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Abstract Peritoneal fibrosis has been linked to hypoxia-inducible factor 1-alpha (HIF-1α) as well as O-linked-N-acetylglucosaminylation (O-GlcNAcylation) in peritoneal dialysis (PD). Genistein, recognized for its HIF-1α inhibitory and antifibrotic effects, presents a potential intervention against peritoneal mesothelial-mesenchymal transition (MMT) as well as fibrosis in PD. This study employed human peritoneal mesothelial cells (HPMCs) together with adenine-induced chronic kidney disease (CKD) rats undergoing peritoneal dialysis to explore Genistein’s role in high glucose-induced peritoneal MMT and fibrosis. Our findings reveal that Genistein exerts anti-MMT and anti-fibrotic effects by inhibiting HIF-1α in HPMCs under high glucose conditions. Genistein inhibited O-GlcNAcylation status of HIF-1α through the mTOR/O-GlcNAc transferase (OGT) pathway, promoting its ubiquitination as well as the subsequent proteasomal degradation. In adenine-induced CKD rats undergoing peritoneal dialysis, Genistein suppressed the mTOR/OGT expression and reduced the abundance of O-GlcNAcylation along with HIF-1α in the peritoneum. Additionally, Genistein protected against increased peritoneal thickness, fibrosis, and angiogenesis, while improving peritoneal function. Based on our results, it could be inferred that Genistein might inhibit the abundance of HIF-1α via the mTOR/OGT pathway, thereby ameliorating MMT as well as fibrosis in PD.

Abstract SHP-1, a nonreceptor protein tyrosine phosphatase encoded by ptpn6, has been regarded as a regulatory protein of hematopoietic cell biology for years. However, there is now increasing evidence to support its role in tumors. Thus, the role of ptpn6 for prognosis and immune regulation across 33 tumors was investigated, aiming to explore its functional heterogeneity and clinical significance in pan-cancer. Differential expression of ptpn6 was found between cancer and adjacent normal tissues, and its expression was significantly correlated with the prognosis of tumor patients. In most cancers, ptpn6 expression was significantly associated with immune infiltration. This was further confirmed by ptpn6-related genes/proteins enrichment analysis. Additionally, genetic alterations in ptpn6 was observed in most cancers. As for epigenetic changes, it’s phosphorylation levels significantly altered in 6 tumors, while methylation levels significantly altered in 12 tumors. Notably, the methylation levels of ptpn6 were significantly decreased in 11 tumors, accompanied by its increased expression in 8 of them, suggesting that the hypomethylation may be related to its increased expression. Our results show that ptpn6 plays a specific role in tumor immunity and exerts a pleiotropic effect in a variety of tumors. It can serve as a prognostic factor for some cancers. Especially in LGG, KIRC, UCS and TGCT, the increased expression of ptpn6 is associated with poor prognosis and high immune infiltration. This aids in understanding the role of ptpn6 in tumor biology, and can provide insight into presenting a potential biomarker for poor prognosis and immune infiltration in cancers.

Abstract Risk assessment and categorization of terrorist attacks can assist enhance awareness of terrorism and give crucial information support for anti-terrorism efforts. This study utilizes quantitative approaches for the risk assessment and categorization of terrorist attacks. A total of 210,454 terrorist attacks that occurred worldwide from 1970 through 2020 were collected in the Global Terrorism Database, and 22 indicators related to the risk of terrorist attacks were selected. Then, the moment estimation theory and four comprehensive evaluation models were utilized to identify the top 10 riskiest terrorist attacks in the world. Furthermore, the five clustering analysis methods and three evaluation criteria were performed for the risk categorization of terrorist attacks, and the visual analysis was carried out using the kernel density estimation method. The research results have identified the top 10 riskiest global terrorist attacks, which were led by the September 11 terrorist attack event, along with their downward counterfactual events. The spatial distribution of global terrorist attack risk is primarily composed of four “turbulent cores” in the region of Central Asia, Middle East & North Africa, South Asia, and Central America & Caribbean. This study also provided insights and recommendations for anti-terrorism efforts. It has realized the risk assessment and categorization of terrorist attacks, aiding in the swift identification of its risk levels, and holds immense significance for safeguarding global national security and societal stability under new circumstances.

Abstract The current research focuses on the effects of nutritional supplementation and exercise on dialysis patients, but whether physical activity (PA) can reduce the risk of adverse outcomes for patients with different nutritional status is not clear. The maintenance hemodialysis (MHD) patients were recruited from April 2021 to April 2022. The information of PA was obtained from the international physical activity questionnaire (IPAQ). The outcomes were cardiovascular death, myocardial infarction, stroke, heart failure, atrial fibrillation, tumor and all-cause death. We used COX proportional risk model to estimate the association between PA and the outcomes of MHD patients. Patients are classified into two groups based on geriatric nutritional risk index (GNRI) and classified by age, and we used COX proportional risk model to estimate the association of PA and outcomes in subgroups. The isotemporal substitution model (ISM) was used to estimate the effects of replacing light physical activity (LPA) with moderate physical activity (MPA) or vigorous physical activity (VPA) on risk of cardiovascular events, tumors, and all-cause death in different subgroups. The effects of PA on ankle-brachial index (ABI) and body fat content were analyzed in different IPAQ groups. A total of 241 maintenance hemodialysis patients were included, 105 peoples developed cardiovascular death, myocardial infarction, stroke, heart failure, atrial fibrillation, tumor and all-cause death (43.6%). The median follow-up time was 12 months. MPA reduced the risk of outcome in MHD patients or high GNRI patients (40% vs 39%).In MHD patients who was under 65 years with high GNRI, MPA reduced cardiovascular death, myocardial infarction, stroke, heart failure, atrial fibrillation, tumor and all-cause death by 55%.PA reduced the risk of cardiovascular event by 65%, but did not reduce the risk of tumor or all-cause death. Replacing LPA with VPA did not improve clinical outcomes. It actually increases the risk of heart failure 0.4%. MPA reduced the risk of cardiovascular death, myocardial infarction, stroke, heart failure, atrial fibrillation, tumor, all-cause death in MHD patients under 65 years, while VPA had no health benefit. Trial registration: ChiCTR210050998.

Abstract Background Some previous observational studies have linked deep venous thrombosis (DVT) to thyroid diseases; however, the findings were contradictory. This study aimed to investigate whether some common thyroid diseases can cause DVT using a two-sample Mendelian randomization (MR) approach. Methods This two-sample MR study used single nucleotide polymorphisms (SNPs) identified by the FinnGen genome-wide association studies (GWAS) to be highly associated with some common thyroid diseases, including autoimmune hyperthyroidism (962 cases and 172,976 controls), subacute thyroiditis (418 cases and 187,684 controls), hypothyroidism (26,342 cases and 59,827 controls), and malignant neoplasm of the thyroid gland (989 cases and 217,803 controls. These SNPs were used as instruments. Outcome datasets for the GWAS on DVT (6,767 cases and 330,392 controls) were selected from the UK Biobank data, which was obtained from the Integrative Epidemiology Unit (IEU) open GWAS project. The inverse variance weighted (IVW), MR-Egger and weighted median methods were used to estimate the causal association between DVT and thyroid diseases. The Cochran’s Q test was used to quantify the heterogeneity of the instrumental variables (IVs). MR Pleiotropy RESidual Sum and Outlier test (MR-PRESSO) was used to detect horizontal pleiotropy. When the causal relationship was significant, bidirectional MR analysis was performed to determine any reverse causal relationships between exposures and outcomes. Results This MR study illustrated that autoimmune hyperthyroidism slightly increased the risk of DVT according to the IVW [odds ratio (OR) = 1.0009; p = 0.024] and weighted median methods [OR = 1.001; p = 0.028]. According to Cochran’s Q test, there was no evidence of heterogeneity in IVs. Additionally, MR-PRESSO did not detect horizontal pleiotropy (p = 0.972). However, no association was observed between other thyroid diseases and DVT using the IVW, weighted median, and MR-Egger regression methods. Conclusions This study revealed that autoimmune hyperthyroidism may cause DVT; however, more evidence and larger sample sizes are required to draw more precise conclusions.

