Increased p38-MAPK is responsible for chemotherapy resistance in human gastric cancer cells

<p>Abstract</p> <p>Background</p> <p>Chemoresistance is one of the main obstacles to successful cancer therapy and is frequently associated with Multidrug resistance (MDR). Many different mechanisms have been suggested to explain the development of an MDR phenotype in cancer cells. One of the most studied mechanisms is the overexpression of P-glycoprotein (P-gp), which is a product of the <it>MDR1 </it>gene. Tumor cells often acquire the drug-resistance phenotype due to upregulation of the <it>MDR1 </it>gene. Overexpression of <it>MDR1 </it>gene has often been reported in primary gastric adenocarcinoma.</p> <p>Methods</p> <p>This study investigated the role of p38-MAPK signal pathway in vincristine-resistant SGC7901/VCR cells. P-gp and MDR1 RNA were detected by Western blot analysis and RT-PCR amplification. Mitgen-activated protein kinases and function of P-gp were demonstrated by Western blot and FACS Aria cytometer analysis. Ap-1 activity and cell apoptosis were detected by Dual-Luciferase Reporter Assay and annexin V-PI dual staining.</p> <p>Results</p> <p>The vincristine-resistant SGC7901/VCR cells with increased expression of the multidrug-resistance 1 (<it>MDR1</it>) gene were resistant to P-gp-related drug and P-gp-unrelated drugs. Constitutive increases of phosphorylated p38-MAPK and AP-1 activities were also found in the drug-resistant cells. Inhibition of p38-MAPK by SB202190 reduced activator protein-1 (AP-1) activity and <it>MDR1 </it>expression levels and increased the sensitivity of SGC7901/VCR cells to chemotherapy.</p> <p>Conclusion</p> <p>Activation of the p38-MAPK pathway might be responsible for the modulation of P-glycoprotein-mediated and P-glycoprotein-unmediated multidrug resistance in the SGC7901/VCR cell line.</p

Hypofractionated radiotherapy with immunochemotherapy for extensive-stage small-cell lung cancer

IntroductionThe combination of a PD-L1 inhibitor plus carboplatin/cisplatin and etoposide (EC/EP) has become a new standard first-line treatment for extensive-stage small-cell lung cancer (ES-SCLC). Combining concurrent palliative hypofractionated radiotherapy of the thorax (HFRT) and immunochemotherapy may have a synergistic effect. In this study, we explored an optimal model of combination radiotherapy with immunochemotherapy as first-line treatment of ES-SCLC.Patients and methodsIn this multicenter single-arm phase 2 trial, patients with ES-SCLC received atezolizumab with EC/EP for two cycles (induction phase), then, those who did not progress received concurrent palliative HFRT and two cycles of atezolizumab with EC/EP (combination phase). Afterward they received atezolizumab every 3 weeks for a maximum of 2 years after study enrolment (maintenance phase). Prophylactic cranial irradiation (PCI) was recommended. The primary endpoints were safety and tolerance; the second endpoints were progression-free survival (PFS).ResultsForty patients were enrolled, and all had completed palliative HFRT and four cycles of immunochemotherapy. There were seven grade 3 adverse events (3 decreased neutrophil count, 1 anemia, 2 pneumonitis, 1 esoenteritis), two grade 4 adverse events (2 decreased white cell count) and no grade 5 toxicities. The pneumonitis rate was 12.5% (three grade 2 and two grade 3 events). At the median follow-up of 14.2 months (range, 6.8–28.7), the median PFS was 8.6 months (95%CI, 6.1–11.1).ConclusionThe addition of concurrent hypofractionated thoracic radiotherapy to first-line immunochemotherapy for ES-SCLC was well tolerated and showed promising clinical efficacy. Additional randomized trials are needed to validate benefits.Clinical trial registrationhttps://clinicaltrials.gov/ (NCT 04636762)

STAT3 Contributes To Oncolytic Newcastle Disease Virus-Induced Immunogenic Cell Death in Melanoma Cells

