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The protective role of sodium glucose cotransporter 2 (SGLT2) inhibitors in renal outcomes has been revealed by large cardiovascular outcome trials among patients with type 2 diabetes. However, the effect of SGLT2 inhibitors on lupus nephritis (LN) and its underlying mechanisms remain unknown. We applied empagliflozin treatment to lupus-prone MRL/ mice to explore the renal protective potential of SGLT2 inhibitors. An SGLT2 knockout monoclonal podocyte cell line was generated using the CRISPR/Cas9 system to examine the cellular and molecular mechanisms. In MRL/ mice treated with empagliflozin, the levels of mouse anti-dsDNA IgG-specific antibodies, serum creatinine and proteinuria were markedly decreased. For renal pathology assessment, both the glomerular and tubulointerstitial damages were lessened by administration of empagliflozin. The levels of SGLT2 expression were increased and colocalised with decreased synaptopodin in the renal biopsy samples from patients with LN and MRL/ mice with nephritis. The SGLT2 inhibitor empagliflozin could alleviated podocyte injury by attenuating inflammation and enhanced autophagy by reducing mTORC1 activity. Nine patients with LN treated with SGLT2 inhibitors with more than 2 months of follow-up showed that the use of SGLT2 inhibitors was associated with a significant decrease in proteinuria from 29.6% to 96.3%. Moreover, the estimated glomerular filtration rate (eGFR) was relatively stable during the treatment with SGLT2 inhibitors. This study confirmed the renoprotective effect of SGLT2 inhibitors in lupus mice, providing more evidence for non-immunosuppressive therapies to improve renal function in classic autoimmune kidney diseases such as LN.

Background Prostate cancer is one of the most common cancers in the world. The results of treatment after hypofractionated radiotherapy only have been reported from several small randomized clinical trials. Therefore, we conducted a meta-analysis to compare clinical outcomes of hypofractionated radiotherapy versus conventional radiotherapy in the treatment of intermediate- to high-risk localized prostate cancer. Methods Relevant studies were identified through searching related databases till August 2018. Hazard ratio (HR) or risk ratio (RR) with its corresponding 95% confidence interval (CI) was used as pooled statistics for all analyses. Results The meta-analysis results showed that overall survival (HR = 1.12, 95% CI: 0.93–1.35, p  = 0.219) and prostate cancer-specific survival (HR = 1.29, 95% CI: 0.42–3.95, p  = 0.661) were similar in two groups. The pooled data showed that biochemical failure was RR = 0.90, 95% CI: 0.76–1.07, p  = 0.248. The incidence of acute adverse gastrointestinal events (grade ≥ 2) was higher in the hypofractionated radiotherapy (RR = 1.70, 95% CI: 1.12–2.56, p  = 0.012); conversely, for late grade ≥ 2 gastrointestinal adverse events, a significant increase in the conventional radiotherapy was found (RR = 0.75, 95% CI: 0.61–0.91, p  = 0.003). Acute (RR = 1.01, 95% CI: 0.89–1.15, p  = 0.894) and late (RR = 0.98, 95% CI: 0.86–1.10, p  = 0.692) genitourinary adverse events (grade ≥ 2) were similar for both treatment groups. Conclusion Results suggest that the efficacy and risk for adverse events are comparable for hypofractionated radiotherapy and conventional radiotherapy in the treatment of intermediate- to high-risk localized prostate cancer.

This study examines the logistical challenges arising in omni-channel retailing, where the interaction between traditional stores and online channels requires flexible and efficient transportation planning. In particular, the growth of Buy-Online-and-Pick-up-in-Store (BOPS) services has intensified the need to manage both forward deliveries and customer returns, the latter being a costly component of reverse logistics. To address these challenges, this study introduces the Shared Capacity Vehicle Routing Problem with Simultaneous Pickup and Delivery (SCVRP-SPD), which minimizes total operational cost by considering both transportation costs and the additional transfer costs incurred when reallocating store visits to more efficient delivery paths. In the SCVRP-SPD, stores are designed to serve a dual role as both pickup and return points, and a shared-capacity mechanism is incorporated to utilize leftover capacity in pre-planned trips, improving efficiency while reducing overall logistics cost. A mixed-integer programming model is developed for the problem, and solutions are obtained using GUROBI (version 11.0) and a newly designed Modified Differential Evolution (MDE) algorithm. Numerical experiments are conducted to evaluate the performance of the proposed MDE algorithm and to generate managerial insights, showing that the SCVRP-SPD is a promising strategy for omni-channel retailers seeking to reduce transportation costs, streamline reverse logistics, and better utilize resources.