Introduction: This study aims to evaluate the therapeutic effects of sodium octanoate (SO), a medium-chain fatty acid salt, on SIMD in a murine model and to explore its underlying mechanisms. Methods: Male mice were subjected to sepsis models through two methods: intraperitoneal injection of lipopolysaccharide (LPS) and cecal ligation and punction (CLP). Mice received interval doses of SO every 2 hours or 4 hours for a total of six times or three times after LPS treatment. The relationship between SO and G protein-coupled receptor 84 (GPR84) was evaluated through GEO data analysis and molecular docking studies. DBA/2 mice were used to study the role of the GPR84 protein in the SO-mediated protection. Energy metabolomics was utilized to comprehensively assess the impact of SO on the levels of cardiac energy metabolic products in septic mice. histone modification identification techniques were used to further identify the specific sites of histone modification in the hearts of SO-treated septic mice. Results: SO treatment significantly improved myocardial contractile function, restored the oxidative stress imbalance and enhanced the myocardium's resistance to oxidative injury. SO significantly promotes the expression of GPR84. The loss of GPR84 function markedly attenuates the protective effects of SO. SO enhanced myocardial energy metabolism by promoting the synthesis of acetyl-CoA and upregulating genes involved in fatty acid β-oxidation which were abolished by medium-chain acyl-CoA dehydrogenase (MCAD) knockdown. SO induced histone acetylation, particularly at H3K123 and H3K80. Conclusion: Our study demonstrates that SO exerts protective effects against SIMD through both GPR84-mediated anti-inflammatory and antioxidant actions and GPR84-independent enhancement of myocardial energy metabolism, possibly mediated by MCAD.

Abstract Background Understanding the tooth anatomy is crucial for ensuring effective endodontic treatment. This study investigated the root canal morphology of the second mesiobuccal (MB2) canal in maxillary first molars (MFMs) in a Chinese population using cone-beam computed tomography (CBCT). Methods This study evaluated 486 MFMs with MB2 canals from 285 participants undergoing CBCT examination and determined the Vertucci’s classification and position of the MB2 canal orifice. The prevalence of the MB2 canal was correlated with the sex, age, and tooth side. The correlations between the prevalence of the MB2 canal and sex and tooth side were assessed using the Fisher's exact test. The chi-square test was used for evaluating the correlation between the prevalence of the MB2 canal and age. Results The number of type II, III, IV, V, VI, VII, and other root canals in the MFMs was 30.9%, 0.6%, 65.0%, 1.2%, 1.2%, 0.4%, and 0.6%, respectively. Among the 201 cases with bilateral inclusion, 87.6% showed consistent canal configuration. Results of the first clear apparent position (FCAP) of the MB2 canals showed that 434, 44, and 3 teeth had FCAP at the upper, middle, and bottom one-third of the root, respectively. The FCAPs of the MB2 canal in the MFMs with types II, IV, and VI, as well as types III and V canals showed significant differences (p

Abstract Kidney Clear Cell Carcinoma (KIRC), the predominant form of kidney cancer, exhibits a diverse therapeutic response to Immune Checkpoint Inhibitors (ICIs), highlighting the need for predictive models of ICI efficacy. Our study has constructed a prognostic model based on 13 types of Programmed Cell Death (PCD), which are intertwined with tumor progression and the immune microenvironment. Validated by analyses of comprehensive datasets, this model identifies seven key PCD genes that delineate two subtypes with distinct immune profiles and sensitivities to anti-PD-1 therapy. The high-PCD group demonstrates a more immune-suppressive environment, while the low-PCD group shows better responses to PD-1 treatment. In particular, TOP2A emerged as crucial, with its inhibition markedly reducing KIRC cell growth and mobility. These findings underscore the relevance of PCDs in predicting KIRC outcomes and immunotherapy response, with implications for enhancing clinical decision-making.

Abstract Physical activity (PA) is linked to a decreased risk of type 2 diabetes mellitus (T2DM). However, the influence of circadian PA trajectories remains uncertain. This study aims to explore the optimal circadian PA trajectory pattern for reducing the risk of T2DM. Methods: A total of 502,400 participants were recruited from the UK Biobank between 2006 and 2010, and 102,323 participants provided valid accelerometer-captured acceleration data. After excluding individuals with prior T2DM, 99,532 participants were included in the final analysis. We initially investigated the association between PA intensity at 24 hourly time points and T2DM. Subsequently, PA trajectories were identified using K-means cluster analysis. Cox proportional hazard models were employed to estimate hazard ratios (HR). Four distinct PA trajectories were identified: consistently low, single peak, double peak, and intense trajectories. Compared to consistently low, single peak, double peak and intense PA trajectory reduced the risk of T2DM progressively. Sensitivity analyses, further excluding individuals with glycated hemoglobin (HbA1c) ≥ 6.5% or random glucose ≥ 11.1 mmol/L and adjusted for daily average acceleration, yielded consistent results. This confirms that the ideal circadian PA trajectory serves as a protective factor, independently of PA intensity. Subgroup analyses indicated that these effects were more pronounced in men and individuals with eGFR

Background An efficient therapeutic strategy for patients with replanted teeth has been extremely challenging because complete displacement of the teeth is inevitably accompanied by severe damage to periodontal tissue. Enamel matrix derivative (EMD) shows promise for periodontal regeneration, but its effects on replanted teeth remain unknown. This study systematically summarized the biological basis of EMD in replantation dental therapy and assessed its effect on clinical prognosis.Methods Potential studies were searched via the Cochrane Library, Web of Science and PubMed databases from inception to November 23, 2023.Results A total of 329 patients with 375 replanted teeth met the inclusion criteria. Our pooling results indicated that EMD did not provide a numerical advantage for restoring normal PDL healing in replanted teeth (RR=0.38, P=0.161). A significantly lower extraction risk was observed in EMD-treated group than non-EMD-treated group (RR=0.47, P=0.001). Moreover, the survival rate of replanted teeth with root resorption was significantly increased by the application of EMD (RR=2.21, P=0.017). Although the pooled outcomes suggested increased incidence of surface resorption (RR=1.19, P=0.730) and decreased risk of inflammation resorption (RR=0.68, P=0.560) among replanted teeth with resorption in the EMD-treated group, neither difference was statistically significant.Conclusion For patients with replanted teeth, EMD treatment may not result in a numerical increase in normal PDL healing. However, as a biological regulator, EMD may arrest the progression of resorption, thus reducing the risk of extraction in the early stage. Well-designed randomized trials are required to validate these results due to the poor quality of evidence.

Background: Breast cancer is a highly malignant disease worldwide, but there are currently no sufficient molecular biomarkers to predict patient prognosis and guide radiotherapy. The tumor microenvironment (TME) is an important factor affecting tumor biological function, and changes in its composition are equally relevant to tumor progression and prognosis during radiotherapy. Methods: Here, we performed bioinformatic analyses using data obtained from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) databases to screen for molecular biomarkers related to the TME that may influence radiotherapy sensitivity. By combining immune scores and stromal scores and performing weighted coexpression network analysis (WGCNA), we identified key modules and hub genes to construct competing endogenous RNA (ceRNA) networks. Then, key pathways and genes were identified using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. Furthermore, we explored the effect of THBS2 on the malignant phenotype of breast cancer through cellular experiments. Results: Genes in the PI3K-AKT pathway in the blue module were significantly enriched. Among the hub genes in the blue module, COL1A1, COL1A2, COL6A3, THBS2 and PDGFRB were negatively associated with RT sensitivity. Cellular experiments confirmed that knockdown of THBS2 inhibited the proliferation and invasion of breast cancer cells. Conclusion: These findings may provide new insights into the mechanisms of radiotherapy sensitivity in breast cancer patients, offering hope for the discovery of new therapeutic targets.

