Search

Background: Inducible cyclooxgenase-2 (COX-2) is commonly overexpressed in breast tumors and is a target for cancer therapy. Here, we studied the association of COX-2 with breast cancer survival and how this association is influenced by tumor estrogen and HER2 receptor status and Akt pathway activation. Methods: Tumor COX-2, HER2 and estrogen receptor α (ER) expression and phosphorylation of Akt, BAD, and caspase-9 were analyzed immunohistochemically in 248 cases of breast cancer. Spearman's correlation and multivariable logistic regression analyses were used to examine the relationship between COX-2 and tumor characteristics. Kaplan-Meier survival and multivariable Cox proportional hazards regression analyses were used to examine the relationship between COX-2 and disease-specific survival. Results: COX-2 was significantly associated with breast cancer outcome in ER-negative [Hazard ratio (HR) = 2.72; 95% confidence interval (CI), 1.36-5.41; comparing high versus low COX-2] and HER2 overexpressing breast cancer (HR = 2.84; 95% CI, 1.07-7.52). However, the hazard of poor survival associated with increased COX-2 was highest among patients who were both ER-negative and HER2-positive (HR = 5.95; 95% CI, 1.01-34.9). Notably, COX-2 expression in the ER-negative and HER2-positive tumors correlated significantly with increased phosphorylation of Akt and of the two Akt targets, BAD at Ser136 and caspase-9 at Ser196. Conclusions: Up-regulation of COX-2 in ER-negative and HER2-positive breast tumors is associated with Akt pathway activation and is a marker of poor outcome. The findings suggest that COX-2-specific inhibitors and inhibitors of the Akt pathway may act synergistically as anticancer drugs in the ER-negative and HER2-positive breast cancer subtype. [ABSTRACT FROM AUTHOR]

Background: Carbamoyl phosphate synthetase 1 (CPS1) deficiency (OMIM 237300), an autosomal recessive rare and severe urea cycle disorder, is associated with hyperammonemia and high mortality., Methods: Herein we present 12 genetic variants identified in seven clinically well-characterized Chinese patients with CPS1 deficiency who were admitted to the Children's Medical Center of Peking University First Hospital from September 2014 to August 2023., Results: Seven patients (two male and five female patients including two sisters) experienced symptoms onset between 2 days and 13 years of age, and they were diagnosed with CPS1 deficiency between 2 months and 20 years. Peak blood ammonia levels ranged from 160 to 1,000 µmol/L. Three patients showed early-onset CPS1 deficiency, with only one surviving after treatment with sodium phenylbutyrate, N-carbamoyl-L-glutamate, and liver transplantation at 4 months, showing a favorable outcome. The remaining four patients had late-onset CPS1 deficiency, presenting with mental retardation, psychiatric symptoms, and self-selected low-protein diets. Among the 12 CPS1 variants identified in these patients, 10 were novel, with all patients exhibiting compound heterozygosity for CPS1 mutant alleles. Seven variants (c.149T > C, c.616 A > T, c.1145 C > T, c.1294G > A, c.3029 C > T, c.3503 A > T, and c.3793 C > T) resulted in single amino acid substitutions. Three frameshift variations (c.2493del, c.3067dup, and c.3241del) were identified, leading to enzyme truncation. One mutation (c.3506_3508del) caused an in-frame single amino acid deletion, while another (c.2895 + 2T > C) resulted in aberrant splicing., Conclusions: Except for two known variants, all other variants were identified as novel. No hotspot variants were observed among the patients. Our data contribute to expanding the mutation spectrum of CPS1., (© 2024. The Author(s).)