Pulmonary embolism (PE) is associated with acute kidney injury (AKI). This study aimed to develop a nomogram to predict AKI in PE patients admitted to the intensive care unit. The data of patients with PE were obtained from the Medical Information Mart for Intensive Care-IV (MIMIC-IV) and the eICU Collaborative Research Database, with AKI as the primary outcome. Patients from MIMIC-IV were divided into training (80%) and internal validation (20%) cohorts, and external validation was performed using the eICU. Independent risk factors for AKI were identified using univariable logistic regression and stepwise logistic regression. A nomogram was constructed based on the stepwise analysis. Its performance was evaluated using the receiver operating characteristic (ROC) area under the curve (AUC), calibration plots, decision curve analysis (DCA), and sensitivity analysis, and compared to the simplified acute physiology score (SAPS) II score. Six independent risk factors for AKI were identified. The nomogram's AUC was 0.717 in the training cohort, 0.758 in the internal validation cohort, and 0.889 in the external validation cohort. The AUC of the nomogram was higher than the SAPS II score (  < 0.05). Calibration plots showed good consistency, and DCA confirmed its clinical applicability. Sensitivity analysis confirmed its stability and reliability. The nomogram might help clinicians identify PE patients at risk for developing AKI and increase attention to these patients. It was externally validated in the eICU cohort and demonstrated good predictive ability.

A recent genome-wide association study (GWAS) of Asian ancestry reported that single nucleotide polymorphism (SNP) in TERT (telomerase reverse transcriptase) was associated with systemic lupus erythematosus (SLE). TERT has a critical role in maintaining the chromosomal stability and the length of telomere. Given that only a small portion of the genetic heritability of SLE has been explained so far, we aimed to identify novel loci in telomere-related genes responsible for SLE susceptibility in Chinese populations. We performed a comprehensive genetic association analysis of SLE with telomere-related genes. To identify functional significance, we analyzed the publicly available HaploReg v4.1 and RegulomeDB databases. Differential gene expression analysis was also performed using ArrayExpress. A novel signal of PINX1 rs6984094 was identified (Pdiscovery=4.13×10−2, OR=0.58, 95% CI 0.35-0.98) and successfully replicated (Preplication=5.73×10−3, OR=0.45, 95% CI 0.26-0.81). Multiple layers of functional analysis suggested that the PINX1 rs6984094 risk T allele exhibited increased nuclear protein binding. We also observed an increased expression of PINX1 mRNA in peripheral blood mononuclear cells from SLE patients compared with healthy controls. Overall, we observed a novel genetic association between PINX1 (encodes the PinX1 protein, an inhibitory telomerase enzyme that lengthens telomeres) and SLE susceptibility in Chinese populations.

In recent years, the human gut microbiome has been recognised to play a pivotal role in the health of the host. Intestinal homeostasis relies on this intricate and complex relationship between the gut microbiota and the human host. While much effort and attention has been placed on the characterization of the organisms that inhabit the gut microbiome, the complex molecular cross-talk between the microbiota could also exert an effect on gastrointestinal conditions. Blastocystis is a single-cell eukaryotic parasite of emerging interest, as its beneficial or pathogenic role in the microbiota has been a subject of contention even to-date. In this study, we assessed the function of the Blastocystis tryptophanase gene ( Bh TnaA), which was acquired by horizontal gene transfer and likely to be of bacterial origin within Blastocystis . Bioinformatic analysis and phylogenetic reconstruction revealed distinct divergence of Bh TnaA versus known bacterial homologs. Despite sharing high homology with the E . coli tryptophanase gene, we show that Blastocystis does not readily convert tryptophan into indole. Instead, Bh TnaA preferentially catalyzes the conversion of indole to tryptophan. We also show a direct link between E . coli and Blastocystis tryptophan metabolism: In the presence of E . coli , Blastocystis ST7 is less able to metabolise indole to tryptophan. This study examines the potential for functional variation in horizontally-acquired genes relative to their canonical counterparts, and identifies Blastocystis as a possible producer of tryptophan within the gut.