BackgroundThe association of Remnant cholesterol (RC) with renal function and its progression in patients with Type 2 diabetes (T2DM) related chronic kidney disease (CKD) remains unclear.Methods8,678 patients with T2DM-related CKD were included in cross-sectional analysis, and 6,165 patients were enrolled in longitudinal analysis and followed up for a median of 36.0 months. The outcomes were renal composite endpoint event and rapid progression of renal function.Results24.54% developed a renal composite endpoint event, and 27.64% rapid progression of renal function. RC levels above 0.56 mmol/L independently increased the risk of both renal composite endpoint (HR, 1.17; 95% CIs, 1.03-1.33) and rapid progression of renal function (OR, 1.17; 95% CIs, 1.01- 1.37). TG levels above 1.65 mmol/L only increased the risk of renal composite endpoint (HR, 1.16; 95% CIs, 1.02 -1.32). TC levels above 5.21 mmol/L increased the risk of renal composite endpoint (HR, 1.14; 95% CIs, 1.01-1.29) only in patients with proteinuria≥0.5g/d. Conversely, HDL-C levels below 1.20 mmol/L or above 1.84 mmol/L increased the risk of rapid progression of renal function (OR, 0.88; 95% CIs, 0.70 -0.99) in patients with proteinuria

Abstract Background There is a lack of relevant studies evaluating the long-term impact of cardiovascular health factor (CVH) metrics on chronic kidney disease (CKD). Objective This study investigates the long-term change in CVH metrics in older people and explores the relationship between CVH metrics trajectory and CKD. Methods In total, 27,635 older people aged over 60 from the community-based Tianjin Chronic Kidney Disease Cohort study were enrolled. The participants completed five annual physical examinations between January 01, 2014, and December 31, 2018, and a subsequent follow-up between January 01, 2019, and December 31, 2021. CVH metrics trajectories were established by the group-based trajectory model to predict CKD risk. The relationships between baseline CVH, CVH change (ΔCVH), and CKD risk were also explored by logistic regression and restricted cubic spline regression model. In addition, likelihood ratio tests were used to compare the goodness of fit of the different models. Results Six distinct CVH metrics trajectories were identified among the participants: low-stable (11.19%), low-medium-stable (30.58%), medium-stable (30.54%), medium-high-decreased (5.46%), medium-high-stable (18.93%), and high-stable (3.25%). After adjustment for potential confounders, higher CVH metrics trajectory was associated with decreased risk of CKD (P for trend

Background In the context of the deep integration of information technology with various industries, as well as the strong promotion of the development of smart healthcare by the country, the management of chronic diseases in community has also been gradually explored and transformed from the traditional mode to the informationized and intelligent management mode. In the case of deep aging gradually, it is necessary to clarify whether informationized chronic disease management is effective for the elderly population.Objective To understand the role of mobile network in the management of chronic diseases in the elderly, so as to provide reference for research on informationized management of related chronic diseases.Methods Using convenience sampling method, a total of 650 elderly hypertensive patients registered with community health service centers in four communities under the jurisdiction of Linghe District, Jinzhou City were selected as study subjects from January to July 2022. The study subjects were divided into the intervention group and control group based on the principle of prioritizing the proximity of living location under informed voluntary consent, with 325 cases in each group. The control group was treated with routine community chronic disease management and face-to-face follow-up once every two months. The intervention group was treated with network hypertension management based on the control group, with an intervention of 6 months. The effects were evaluated using the Hypertension Knowledge Level Scale (HK-LS), Therapeutic Adherence Scale for Hypertensive Patients (TASHP), and Hypertension Patients Self-Management Behavior Rating Scale (HPSMBRS), and a satisfaction survey was conducted.Results After the intervention, the scores of HK-LS, TASHP and HPSMBRS dimensions in the intervention group were higher than those in the control group (P

Abstract Tumor metastasis severely limits the prognosis of gastric cancer patients. RNA-binding proteins (RBPs) are crucial in tumor metastasis, yet there is limited research into their involvement in gastric cancer. Here, we found that ESRP1, a RBP specific in epithelial cells, is important in regulating the metastasis of gastric cancer cells. ESRP1 is negatively correlated with distant metastasis and lymph node metastasis in gastric cancer patients. And we demonstrated that ESRP1 inhibit migration and invasion of gastric cancer in vitro and in vivo. Mechanistically, ESRP1 promotes exon 11 alternative splicing of CLSTN1 pre-mRNA. The post-splicing short CLSTN1 stabilizes the Ecadherin/β-catenin binding structure, and promotes β-catenin protein ubiquitination and degradation, thereby inhibiting the migration and invasion of gastric cancer cells. Our study highlights the role of ESRP1 in regulating metastasis of gastric cancer and extends its mechanism. These results provide a possibility for ESRP1 and CLSTN1 to become therapeutic targets for metastasis of gastric cancer.

In this paper, we provide a symmetric formula and a duality formula relating multiple zeta values and zeta-star values. We find that the summation ∑a+b=r−1(−1)aζ★(a+2,{2}p−1)ζ★({1}b+1,{2}q) equals ζ★({2}p,{1}r,{2}q)+(−1)r+1ζ★({2}q,r+2,{2}p−1). With the help of this equation and Zagier’s ζ★({2}p,3,{2}q) formula, we can easily determine ζ★({2}p,1,{2}q) and several interesting expressions.

Background: Alternative polyadenylation (APA) plays a vital regulatory role in various diseases. It is widely accepted that APA is regulated by APA regulatory factors. Objective: Whether APA regulatory factors affect the prognosis of renal cell carcinoma remains unclear, and this is the main topic of this study. Methods: We downloaded the transcriptome and clinical data from The Cancer Genome Atlas (TCGA) database. We used the Lasso regression system to construct an APA model for analyzing the relationship between common APA regulatory factors and renal cell carcinoma. We also validated our APA model using independent GEO datasets (GSE29609, GSE76207). Results: It was found that the expression levels of 5 APA regulatory factors (CPSF1, CPSF2, CSTF2, PABPC1, and PABPC4) were significantly associated with tumor gene mutation burden (TMB) score in renal clear cell carcinoma, and the risk score constructed using the expression level of 5 key APA regulatory factors could be used to predict the outcome of renal clear cell carcinoma. The TMB score is associated with the remodeling of the immune microenvironment. Conclusions: By identifying key APA regulatory factors in renal cell carcinoma and constructing risk scores for key APA regulatory factors, we showed that key APA regulators affect prognosis of renal clear cell carcinoma patients. In addition, the risk score level is associated with TMB, indicating that APA may affect the efficacy of immunotherapy through immune microenvironment-related genes. This helps us better understand the mRNA processing mechanism of renal clear cell carcinoma.

