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Mass rapid transit (MRT) maintenance systems enable owners to make optimal decisions for site selection and preventive maintenance plans while considering the total operating costs. To ensure that the MRT planning system is effective, it is essential to construct a maintenance cost plan. This study implements the mathematical planning method to establish a comprehensive plan for route maintenance and preventive maintenance for the Taoyuan MRT based on the minimum total operating cost as the target, and meets the practical emergency repair time limit, site location distance and other relevant constraints. This study developed and evaluated novel heuristic algorithms with CPLEX software. Sensitivity analysis was also conducted to test the model's effectiveness. The proposed model establishes the optimum maintenance cost and finds the critical parameters that affect overall cost within 1% error, maintaining service quality. The proposed model is an accurate tool for engineers to reduce time-consuming procedures. [ABSTRACT FROM AUTHOR]

Abstract Background Chemoresistance is an obstacle to the successful treatment of nasopharyngeal carcinoma (NPC). Lapatinib is a targeted tyrosine kinase inhibitor therapeutic drug also used to treat NPC, but high doses are often required to achieve a result. To investigate the mechanism for the development of Lapatinib resistance, we characterised a number of NPC cell lines to determine the role of FOXO3 and sirtuins in regulating NPC resistance. Methods Sulforhodamine B (SRB) assays, Clonogenic assays, Protein extraction, quantification and western blotting, RT qPCR, Co-immunoprecipitation assay. Results To explore novel treatment strategies, we first characterized the Lapatinib-sensitivity of a panel of NPC cell lines by SRB and clonogenic cytotoxic assays and found that the metastatic NPC (C666–1 and 5-8F) cells are highly resistant whereas the poorly metastatic lines (6-10B, TW01 and HK-1) are sensitive to Lapatinib. Western blot analysis of the Lapatinib-sensitive 6-10B and resistant 5-8F NPC cells showed that the expression of phosphorylated/inactive FOXO3 (P-FOXO3;T32), its target FOXM1 and its regulator SIRT2 correlate negatively with Lapatinib response and sensitivity, suggesting that SIRT2 mediates FOXO3 deacetylation to promote Lapatinib resistance. In agreement, clonogenic cytotoxic assays using wild-type and foxo1/3/4 −/− mouse embryonic fibroblasts (MEFs) showed that FOXO1/3/4-deletion significantly attenuates Lapatinib-induced cytotoxicity, confirming that FOXO proteins are essential for mediating Lapatinib response. SRB cell viability assays using chemical SIRT inhibitors (i.e. sirtinol, Ex527, AGK2 and AK1) revealed that all SIRT inhibitors can reduce NPC cell viability, but only the SIRT2-specific inhibitors AK1 and AGK2 further enhance the Lapatinib cytotoxicity. Consistently, clonogenic assays demonstrated that the SIRT2 inhibitors AK1 and AGK2 as well as SIRT2-knockdown increase Lapatinib cytotoxicity further in both the sensitive and resistant NPC cells. Co-immunoprecipitation studies showed that besides Lapatinib treatment, SIRT2-pharmaceutical inhibition and silencing also led to an increase in FOXO3 acetylation. Importantly, SIRT2 inhibition and depletion further enhanced Lapatinib-mediated FOXO3-acetylation in NPC cells. Conclusion Collectively, our results suggest the involvement of SIRT2-mediated FOXO3 deacetylation in Lapatinib response and sensitivity, and that SIRT2 can specifically antagonise the cytotoxicity of Lapatinib through mediating FOXO3 deacetylation in both sensitive and resistant NPC cells. The present findings also propose that SIRT2 can be an important biomarker for metastatic and Lapatinib resistant NPC and that targeting the SIRT2-FOXO3 axis may provide novel strategies for treating NPC and for overcoming chemoresistance.

This study assesses the efficacy and safety of dapagliflozin in Chinese patients with heart failure through a systematic review of randomized controlled trials from PubMed and the China National Knowledge Infrastructure databases. Focusing on 977 patients across eight trials, the meta-analysis used Review Manager 5.4.1 for data analysis. Key findings include a significant reduction in N-terminal pro-B-type natriuretic peptide levels (standardized mean difference: -2.88, 95% CI: -4.31 to -1.44, p<0.001) and an increase in left ventricular ejection fraction (weighted mean difference: 5.10, 95% CI: 2.32 to 10.32, p<0.001). However, changes in left ventricular end-diastolic diameter were not significant (weighted mean difference: -1.33, 95% CI: -2.80 to 0.15, p=0.08), and the relative risk of adverse reactions was comparable between the control and observation groups (RR: 1.17, 95% CI: 0.82 to 1.68, p=0.38). Overall, dapagliflozin demonstrates good efficacy and safety in treating heart failure in this population. [ABSTRACT FROM AUTHOR]

