed, EMBASE, and Cochrane Library databases were searched to collect open human COVID-19 vaccines randomized controlled trials, without limiting the search time and language. The research papers collected in the above-mentioned databases were initially screened according to the title and abstract content and merged, and the repeated ones were removed. After reading the full text of the remaining research, the studies that did not meet the inclusion criteria were excluded, and finally, nine studies were obtained. After extracting the statistical data of adverse events in the study, load them into Review Manager for heterogeneity analysis. RESULTS: The incidence of adverse reactions of inactivated virus vaccines, RNA vaccines, and adenovirus vector vaccines was higher than that of placebo. Common adverse reactions included pain, swelling, and fever at the injection site. CONCLUSION: From the perspective of effectiveness, RNA vaccine > adenovirus vector vaccine > inactivated virus vaccine. From the perspective of safety, the incidence of adverse reactions of the three vaccines is higher than that of a placebo, and the incidence of adverse reactions of the adenovirus vector vaccine is higher.

Shexiang Tongxin dropping pill protects against isoproterenol-induced myocardial ischemia in vivo and in vitro.

Shexiang Tongxin dropping pill (STDP) is a formulae of Chinese Medicine commonly used to treating angina pectoris in China. However, its mechanism of action is still yet unclear. This study investigated the roles of STDP on myocardial ischemia injury. We constructed a rat model of myocardial injury (isoproterenol subcutaneous injection, i.h, 85 mg/kg/day for 2 days), and compared among 4 groups: CON (control), ISO (ischemic injury model), MET (metoprolol), and STDP. Serum contents of Troponin I (cTnI), creatine kinase (CK), CK-MB, lactate dehydrogenase (LDH), alpha-hydroxybutyric dehydrogenase (α-HBD), and Aspartate Aminotransferase were detected and five STDP doses (1, 10, 100, 1000 and 10000 mg/kg/day) were chosen to obtain a dose-response curve. Western-blot was used to detect phosphorylations of extracellular signal-regulated kinase 1/2 (ERK1/2), protein kinase B (AKT), and camodulin kinase II (CamkII). Furthermore, an ERK1/2 inhibitor PD98059, a phosphatidylinositol-3-kinase inhibitor, LY294002, and a CamKII inhibitor, KN-93 were administered i.h. RESULTS: cTnI, CK, CK-MB, α-HBD, and LDH were significantly lower in STDP than ISO (P<0.05). STDP exhibited a dose-dependent effect with a half maximal inhibitory concentration of 42 mg/kg/day. Phosphorylation of ERK1/2 was enhanced in the STDP group (vs. ISO, P<0.05), while AKT and CamkII were not changed. Further, the protective effects of STDP were offset by PD98059 administration i.h. In conclusion, STDP protected against the ISO-induced myocardial ischemic injury via an ERK1/2 signaling pathway, which provided a mechanism to support clinical applications of STDP as treatment for ischemic heart disease.