F-box only protein 38 (FBXO38) is a member of the F-box family that mediates the ubiquitination and proteasome degradation of programmed death 1 (PD-1), and thus has important effects on T cell-related immunity. While its powerful role in adaptive immunity has attracted much attention, its regulatory roles in innate immune pathways remain unknown. The cyclic GMP–AMP synthase–stimulator of interferon genes (cGAS–STING) pathway is an important innate immune pathway that regulates type I interferons. STING protein is the core component of this pathway. In this study, we identified that FBXO38 deficiency enhanced tumor proliferation and reduced tumor CD8+ T cells infiltration. Loss of FBXO38 resulted in reduced STING protein levels in vitro and in vivo, further leading to preventing cGAS–STING pathway activation, and decreased downstream product IFNA1 and CCL5. The mechanism of reduced STING protein was associated with lysosome-mediated degradation rather than proteasomal function. Our results demonstrate a critical role for FBXO38 in the cGAS–STING pathway.

Abstract Obesity, a worldwide epidemic in recent years, is mainly due to the uncontrolled development of adipose tissues, which includes adipocyte hypertrophy and hyperplasia. Adipocyte differentiation is a process involving multiple transcription factor cascades, and the exact mechanism has not yet been defined. As a bHLH transcription factor, Twist1 exerts its activity by forming homo- or heterodimers with other factors. In this study, we showed Twist1 restricts adipogenesis through PPARγ. Expression of various differentiation markers (including PPARγ and adiponectin) and triglyceride-containing lipid droplets were decreased with overexpression of Twist1. Pathway enrichment analysis of RNA-seq data showed that differentially expressed genes (DEGs) caused by Twist1 overexpression were significantly related to lipolysis and PPARγ signaling. This implicates that Twist1 plays important regulatory roles in these processes. ChIP and dual luciferase assays showed that Twist1 could bind either PPARγ or adiponectin promoter to repress their respective transcription or directly to PPARγ protein to regulate its transcriptional activity. Furthermore, Twist1 directly interacted RXRα, which usually forms heterodimer with PPARγ to regulate adipogenesis. Taken together, our results suggest that Twist1 is an inhibitory modulator of adipogenesis and its function is likely through direct interaction with PPARγ protein or its gene promoter.

Abstract Background Acute compartment syndrome (ACS) is one of the most common complications of musculoskeletal injury, leading to the necrosis and demise of skeletal muscle cells. Our previous study showed that embryonic stem cells-derived mesenchymal stem cells (ESC–MSCs) are novel therapeutics in ACS treatment. As extracellular vesicles (EVs) are rapidly gaining attention as cell-free therapeutics that have advantages over parental stem cells, the therapeutic potential and mechanisms of EVs from ESC–MSCs on ACS need to be explored. Method In the present study, we examined the protective effects in the experimental ACS rat model and investigated the role of macrophages in mediating these effects. Next, we used transcriptome sequencing to explore the mechanisms by which ESC–MSC-EVs regulate macrophage polarization. Furthermore, miRNA sequencing was performed on ESC–MSC-EVs to identify miRNA candidates associated with macrophage polarization. Results We found that intravenous administration of ESC–MSC-EVs, given at the time of fasciotomy, significantly promotes the anti-inflammation process, angiogenesis, and functional recovery of muscle in ACS. The beneficial effects were associated with ESC–MSC-EVs affecting macrophage polarization by delivering various miRNAs which regulate NF-κB, JAK/STAT, and PI3K/AKT pathways. Our data further illustrate that ESC–MSC-EVs mainly modulate macrophage polarization via the miR-21/PTEN, miR-320a/PTEN, miR-423/NLRP3, miR-100/mTOR, and miR-26a/TLR3 axes. Conclusion Together, our results demonstrated the beneficial effects of ESC–MSC-EVs in ACS, wherein the miRNAs present in ESC–MSC-EVs regulate the polarization of macrophages.

Abstract Objective The impact of inflammatory response on tumor development and therapeutic response is of significant importance in clear cell renal cell carcinoma (ccRCC). The customization of specialized prognostication approaches and the exploration of supplementary treatment options hold critical clinical implications in relation to the inflammatory response. Methods In the present study, unsupervised clustering was implemented on TCGA-KIRC tumors using transcriptome profiles of inflammatory response genes, which was then validated in two ccRCC datasets (E-MATB-1980 and ICGC) and two immunotherapy datasets (IMvigor210 and Liu et al.) via SubMap and NTP algorithms. Combining co-expression and LASSO analyses, inflammatory response-based scoring system was defined, which was evaluated in pan-cancer. Results Three reproducible inflammatory response subtypes (named IR1, IR2 and IR3) were determined and independently verified, each exhibiting distinct molecular, clinical, and immunological characteristics. Among these subtypes, IR2 had the best OS outcomes, followed by IR3 and IR1. In terms of anti-angiogenic agents, sunitinib may be appropriate for IR1 patients, while axitinib and pazopanib may be suitable for IR2 patients, and sorafenib for IR3 patients. Additionally, IR1 patients might benefit from anti-CTLA4 therapy. A scoring system called IRscore was defined for individual ccRCC patients. Patients with high IRscore presented a lower response rate to anti-PD-L1 therapy and worse prognostic outcomes. Pan-cancer analysis demonstrated the immunological features and prognostic relevance of the IRscore. Conclusion Altogether, characterization of inflammatory response subtypes and IRscore provides a roadmap for patient risk stratification and personalized treatment decisions, not only in ccRCC, but also in pan-cancer.

O-GlcNAcylation is a post-translational modification of proteins that regulates various biological processes. However, its involvement in peritoneal dialysis fibrosis remains unclear. This study aimed to investigate the impact of O-GlcNAcylation on human peritoneal mesothelial cells (HPMCs) cultured in control and high-glucose medium. To manipulate cellular conditions, we employed knockdown techniques targeting HIF-1α and OGT, along with the administration of pharmacological agents (PUGNAc, OSMI-1, MG-132, FG-4592, and HIF-1α inhibitor). Our findings revealed that elevated glucose levels increased global O-GlcNAcylation and the abundance of HIF-1α, α-SMA, fibronectin, and COL1A2. Conversely, the expression of E-Cadherin was decreased. Significantly, a positive correlation was observed between O-GlcNAcylation, HIF-1α, mesothelial-to-mesenchymal transition (MMT), and fibrosis in HPMCs. Notably, O-GlcNAcylation was found to regulate HIF-1α, thereby promoting MMT and fibrosis under high glucose conditions. Furthermore, we discovered that high glucose levels induced O-GlcNAcylation of HIF-1α, preventing its ubiquitination and proteasomal degradation. In summary, our study demonstrates the critical role of O-GlcNAcylation-mediated regulation of HIF-1α in MMT and fibrosis during peritoneal dialysis.

Abstract Background Greater trochanteric pain syndrome (GTPS) possesses a harmful influence on quality of life. Numerous conservative management modalities with varying success have been proposed for patients with GTPS. However, it is not clear which treatment is more effective for reducing pain. The purpose of this Bayesian analysis was to assess the current evidence for the effectiveness of conservative treatments on improving Visual Analog Scale (VAS) pain scoring of GTPS and to determine the most effective treatment protocol. Methods A comprehensive study search was performed from inception until July 18, 2022, via the electronic databases PubMed, the Cochrane Library, and Web of Science for potential research. The risk of bias assessment for the included studies was independently performed based on the Cochrane Collaboration Risk of Bias Tool. Bayesian analysis was conducted by using ADDIS software (v1.16.5). The DerSimonian-Laird random effects model was used to perform the traditional pairwise meta-analysis. Results Eight full-text articles with a total of 596 patients with GTPS were included in the analysis. In comparing ultrasound-guided platelet-rich plasma application (PRP-U) to ultrasound-guided corticosteroid injection (CSI-U), patients who received PRP therapy experienced reduced pain as the VAS decreased significantly (MD, -5.21; 95% CI, -6.24 to -3.64). VAS score in group of extracorporeal shockwave treatment (ESWT) was significant improved than that in exercise (EX) group (MD, -3.17; 95% CI, -4.13 to -2.15). There were no statistically significantly different VAS scores between the CSI-U group and the CSI under landmark (CSI-B) group. The treatment efficacy rankings of the different treatments on improving VAS scores showed that the most likely efficacious treatment was PRP-U (99%) followed by ESWT (81%), CIS-U (58%), usual care (48%), CIS-B (54%), and EX (84%). Conclusion Bayesian analysis revealed that PRP injection and ESWT are relatively safe and effective in the treatment of GTPS. More multicenter high-quality randomized clinical trials with large sample sizes are still needed in the future to provide further evidence.