Background: The Smoking paradox has generated inconsistent findings concerning the clinical prognosis of acute ST-segment elevation myocardial infarction (STEMI) patients, while providing limited insights into coronary anatomy and function which are crucial prognostic factors. Therefore, this study aimed to further investigate the existence of smoking paradox in coronary anatomy and function., Methods: This study divided STEMI patients into smokers and non-smokers. Quantitative coronary angiography, angiography‑derived microcirculatory resistance (AMR) and quantitative flow ratio (QFR) were utilized to analyze coronary anatomy and function. These parameters were compared using multivariable analysis and propensity score matching. The clinical outcomes were evaluated using Kaplan-Meier curve and Cox regression., Results: The study included 1258 patients, with 730 in non-smoker group and 528 in smoker group. Smokers were significantly younger, predominantly male, and had fewer comorbidities. Without adjusting for confounders, smokers exhibited larger lumen diameter [2.03(1.45-2.57) vs. 1.90(1.37-2.49), P = 0.033] and lower AMR [244(212-288) vs. 260(218-301), P = 0.006]. After matching and multivariate adjustment, smokers exhibited inversely smaller lumen diameter [1.97(1.38-2.50) vs. 2.15(1.63-2.60), P = 0.002] and higher incidence of coronary microvascular dysfunction [233(53.9%) vs. 190(43.6%), P = 0.002], but showed similar AMR and clinical outcomes compared to non-smokers. There was no difference in QFR between two groups., Conclusion: Smoking among STEMI patients undergoing pPCI was associated with smaller lumen diameter and higher occurrence of coronary microvascular dysfunction, although it had no further impact on clinical prognosis. The smoking paradox observed in coronary anatomy or function may be explained by younger age, gender, and lower prevalence of comorbidities., (© 2024. The Author(s).)

Background: Although immune checkpoint inhibitors (ICIs) have revolutionized the landscape of cancer treatment, only a minority of colorectal cancer (CRC) patients respond to them. Enhancing tumor immunogenicity by increasing major histocompatibility complex I (MHC-I) surface expression is a promising strategy to boost the antitumor efficacy of ICIs., Methods: Dual luciferase reporter assays were performed to find drug candidates that can increase MHC-I expression. The effect of nilotinib on MHC-I expression was verified by dual luciferase reporter assays, qRT-PCR, flow cytometry and western blotting. The biological functions of nilotinib were evaluated through a series of in vitro and in vivo experiments. Using RNA-seq analysis, immunofluorescence assays, western blotting, flow cytometry, rescue experiments and microarray chip assays, the underlying molecular mechanisms were investigated., Results: Nilotinib induces MHC-I expression in CRC cells, enhances CD8 + T-cell cytotoxicity and subsequently enhances the antitumor effects of anti-PDL1 in both microsatellite instability and microsatellite stable models. Mechanistically, nilotinib promotes MHC-I mRNA expression via the cGAS-STING-NF-κB pathway and reduces MHC-I degradation by suppressing PCSK9 expression in CRC cells. PCSK9 may serve as a potential therapeutic target for CRC, with nilotinib potentially targeting PCSK9 to exert anti-CRC effects., Conclusion: This study reveals a previously unknown role of nilotinib in antitumor immunity by inducing MHC-I expression in CRC cells. Our findings suggest that combining nilotinib with anti-PDL1 therapy may be an effective strategy for the treatment of CRC., (© 2024. The Author(s).)

Background: Cancer-associated fibroblasts (CAFs) are the prominent cell type in the tumor microenvironment (TME), and CAF subsets have been identified in various tumors. However, how CAFs spatially coordinate other cell populations within the liver TME to promote cancer progression remains unclear., Methods: We combined multi-region proteomics (6 patients, 24 samples), 10X Genomics Visium spatial transcriptomics (11 patients, 25 samples), and multiplexed imaging (92 patients, 264 samples) technologies to decipher the expression heterogeneity, functional diversity, spatial distribution, colocalization, and interaction of fibroblasts. The newly identified CAF subpopulation was validated by cells isolated from 5 liver cancer patients and in vitro functional assays., Results: We identified a liver CAF subpopulation, marked by the expression of COL1A2, COL4A1, COL4A2, CTGF, and FSTL1, and named F5-CAF. F5-CAF is preferentially located within and around tumor nests and colocalizes with cancer cells with higher stemness in hepatocellular carcinoma (HCC). Multiplexed staining of 92 patients and the bulk transcriptome of 371 patients demonstrated that the abundance of F5-CAFs in HCC was associated with a worse prognosis. Further in vitro experiments showed that F5-CAFs isolated from liver cancer patients can promote the proliferation and stemness of HCC cells., Conclusions: We identified a CAF subpopulation F5-CAF in liver cancer, which is associated with cancer stemness and unfavorable prognosis. Our results provide potential mechanisms by which the CAF subset in the TME promotes the development of liver cancer by supporting the survival of cancer stem cells., (© 2024. The Author(s).)