The Microgastrinae (Hymenoptera: Braconidae) from ten islands of the Canadian Arctic Archipelago (CAA) and Greenland were studied based on 2,183 specimens deposited in collections. We report a total of 33 species in six genera, more than doubling the totals previously known. Most of the species (75.7%) have a distribution restricted to the Nearctic, with nine of those (27.3%) confirmed to be High Arctic endemics and another 10 species considered very likely to be High Arctic endemics as well – accounting for all of those, more than half of all species found are endemic to the region. The most diverse genera were Cotesia (10 species), Glyptapanteles (9 species), and Microplitis (7 species), representing 78.8% of the overall species diversity in the region. The six most frequently collected species comprised 84.7% of all examined specimens. The flight period for Microgastrinae in the High Arctic encompasses only two months, with activity peaking during the first half of July, when almost 40% of all available specimens were collected, and then plummeting in the first half to the end of August. Microgastrinae wasps from the High Arctic are currently known to parasitize eight species within four families of Lepidoptera: three species of Noctuidae, two each of Lymantridae and Nymphalidae, and one species of Pterophoridae. However, that information is very preliminary, as only six of the 33 species of microgastrines currently have associated host data. An annotated checklist, including photographs for 24 of the 33 species, is provided, as well as a key to all Microgastrinae genera present in the region.

Breast cancer is the most common type of female cancer. Reactive oxygen species (ROS) are vital in regulating signaling pathways that control cell survival and cell proliferation. Chemotherapeutic drugs such as anthracyclines induce cell death via ROS induction. Chemoresistance development is associated with adaptive response to oxidative stress. NRF2 is the main regulator of cytoprotective response to oxidative stress. NRF2 can enhance cell growth, antioxidant expression, and chemoresistance by providing growth advantage for malignant cells. Previously, we identified BQ323636.1 (BQ), a novel splice variant of nuclear co-repressor NCOR2, which can robustly predict tamoxifen resistance in primary breast cancer. In this study, we found that BQ was overexpressed in epirubicin-resistant cells and demonstrated that BQ overexpression could reduce the levels of epirubicin-induced ROS and confer epirubicin resistance. In vivo analysis using tissue microarray of primary breast cancer showed direct correlation between BQ expression and chemoresistance. In vitro experiments showed BQ could modulate NRF2 transcriptional activity and upregulate antioxidants. Luciferase reporter assays showed that although NCOR2 repressed the transcriptional activity of NRF2, the presence of BQ reduced this repressive activity. Co-immunoprecipitation confirmed that NCOR2 could bind to NRF2 and that this interaction was compromised by BQ overexpression, leading to increased transcriptional activity in NRF2. Our findings suggest BQ can regulate the NRF2 signaling pathway via interference with NCOR2 suppressive activity and reveals a novel role for BQ as a modulator of chemoresistance in breast cancer.

Forkhead Box O3 (FOXO3) is a tumor suppressor whose activity is fine-tuned by post-translational modifications (PTMs). In this study, using the BT474 breast cancer cells and a recently established lapatinib resistant (BT474-LapR) cell line, we observed that higher FOXO3 and acetylated (Ac)-FOXO3 levels correlate with lapatinib sensitivity. Subsequent ectopic expression of EP300 led to an increase in acetylated-FOXO3 in sensitive but not in resistant cells. Drug sensitivity assays revealed that sensitive BT474 cells show increased lapatinib cytotoxicity upon over-expression of wild-type but not acetylation-deficient EP300. Moreover, FOXO3 recruitment to target gene promoters is associated with target gene expression and drug response in sensitive cells and the inability of FOXO3 to bind its target genes correlates with lapatinib-resistance in BT474-LapR cells. In addition, using SIRT1/6 specific siRNAs and chemical inhibitor, we also found that sirtuin 1 and -6 (SIRT1 and -6) play a part in fine-tuning FOXO3 acetylation and lapatinib sensitivity. Consistent with this, immunohistochemistry results from different breast cancer subtypes showed that high SIRT6/1 levels are associated with constitutive high FOXO3 expression which is related to FOXO3 deregulation/inactivation and poor prognosis in breast cancer patient samples. Collectively, our results suggest the involvement of FOXO3 acetylation in regulating lapatinib sensitivity of HER2-positive breast cancers.