Abstract The risk of severe condition caused by Corona Virus Disease 2019 (COVID-19) increases with age. However, the underlying mechanisms have not been clearly understood. The dataset GSE157103 was used to perform weighted gene co-expression network analysis on 100 COVID-19 patients in our analysis. Through weighted gene co-expression network analysis, we identified a key module which was significantly related with age. This age-related module could predict Intensive Care Unit status and mechanical-ventilation usage, and enriched with positive regulation of T cell receptor signaling pathway biological progress. Moreover, 10 hub genes were identified as crucial gene of the age-related module. Protein–protein interaction network and transcription factors-gene interactions were established. Lastly, independent data sets and RT-qPCR were used to validate the key module and hub genes. Our conclusion revealed that key genes were associated with the age-related phenotypes in COVID-19 patients, and it would be beneficial for clinical doctors to develop reasonable therapeutic strategies in elderly COVID-19 patients.

Abstract Objective To investigate the clinical observation of autologous platelet-rich fibrin (PRF) assisting the revascularization of mature permanent teeth. Methods Twenty patients with mature permanent teeth were divided into experimental group and control group. The control group was treated with classic revascularization, and the experimental group was treated with PRF-assisted mature permanent tooth revascularization. Results After treatment, the total effective rate of the experimental group (100.00%) was higher than that of the control group (50.00%); the thickness of the root canal wall of the experimental group was higher than that of the control group, and the crown root length was lower than that of the control group; The bite degree, chewing function, color, overall aesthetic score, and satisfaction rate of the patients were higher, and the difference was statistically significant (P

Camrelizumab, a monoclonal antibody, blocks programmed cell death protein-1 from binding to T cells and programmed cell death ligand 1 on tumor cells, thereby ensuring sustained T cell activation and blocking immune escape of various types of cancer, including nasopharyngeal carcinoma. Reactive cutaneous capillary endothelial hyperplasia (RCCEP) is the most common immune-related adverse event in patients treated with camrelizumab. We report a case nasopharyngeal carcinoma in a patient with camrelizumab-induced RCCEP. A 68-year-old man diagnosed with nasopharyngeal carcinoma developed RCCEP at multiple locations after 3 months of camrelizumab treatment. RCCEP of the right lower eyelid affected closure of the right eye. In this report, we also reviewed previous literature on camrelizumab-induced RCCEP. In summary, the mechanism underlying camrelizumab-induced RCCEP remains unclear. RCCEP typically gradually subsides after discontinuing camrelizumab treatment. Larger nodules can be treated with lasers, ligation, or surgery. Although surgical excision is effective, RCCEP may recur in patients undergoing camrelizumab treatment. RCCEP management may not be required in the absence of adverse effects on the patient’s daily life.

ObjectiveFosinopril and amlodipine are commonly prescribed as first-line pharmacotherapeutic agents for pediatric hypertension, but there is a lack of comparative studies regarding the efficacy of these two drugs. We aimed to evaluate and compare the efficacy of fosinopril and amlodipine monotherapy in pediatric primary hypertension.MethodsThis was a single-center, bidirectional observational study. A total of 175 children and adolescents with primary hypertension receiving antihypertensive monotherapy from July 2020 to February 2023 were enrolled. According to antihypertensive drugs, they were divided into the fosinopril group (n = 96) and the amlodipine group (n = 79). Subgroup analysis was performed to compare the efficacy of the two groups in terms of blood pressure (BP) control rates and reductions following a 4-week treatment.ResultsAfter 4 weeks of treatment, both groups achieved significant reductions in systolic BP (SBP) and diastolic BP (DBP) by more than 18 mmHg and 6 mmHg, respectively, with BP control rates of 61.5% in the fosinopril group and 59.5% in the amlodipine group, revealing no significant differences in the antihypertensive efficacy between the two groups except for DBP control rate (FDR adjusted P > 0.05). Further subsequent subgroup analyses revealed that the reductions in SBP and DBP in the fosinopril group were significantly greater than those in the amlodipine group in patients of females and hypo-HDL-cholesterolemia (FDR adjusted P 0.05).ConclusionsFosinopril and amlodipine monotherapy were both effective in pediatric primary hypertension during a short-term follow-up. Fosinopril may be particularly effective in reducing BP in hypertensive patients of females, central obesity, IR, and hypo-HDL-cholesterolemia. These findings indicate that optimizing antihypertensive medication selection based on the individualized characteristics of children with hypertension may improve the efficacy of antihypertensive treatment.

Background: The drug selection of radical surgery (RS), with hyperthermic intraperitoneal chemotherapy (HIPEC), in pT4 colorectal cancer (CRC) remains controversial. Methods: Adverse events after HIPEC were estimated by common terminology criteria for adverse events version 5.0. The efficacy was evaluated using overall survival (OS) and recurrence-free rate (RFR). Propensity score matching (PSM) was used to reduce the influence of confounders between Mitomycin and Lobaplatin groups. Results: Of the 146 patients, from April 2020 to March 2021, 47 were managed with mitomycin and 99 with lobaplatin. There was no significant difference in the incidence of all adverse events between the two groups after PSM. OS and RFR were not significantly different between the two groups at 22 months (p = 0.410; p = 0.310). OS and RFR of the two groups also showed no significant difference for patients with T4a or T4b stage, tumor size < or ≥ 5 cm. Among patients with colon cancer, RFR at 22 months of the two groups was significantly different (100.0% vs. 63.2%, p = 0.028). Conclusions: In summary, the safety of mitomycin and lobaplatin for HIPEC was not different. Compared with lobaplatin, mitomycin for HIPEC after RS could benefit patients with colon cancer in RFR.

Considerable attention has been focused on the clinical features of coronavirus disease 2019 (COVID-19), but it is also important for clinicians to differentiate it from influenza virus infections. In the present study, the rate of coexisting disease was lower in the severe COVID-19 group than in the influenza A group (p = 0.003). Radiologically, severe COVID-19 patients had fewer instances of pleural effusion (p < 0.001). Clinically, severe COVID-19 patients had relatively better disease severity scores, less secondary bacterial infections, shorter times to beginning absorption on computed tomography, but longer durations of viral shedding from the time of admission (p < 0.05). Although the more severe influenza A patients required noninvasive respiratory support, these two groups ultimately yielded comparable mortalities. Based on the multiple logistic regression analysis, severe COVID-19 infection was associated with a lower risk of severe acute respiratory distress syndrome [odds ratio (OR) 1.016, 95% [confidence interval (CI)] 1.001–1.032, p = 0.041] and a better pneumonia severity index (OR 0.945, 95% [CI] 0.905−0.986, p = 0.009); however, these patients exhibited longer durations of viral shedding (OR 1.192, 95% [CI] 1.047−1.357, p = 0.008) than patients with severe influenza A infection. In conclusion, the conditions of severe influenza A patients appeared to be more critical than that of severe COVID-19 patients. However, relatively lower mortalities of these two severe cases are expected in the context of sufficient medical supplies.