The number of patients with COVID-19 caused by severe acute respiratory syndrome coronavirus 2 is still increasing. In the case of COVID-19 and tuberculosis (TB), the presence of one disease affects the infectious status of the other. Meanwhile, coinfection may result in complications that make treatment more difficult. However, the molecular mechanisms underpinning the interaction between TB and COVID-19 are unclear. Accordingly, transcriptome analysis was used to detect the shared pathways and molecular biomarkers in TB and COVID-19, allowing us to determine the complex relationship between COVID-19 and TB. Two RNA-seq datasets (GSE114192 and GSE163151) from the Gene Expression Omnibus were used to find concerted differentially expressed genes (DEGs) between TB and COVID-19 to identify the common pathogenic mechanisms. A total of 124 common DEGs were detected and used to find shared pathways and drug targets. Several enterprising bioinformatics tools were applied to perform pathway analysis, enrichment analysis and networks analysis. Protein–protein interaction analysis and machine learning was used to identify hub genes (GAS6, OAS3 and PDCD1LG2) and datasets GSE171110, GSE54992 and GSE79362 were used for verification. The mechanism of protein-drug interactions may have reference value in the treatment of coinfection of COVID-19 and TB.

The aim of the current study was to determine the feasibility, efficacy and safety of ovarian castration by high-intensity focused ultrasound (HIFU) in premenopausal patients with estrogen receptor (ER)+/progesterone receptor (PR)+ breast cancer subsequent to radical mastectomy. A total of 88 premenopausal females with pathologically confirmed ER+/PR+ breast cancer following radical mastectomy were randomly and equally divided into two groups that received HIFU therapy or radiation treatment. HIFU therapy was applied twice at an interval of three days and radiotherapy was administered to a total prescribed dose of DT 18 Gy in nine fractions over 11 days. Outcome measures included serum levels of estradiol and estrone, the Kupperman index and the incidence of secondary amenorrhea. Adverse events were monitored and recorded. All patients were followed up for 12 months. Serum levels of estradiol and estrone were comparable prior to treatment between the HIFU and radiation treatment groups. One month following treatment, serum levels of estradiol and estrone were significantly decreased in the two groups, but a greater decline was observed in the HIFU treatment group (P<0.01 and 0.05, respectively). In addition, more patients developed severe menopausal symptoms and amenorrhea in the HIFU therapy group compared with the radiotherapy group (P<0.01 for the two groups). A total of 3 months following treatment, serum levels of estradiol and estrone and the distribution of patients with severe, moderate and mild menopausal symptoms were comparable between the two groups. Following nine menstrual cycles, the incidence of amenorrhea reached 100% in the two groups. HIFU therapy is superior to radiotherapy for ovarian castration in premenopausal females with ER+/PR+ breast cancer subsequent to radical mastectomy in terms of its minimal invasiveness and faster efficacy. HIFU represents a feasible non-surgical approach for ovarian castration.

Objective： To study explores the effect of HLEC on the secreted proteins of epithelial ovarian cancer （EOC） cells （SKOV3-PM4） with directional highly lymphatic metastasis. Methods： Supernatants of four groups of cultured cells, namely, SKOV3 （A）, SKOV3＋HLEC （B）, SKOV3-PM4 （C）, SKOV3-PM4＋HLEC （D）, were collected, and their proteins were detected by antibody arrays and iTRAOcZD-LC-MALDI- TOF/TOF/MS. Significantly differential proteins were further analyzed via bioinformatics and validated in human serums and cell media via ELISA. Results： Results of antibody arrays and mass spectrometry demonstrated that GRN and VEGFA were upregulated in group C （compared with group A）, whereas IGFBP7 and SPARC were downregulated in group D （compared with group C）. Comprehensive bioinformatics analysis results showed that IGFBP7 and VEGFA were closely linked to each other. Further validation with serums showed statistical significance in VEGFA and IGFBP7 levels among groups of patients with ovarian cancers, benign tumors, and control groups. Two proteins were upegulated in the first group. VEGFA in the control group was downregulated. For IGFBP, upregulation in the control group and down-regulation in the first group were also observed. Conclusion： The HLEC microenvironment is closely associated with directional metastasis to lymph nodes and with differential proteins including cell stromal proteins and adhesion factors. The upregulation of VEGFA and GRN and the downregulation of SPARC and IGFBP7 are closely associated with directional metastasis to lymph nodes in EOC cells.