Background: Oncolytic viruses (OVs) are emerging as potent inducers of immunogenic cell death (ICD), releasing danger-associated molecular patterns (DAMPs) that induce potent anticancer immunity. Oncolytic Newcastle disease virus (NDV) has been shown to educe ICD in both glioma and lung cancer cells. The objective of this study is to investigate whether oncolytic NDV induces ICD in melanoma cells and how it is regulated.Methods: Various time points were actuated to check the expression and release of ICD markers induced by NDV strain, NDV/FMW in melanoma cell lines. The expression and release of ICD markers induced by oncolytic NDV strain, NDV/FMW, in melanoma cell lines at various time points were determined. Surface-exposed calreticulin (CRT) was inspected by confocal imaging. The supernatants of NDV/FMW infected cells were collected and concentrated for the determination of ATP secretion by ELISA, HMGB1, and HSP70/90 expression by immunoblot (IB) analysis. Pharmacological inhibition of apoptosis, autophagy, necroptosis, ER Stress, and STAT3 (signal transducer and activator of transcription 3) was achieved by treatment with small molecule inhibitors. Melanoma cell lines stably depleted of STAT3 were established with lentiviral constructs. Supernatants from NDV-infected cells were intratumorally injected to mice bearing melanoma cells-derived tumors.Results: Oncolytic NDV induced CRT exposure, the release of HMGB1 and HSP70/90 as well as secretion of ATP in melanoma cells. Inhibition of apoptosis, autophagy, necroptosis or ER stress attenuated NDV/FMW-induced release of HMGB1 and HSP70/90. Moreover, NDV/FMW-induced ICD markers in melanoma cells were also suppressed by either treatment with a STAT3 inhibitor or shRNA-mediated depletion of STAT3. Of translational importance, treatment of mice bearing melanoma cells-derived tumors with supernatants from NDV/FMW-infected cells significantly inhibited tumor growth.Conclusions: Our data authenticate that oncolytic NDV/FMW might be a potent inducer of ICD in melanoma cells, which is amalgamated with several forms of cell death. We also show that STAT3 plays a role in NDV/FMW-induced ICD in melanoma cells. Together, our data highlight oncolytic NDV as propitious for cancer therapeutics by stimulatingan anti-melanoma immune response

Business Group-Affiliation and Corporate Social Responsibility: Evidence from Listed Companies in China

Business groups have played a vital role in the development of emerging markets. However, we share very limited understanding in the role of business group that act on affiliated firms’ CSR performance. Using manually sorted data on A-share listed companies and business groups in China from 2010–2017, we examine whether a company’s business group-affiliation affects its corporate social responsibility (CSR) performance and the mediating mechanisms of this association. Our empirical models show that group companies bear a higher level of social responsibility compared to independent companies. This positive relationship between group-affiliation and social responsibility relies on resource allocation through internal capital markets, rent-seeking initiatives, and consideration of corporate reputation. Moreover, group affiliation benefits the firm’s CSR performance in employee’s responsibilities, consumers’ responsibilities and environmental responsibilities, while significantly lower the shareholders’ responsibilities. Our empirical valuation of group companies’ CSR levels can serve as a benchmark for emerging market companies implementing social responsibility policies

Do Fiscal Environmental Protection Expenditures Crowd Out Corporate Environmental Protection Investments?

This research investigates how fiscal environmental expenditures impact corporate environmental investments and whether corporations act as free-riders. Using a sample of 1688 firm-year observations from 2008 to 2019 in the Chinese context, we observe that fiscal environmental expenditures have a significantly negative “crowding-out” effect on corporate green investments, which is mediated by the disclosure of pollution emissions. Additionally, a heterogeneity analysis reveals that this negative impact is more pronounced for non-heavily polluted and state-owned corporations and corporations located in three major agglomerations. This finding remains robust when employing an instrumental variable approach to address potential endogeneity. Our study contributes to the current literature by providing new insights regarding government environmental protection behaviors’ impacts on corporate green behaviors. The study also provides insights for policymakers to focus more on light-polluting corporations and state-owned corporations, because they have more chances to avoid environmental responsibilities

Do Fiscal Environmental Protection Expenditures Crowd Out Corporate Environmental Protection Investments?