Abstract Background The budding yeast Komagataella phaffii (Pichia pastoris) is widely employed to secrete proteins of academic and industrial interest. For secretory proteins, signal peptides are the sorting signal to direct proteins from cytosol to extracellular matrix, and their secretion efficiency directly impacts the yields of the targeted proteins in fermentation broth. Although the α-mating factor (MF) secretion signal from S. cerevisiae, the most common and widely used signal sequence for protein secretion, works in most cases, limitation exists as some proteins cannot be secreted efficiently. As the optimal choice of secretion signals is often protein specific, more secretion signals need to be developed to augment protein expression levels in K. phaffii. Results In this study, the secretion efficiency of 40 α-MF secretion signals from various yeast species and 32 endogenous signal peptides from K. phaffii were investigated using enhanced green fluorescent protein (EGFP) as the model protein. All of the evaluated α-MF secretion signals successfully directed EGFP secretion except for the secretion signals of the yeast D. hansenii CBS767 and H. opuntiae. The secretion efficiency of α-MF secretion signal from Wickerhamomyces ciferrii was higher than that from S. cerevisiae. 24 out of 32 endogenous signal peptides successfully mediated EGFP secretion. The signal peptides of chr3_1145 and FragB_0048 had similar efficiency to S. cerevisiae α-MF secretion signal for EGFP secretion and expression. Conclusions The screened α-MF secretion signals and endogenous signal peptides in this study confer an abundance of signal peptide selection for efficient secretion and expression of heterologous proteins in K. phaffii.

Background Nafamostat mesilate (NM), a broad-spectrum and potent serine protease inhibitor, can be used as an anticoagulant during extracorporeal circulation, as well as a promising drug effective against coronavirus disease 2019 (COVID-19). We conducted a systematic meta-analysis to evaluate the safety and efficacy of NM administration in critically ill patients who underwent blood purification therapy (BPT).Methods The Cochrane Library, Web of Science and PubMed were comprehensively searched from inception to August 20, 2021, for potential studies.Results Four randomized controlled trials (RCTs) and seven observational studies with 2723 patients met the inclusion criteria. The meta-analysis demonstrated that conventional therapy (CT) significantly increased hospital mortality compared with NM administration (RR = 1.25, p = 0.0007). In subgroup analyses, the in-hospital mortality of the NM group was significantly lower than that of the anticoagulant-free (NA) group (RR = 1.31, p = 0.002). The CT interventions markedly elevated the risk ratio of bleeding complications by 45% (RR = 1.45, p = 0.010) compared with NM interventions. In another subgroup analysis, NM used exhibited a significantly lower risk of bleeding complications than those of the low-molecular-weight heparin (LMWH) used (RR = 4.58, p = 0.020). The filter lifespan was decreased significantly (MD = −10.59, p

Rehabilitation therapy is beneficial for patients with ischemic stroke. Our previous study showed that treadmill training is conducive to neurological function in rats that underwent middle cerebral artery occlusion (MCAO). However, whether exercise benefits cerebral edema and the underlying mechanism remain unclear. This study investigated the influence of treadmill exercise on brain edema and the mechanism of its formation and elimination. The MCAO model was established with Sprague-Dawley (SD) rats, and lentivirus-mediated caveolin-1 shRNA was used to investigate the role of caveolin-1 in brain edema. As expected, we found that treadmill exercise has a beneficial effect on brain edema after stroke. Training led to a significant increase in the expression of caveolin-1 and TRPV4; and reduced brain water content and blood-brain barrier (BBB) damage. This treatment also changed the localization of aquaporin-4 (AQP4). Moreover, the effect of treadmill training on the polar expression of AQP4 differed over time. The results showed that early treadmill training inhibited the polar expression of AQP4, and later promoted its expression. However, the rats that were injected with the caveolin-1 shRNA lentivirus exhibited enhanced edema. Caveolin-1 shRNA eliminated the protective effect induced by exercise, which is consistent with the downregulation of TRPV4 expression. The findings indicate that treadmill training improves brain edema through the caveolin-1/TRPV4/AQP4 pathway.

Abstract Background As a key process in transcriptional regulatory mechanisms, alternative splicing (AS) plays a crucial role in maintaining the diversity of RNA and protein expression, and mediates the immune response in infectious diseases, especially for the COVID-19. Therefore, urgent data gathering and more research of AS profiles in microbe-infected human cells are needed to improve understanding of COVID-19 and related infectious diseases. Herein, we have created CASA, the COVID-19 Alternative Splicing Atlas to provide a convenient computing platform for studies of AS in COVID-19 and COVID-19-related infectious diseases. Methods In CASA, we reanalyzed thousands of RNA-seq datasets generated from 65 different tissues, organoids and cell lines to systematically obtain quantitative data on AS events under different conditions. A total of 262,994 AS events from various infectious diseases with differing severity were detected and visualized in this database. In order to explore the potential function of dynamics AS events, we performed analysis of functional annotations and drug-target interactions affected by AS in each dataset. RNA-binding proteins (RBPs), which may regulate these dynamic AS events are also provided for users in this database. Results CASA displays microbe-induced alterations of the host cell splicing landscape across different virus families and helps users identify condition-specific splicing patterns, as well as their potential regulators. CASA may greatly facilitate the exploration of AS profiles and novel mechanisms of host cell splicing by viral manipulation. CASA is freely available at http://www.splicedb.net/casa/ .

The cGAS/STING signaling pathway plays a pivotal role in regulating innate immunity. Emerging novel drugs aim to regulate the anti-tumor immune response by activating innate immunity. The anti-diabetic drug metformin has been reported to exhibit anti-cancer effect against various types of cancer. However, the role of metformin in regulating the cGAS/STING signaling pathway in gastric cancer remains unknown. In our study, we first used bioinformatic analysis to detect that metformin is closely related to tumor immunity in multiple tumors. Next, we validated the function of metformin in activating the cGAS/STING signaling pathway in gastric cancer cell lines. In addition, KEGG pathway enrichment analysis showed that metformin is negatively correlated with the PI3K/AKT signaling pathway in gastric cancer. We further verified that metformin activates the cGAS/STING signaling pathway by blocking AKT phosphorylation. Moreover, we found that metformin regulates the AKT signaling pathway by mediating the transcription factor SOX2. Thus, our study indicates that metformin activates the cGAS/STING signaling pathway by suppressing SOX2/AKT and has promising potential in gastric cancer immunotherapy.

The efficiency and performance of proton exchange membrane fuel cells (PEMFCs) are primarily influenced by ORR electrocatalysts. In recent years, atomically dispersed metal–nitrogen–carbon (M-N-C) catalysts have gained significant attention due to their high active center density, high atomic utilization, and high activity. These catalysts are now considered the preferred alternative to traditional noble metal electrocatalysts. The unique properties of M-N-C catalysts are anticipated to enhance the energy conversion efficiency and lower the manufacturing cost of the entire system, thereby facilitating the commercialization and widespread application of fuel cell technology. This article initially delves into the origin of performance and degradation mechanisms of Fe-N-C catalysts from both experimental and theoretical perspectives. Building on this foundation, the focus shifts to strategies aimed at enhancing the activity and durability of atomically dispersed Fe-N-C catalysts. These strategies encompass the use of bimetallic atoms, atomic clusters, heteroatoms (B, S, and P), and morphology regulation to optimize catalytic active sites. This article concludes by detailing the current challenges and future prospects of atomically dispersed Fe-N-C catalysts.