This research investigates how fiscal environmental expenditures impact corporate environmental investments and whether corporations act as free-riders. Using a sample of 1688 firm-year observations from 2008 to 2019 in the Chinese context, we observe that fiscal environmental expenditures have a significantly negative &ldquo;crowding-out&rdquo; effect on corporate green investments, which is mediated by the disclosure of pollution emissions. Additionally, a heterogeneity analysis reveals that this negative impact is more pronounced for non-heavily polluted and state-owned corporations and corporations located in three major agglomerations. This finding remains robust when employing an instrumental variable approach to address potential endogeneity. Our study contributes to the current literature by providing new insights regarding government environmental protection behaviors&rsquo; impacts on corporate green behaviors. The study also provides insights for policymakers to focus more on light-polluting corporations and state-owned corporations, because they have more chances to avoid environmental responsibilities

Efficient splicing of the CPE intein derived from directed evolution of the Cryptococcus neoformans PRP8 intein

Intein-mediated protein splicing has been widely used in protein engineering; however, the splicing efficiency and extein specificity usually limit its further application. Thus, there is a demand for more general inteins that can overcome these limitations. Here, we study the trans-splicing of CPE intein obtained from the directed evolution of Cne PRP8, which shows that its splicing rate is ~29- fold higher than that of the wild-type. When the +1 residue of C-extein is changed to cysteine, CPE also shows high splicing activity. Faster association and higher affinity may contribute to the high splicing rate compared with wild-type intein. These findings have important implications for the future engineering of inteins and provide clues for fundamental studies of protein structure and folding

Research on Typhoon Precipitation Prediction over Hainan Island Based on Dynamical–Statistical–Analog Technology

Based on the Dynamical–Statistical–Analog Ensemble Forecast model for Landfalling Typhoon Precipitation (DSAEF_LTP model), the optimal forecast scheme for the tropical cyclone (TC) accumulated precipitation over Hainan Island, China (DSAEF_LTP_HN) is established. To test the forecasting performance of DSAEF_LTP_HN, its forecasting results are compared with other numerical models. The average threat score (TS) of accumulated precipitation forecast by DSAEF_LTP_HN is compared with other numerical models over independent samples. The results show that for accumulated precipitation ≥ 100 mm, the TS produced by DSAEF_LTP_HN reaches 0.39, ranking first, followed by ECMWF (0.36). For accumulated precipitation ≥ 250 mm, the TS of DSAEF_LTP_HN (0.04) is second only to ECMWF (0.19). Further analysis reveals that the forecasting performance of DSAEF_LTP_HN for TC precipitation is closely related to the TC characteristics. The longer the TC impacts Hainan Island and the heavier the precipitation delivered to Hainan Island, the better the forecasting performance of DSAEF_LTP_HN is. DSAEF_LTP_HN can successfully capture the center of heavy precipitation. However, there is still a phenomenon of false forecasts for some TC heavy precipitation, which requires further improvement of the model in the future

Interclass Interference Suppression in Multi-Class Problems

Multi-classifiers are widely applied in many practical problems. But the features that can significantly discriminate a certain class from others are often deleted in the feature selection process of multi-classifiers, which seriously decreases the generalization ability. This paper refers to this phenomenon as interclass interference in multi-class problems and analyzes its reason in detail. Then, this paper summarizes three interclass interference suppression methods including the method based on all-features, one-class classifiers and binary classifiers and compares their effects on interclass interference via the 10-fold cross-validation experiments in 14 UCI datasets. Experiments show that the method based on binary classifiers can suppress the interclass interference efficiently and obtain the best classification accuracy among the three methods. Further experiments were done to compare the suppression effect of two methods based on binary classifiers including the one-versus-one method and one-versus-all method. Results show that the one-versus-one method can obtain a better suppression effect on interclass interference and obtain better classification accuracy. By proposing the concept of interclass inference and studying its suppression methods, this paper significantly improves the generalization ability of multi-classifiers