Background: Current studies have demonstrated that disintegrin and metalloproteinase 17 (ADAM17) plays a critical role in the pathogenesis of sepsis. MicroRNA (miR)-145 is known to control immune responses as an anti-inflammatory modulatory molecule. However, a fundamental understanding of how miR-145 regulates ADAM17 and, more broadly, sepsis-induced inflammatory response remains unknown. Methods: We used western blotting and quantitative real-time PCR (qRT-PCR) to measure expression levels of ADAM17 and miR-145. Enzyme-linked immunosorbent assays (ELISA) were performed to measure cytokine production. To determine if ADAM17 is a target gene of miR-145, bioinformatics analyses and luciferase reporter assays were conducted. The impacts of ADAM17 and miR-145 on sepsis-induced inflammatory responses were accessed in vitro using human umbilical endothelial cells (HUVECs) treated with lipopolysaccharide (LPS). Sepsis-induced inflammatory response was measured in vivo using a polymicrobial septic mouse model induced by cecal ligation and puncture (CLP) with pre-injection of a miR-145 agomir. Results: In HUVECs treated with LPS, miR-145 expression was downregulated and miR-145 negatively regulated ADAM17 expression through direct binding to the ADAM17 transcript 3′-UTR. MiR-145 overexpression markedly reduced LPS-induced inflammatory cytokine production by targeting ADAM17 in HUVECs. In comparison to CLP-induced septic mice treated with a control agomir, treatment with a miR-145 agomir significantly reduced the expression of ADAM17, numerous downstream cytokines such as IL-6, TNF-α, IL-1β and MCP-1, and the endothelial injury factors ICAM-1, VCAM-1. The miR-145 agomir also alleviated acute lung and kidney injury and improved the survival rate of septic mice. Conclusions: This study showed that miR-145, by specifically targeting ADAM17, negatively regulates sepsis-induced inflammatory responses and vascular endothelial injury, and ultimately improved organ injury and survival during sepsis. The underlying mechanism for the regulation of ADAM17 expression by miR-145 and sepsis-induced inflammatory reactions may offer sepsis patients a novel therapeutic option.

Abstract Background Regulatory T cells (Treg cells) in the peripheral blood of patients with pulmonary tuberculosis (PTB) may be closely related to the progression of PTB. In this study, the distribution characteristics and clinical importance of CD8+CD28− Treg cells in patients with tuberculosis were systematically analyzed, and the role and importance of CD8+CD28− Treg cells in influencing the immune response and progression of tuberculosis were discussed, which will provide immunological indices and reference values for the clinical diagnosis of tuberculosis. Methods Flow cytometry, sputum smears and computed tomography imaging were used to analyze the distribution characteristics of CD8+CD28− Treg cells in the peripheral blood of patients with PTB and the correlation between CD8+CD28−Treg cells and clinical and immune indices. Results The percentages of CD4+CD25high and CD8+CD28− Treg cells in the peripheral blood of patients with PTB were significantly higher than those in the healthy control (HC) group. Further analysis showed that the percentage of CD4+CD25highTreg cells in the Stage II group was significantly higher than that in the HC group. The percentages of CD4+CD25high and CD8+CD28− Treg cells increased significantly in patients in the Stage II group. The proportion of CD8+CD28− Treg cells was directly proportional to the degree of positivity in sputum smears, while CD4+CD25highTreg cells did not exhibit this trend. The correlations between the percentage of CD4+CD25high and CD8+CD28− Treg cells and the percentage of lymphocyte subsets were examined. The percentage of CD8+CD28− Treg cells was negatively correlated with the percentage of CD4+T cells and positively correlated with the CD8+T cell percentage in the HC and PTB groups. The percentage of CD4 + CD25highTreg cells was positively correlated with the percentage of CD4+T cells only in the PTB group. Conclusions This study was the first to show that the proportion of CD8+CD28− Treg cells in the peripheral blood of patients with PTB was significantly increased, and the increase in CD8+CD28− Treg cells was related to the progression of PTB, which may affect the proportion of immune cell subsets by inhibiting the immune response, resulting in the progression of PTB.

Abstract Gastric neuroendocrine carcinoma (GNEC) is a common type of neuroendocrine carcinoma (NEC) with a poor prognosis and limited therapeutic options. The underlying mechanisms of chemoresistance in patients with GNEC and those with NEC are largely unknown, and thus, reliable biomarkers and therapeutic targets that could improve treatment outcomes in patients with NECs are lacking. The aim of this study was to identify specific targets and investigate their roles in GNEC progression and treatment resistance. Differentially expressed genes (DEGs) were identified in GNEC specimens and were further analysed by focusing on their roles in chemoresistance. Gene Ontology (GO) and pathway enrichment analyses of GNEC DEGs revealed that synapse-related function was the most prominent cellular function perturbed in GNEC. SNAP25 was identified as the target gene involved in most of the enriched pathways. In vitro and in vivo experiments showed that SNAP25 plays a role in proliferation and chemoresistance in GNEC cell lines. AKT has been identified as a downstream target, and SNAP25 binds to AKT protein and promotes AKT protein half-life. Further analysis of other types of NEC as well as small cell lung cancer, which resembles NEC on a molecular level, has identified RUNDC3A as an upstream molecule that regulates SNAP25 expression and the associated phenotypes that could enhance chemoresistance in NECs. Our results show that SNAP25 expression in GNEC is mediated by RUNDC3A and promotes GNEC progression and chemoresistance via posttranslational modification of AKT. Thus, our results suggest that the RUNDC3A/SNAP25/Akt axis could be a potential therapeutic target in GNEC.

Introduction:Taxus species are used as medicinal plants all over the world. The leaves of Taxus species are sustainable medicinal resources that are rich in taxoids and flavonoids. However, traditional identification methods cannot effectively identify Taxus species on the basis of leaces used as raw medicinal materials, because their appearance and morphological characteristics are almost the same, and the probability of error identification increases in accordance with the subjective consciousness of the experimenter. Moreover, although the leaves of different Taxus species have been widely used, their chemical components are similar and lack systematic comparative research. Such a situation is challenging for quality assessment.Materials and methods: In this study, ultra-high-performance liquid chromatography coupled with triple quadrupole mass spectrometry combined with chemometrics was applied for the simultaneous determination of eight taxoids, four flavanols, five flavonols, two dihydroflavones, and five biflavones in the leaves of six Taxus species, namely, T. mairei, T. chinensis, T. yunnanensis, T. wallichiana, T. cuspidata, and T. media. Chemometric methods, including hierarchical cluster analysis, principal component analysis, orthogonal partial least squares-discriminate analysis, random forest iterative modeling, and fisher linear discriminant analysis, were utilized to differentiate and evaluate the six Taxus species.Results: This proposed method exhibited good linearity (R2 = 0.9999–0.9972) with a lower quantification limits of 0.94–3.05 ng/mL for all analytes. The intra- and inter-day precisions were within 6.83%. Six compounds, namely, 7-xylosyl-10-deacetyltaxol, ginkgetin, rutin, aromadendrin, 10-deacetyl baccatin III, and epigallocatechin, were identified through chemometrics for the first time. These compounds can be used as important chemical markers to distinguish the above six Taxus species rapidly.Conclusion: This study established a method for determination of the leaves of six Taxus species, and revealing the differences in the chemical components of these six Taxus species.

The catalytic asymmetric benzylations of prochiral nucleophiles are very limited. Here, the authors disclose an asymmetric α−benzylation of N-unprotected amino acids with benzyl alcohol derivatives by a chiral aldehyde-involved catalytic system.

Abstract The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global pandemic of novel coronavirus disease (COVID-19). The neutralizing monoclonal antibodies (mAbs) targeting the receptor-binding domain (RBD) of SARS-CoV-2 are among the most promising strategies to prevent and treat COVID-19. However, SARS-CoV-2 variants of concern (VOCs) profoundly reduced the efficacies of most of mAbs and vaccines approved for clinical use. Herein, we demonstrated mAb 35B5 efficiently neutralizes both wild-type (WT) SARS-CoV-2 and VOCs, including B.1.617.2 (delta) variant, in vitro and in vivo. Cryo-electron microscopy (cryo-EM) revealed that 35B5 neutralizes SARS-CoV-2 by targeting a unique epitope that avoids the prevailing mutation sites on RBD identified in circulating VOCs, providing the molecular basis for its pan-neutralizing efficacy. The 35B5-binding epitope could also be exploited for the rational design of a universal SARS-CoV-2 vaccine.

Two major posttranscriptional mechanisms—alternative splicing (AS) and alternative polyadenylation (APA)—have attracted much attention in cancer research. Nevertheless, their roles in clear cell renal carcinoma (ccRCC) are still ill defined. Herein, this study was conducted to uncover the implications of AS and APA events in ccRCC progression. Through consensus molecular clustering analysis, two AS or APA RNA processing phenotypes were separately constructed with distinct prognosis, tumor-infiltrating immune cells, responses to immunotherapy, and chemotherapy. The AS or APA score was constructed to quantify AS or APA RNA processing patterns of individual ccRCCs with principal-component analysis. Both high AS and APA scores were characterized by undesirable survival outcomes, relatively high response to immunotherapy, and low sensitivity to targeted drugs, such as sorafenib and pazopanib. Moreover, several small molecular compounds were predicted for patients with a high AS or APA score. There was a positive correlation between AS and APA scores. Their interplay contributed to poor prognosis and reshaped the tumor immune microenvironment. Collectively, this study is the first to comprehensively analyze two major posttranscriptional events in ccRCC. Our findings uncovered the potential functions of AS and APA events and identified their therapeutic potential in immunotherapy and targeted therapy.

BackgroundThe clinical outcome of triple-negative breast cancer (TNBC) is poor. Finding more targets for the treatment of TNBC is an urgent need. SENPs are SUMO-specific proteins that play an important role in SUMO modification. Among several tumor types, SENPs have been identified as relevant biomarkers for progression and prognosis. The role of SENPs in TNBC is not yet clear.MethodsThe expression and prognosis of SENPs in TNBC were analyzed by TCGA and GEO data. SENP3 coexpression regulatory networks were determined by weighted gene coexpression network analysis (WGCNA). Least absolute shrinkage and selection operator (LASSO) and Cox univariate analyses were used to develop a risk signature based on genes associated with SENP3. A time-dependent receiver operating characteristic (ROC) analysis was employed to evaluate a risk signature’s predictive accuracy and sensitivity. Moreover, a nomogram was constructed to facilitate clinical application.ResultsThe prognostic and expression effects of SENP family genes were validated using the TCGA and GEO databases. SENP3 was found to be the only gene in the SENP family that was highly expressed and associated with an unfavorable prognosis in TNBC patients. Cell functional experiments showed that knockdown of SENP3 leads to growth, invasion, and migration inhibition of TNBC cells in vitro. By using WGCNA, 273 SENP3-related genes were identified. Finally, 11 SENP3-related genes were obtained from Cox univariate analysis and LASSO regression. Based on this, a prognostic risk prediction model was established. The risk signature of SENP3-related genes was verified as an independent prognostic marker for TNBC patients.ConclusionAmong SENP family genes, we found that SENP3 was overexpressed in TNBC and associated with a worse prognosis. SENP3 knockdown can inhibit tumor proliferation, invasion, and migration. In TNBC patients, a risk signature based on the expression of 11 SENP3-related genes may improve prognosis prediction. The established risk markers may be promising prognostic biomarkers that can guide the individualized treatment of TNBC patients.

ObjectivesEven underwent radical resection, some patients of thoracic esophageal squamous cell carcinoma (ESCC) are still exposed to local recurrence in a short time. To this end, the present study sought to differentiate patient subgroups by assessing risk factors for postoperative early (within one year) local lymph node recurrence (PELLNR).MethodsESCC patients were selected from a prospective database, and divided into high- and low-risk groups according to the time of their local lymphatic recurrence (within one year or later). Survival analysis was conducted by the Cox regression model to evaluate the overall survival (OS) between the two groups. The hazard ratio (HR) and 95% confidence interval (CI) of different variables were also calculated. Logistic regression analysis was used to explore the high-risk factors for PELLNR with the odds ratio (OR) and 95% CI calculated.ResultsA total of 432 cases were included. The survival of patients in the high-risk group (n = 47) was significantly inferior to the low-risk group (n = 385) (HR = 11.331, 95% CI: 6.870–16.688, P

Abstract A successive tooth forming process for producing large modulus spur gears (m>2.5 mm) is firstly proposed in this paper to break the restrictions of large forming load and large equipment structure of traditional plastic forming. It contains the preforming stage and the finishing stage. In the first stage, the die with a single-tooth preforms gear teeth one by one through several passes. In the second stage, the other die with multi-teeth refines the preformed teeth into required shape. The influence of total pressing depth and feed distribution in preforming stage on final forming quality is analyzed by numerical simulation, and the reasonable process parameters are presented. Successive tooth forming experiments are carried out on the self-designed gear forming device to verify the optimal simulation results. Gears without fold defects are well formed both in simulations and experiments, proving the feasibility of this method. Compared with the whole die forging process, the new technology has advantages of smaller load and simpler tooling, which shows a good potential for manufacturing large modulus and large size spur gears.

Introduction: In the tumor microenvironment, interferon gamma (IFN-γ) secreted by tumor infiltrating lymphocytes can upregulate programmed cell death 1 ligand 1 (PD-L1) expression in many cancers. The present study evaluated the expression of PD-L1 in selected colorectal cancer cell lines with IFN-γ treatment and explored the correlation between programmed cell death 1 ligand 1 expression and KRAS/TP53 mutation status.Methods: The selected colorectal cancer cell lines had known KRAS mutations or TP53 mutations. TCGA data analysis were used to investigate the correlation between overall survival of patient with anti-PD-1/PD-L1 immunotherapy and KRAS/TP53 mutation status. Besides, the correlation between PD-L1 expression and KRAS/TP53 mutation status were also investigated by using TCGA data analysis. In vitro experiments were used to explore the mechanism underlying KRAS- and TP53-related PD-L1 expression.Results: Firstly, TCGA data analysis for gene expression and overall survival and an in vitro study revealed that the wild-type KRAS/TP53 cell lines exhibited hyperresponsiveness to interferon gamma exposure and correlated with better survival in patients receiving anti-PD-1/PD-L1 treatment. Secondly, experimental data revealed that interferon gamma induced the upregulation of programmed cell death 1 ligand 1 mainly through regulating MYC in wild-type KRAS and TP53 colorectal cancers.Discussion: Our findings revealed that the response to anti-PD-1/PD-L1 cancer immunotherapy frequently happened in wild-type KRAS and TP53 colorectal cancers, which were also found to show higher programmed cell death 1 ligand 1 expression. Our results indicate that the wild-type KRAS/TP53 colorectal cancer cell lines may respond better to interferon gamma treatment, which causes increased programmed cell death 1 ligand 1 expression and may be a mechanism underlying the better responses to anti-PD-1/PD-L1 therapies in wild-type KRAS and wild-type TP53 colorectal cancer. Furthermore, the experimental results suggest that interferon gamma regulated programmed cell death 1 ligand 1 expression through the regulation of MYC, which may further affect the response to PD-1/PD-L1 cancer immunotherapy. These results suggest a novel potential treatment strategy for enhancing the efficacy of PD-1/PD-L1 blockade immunotherapy in most colorectal cancer patients.