Background: Nurses' nursing competence and nutritional care literacy directly affect patients' health and safety. Self-directed learning ability was pervasive throughout the entire work process of nursing work and was the basis for improving both. However, there are few studies has explored the mechanism from the perspective of nutritional care literacy. The purpose of this study was to analyze the relationship between self-directed learning ability and nursing competence, and to explore the mediating role of nutritional care literacy between self-directed learning and nursing competence among clinical nurses in China., Methods: A cross-sectional survey was conducted among 805 clinical nurses recruited from seven general hospitals in Hunan Province, China, between January 25 and March 6, 2022. The self-directed learning ability, nutritional care literacy and nursing competence of nurses were evaluated through investigation. A total of 799 questionnaires were received, resulting in an response rate of 99.25%.We performed an intermediary modeling to examine the mediating roles of nutritional care literacy on the relationship between self-directed learning ability and nursing competence in clinical nurses., Results: Self-directed learning ability was positively correlated with nutritional care  literacy (r=0.792, P<0.001) and nursing competence (r=0.696, P<0.001). Nutritional care literacy was positively correlated with nursing competence (r=0.658, P<0.001). Nutritional care literacy mediated the relationship between self-directed learning ability and nursing competence. The mediating effect accounted for 32.48% of the total effect and 48.10% of the direct effect ., Conclusions: This study confirmed the positive correlation between self-directed learning ability, nutritional care literacy, and nursing competence. Nutritional care  literacy played a mediating role in the relationship between self-directed learning ability and nursing competence. The findings not only provide a novel strategy for cultivating nursing professionals and improving nurse disease care abilities, but also offer a new perspective for nursing educators and managers., (© 2024. The Author(s).)

Objective: Employing network pharmacology and molecular docking, the study predicts the active compounds in garlic and elucidates their mechanism in inhibiting the development of alcoholic liver disease (ALD). ALD is a global chronic liver disease with potential for hepatocellular carcinoma progression., Methods: The main active ingredients and targets of garlic were identified through screening the TCMSP, TCM-ID, and ETCM databases. ALD disease targets were sourced from DisGeNET, GeneCards, and DiGSeE databases, and intervention targets for garlic were determined through intersections. Protein interaction networks were constructed using the STRING platform, and GO and KEGG pathway enrichment analyses were performed with R software. The garlic component-disease-target network was established using Cytoscape software. Validation of active ingredients against core targets was conducted through molecular docking simulations using AutoDock Vina software. Expression validation of core targets was carried out using human sequencing data of ALD obtained from the GEO database., Results: Integration of garlic drug targets with ALD disease targets identified 83 target genes. Validation through an alcohol-induced ALD mouse model supported certain network pharmacology findings, suggesting that garlic may impede disease progression by mitigating the inflammatory response and promoting ethanol metabolism., Conclusion: This study provides insights into the potential therapeutic mechanisms of garlic in inhibiting ALD development. The identified active ingredients offer promising avenues for further investigation and development of treatments for ALD, emphasizing the importance of botanical remedies in liver disease management., (© 2024. The Author(s).)

Background and Objective: The prevalence of 12-hour shift work is increasing in various occupations. Shift work has been linked to circadian rhythm disruption, which may lead to hormonal changes and metabolic disorders, including alterations in glucose, lipid, and purine metabolism. Despite this, there is limited research on the potential connection between work shifts and abnormal serum uric acid (SUA) levels. Furthermore, the factors that contribute to abnormal SUA levels in shift workers are not well-understood. Therefore, this study aimed to analyze the SUA levels of shift workers employed in an aircraft maintenance company, investigate the potential association between shift work and SUA levels, and explore the factors that may influence abnormal SUA levels in shift workers., Methods: A total of 2263 male workers from an aircraft maintenance company were included in this study using the cluster sampling method. The workers were divided into two groups based on their working shifts: night shift (N = 1047, 46.27%) and day working (N = 1216, 53.73%). A survey was conducted between April 1st and June 30th, 2022 to gather information on work, lifestyle, physical examination results, and other relevant factors. The survey included a self-designed demographic information questionnaire to collect data on workers' characteristics, medical history, years of employment, smoking and drinking habits, and main lifestyle behaviors. The workers' SUA levels were measured using uricase colorimetry. One-way ANOVA was used to compare the difference in the abnormal detection rate of SUA between the two groups, and multi-factor logistic regression analysis was used to identify the factors that influence abnormal SUA levels., Results: The study indicated that 48.9% of night shift workers and 43.8% in the regular day workers had abnormal SUA levels, with a significant difference between the two groups (χ 2  = 6.125, P = 0.013). Factors such as circadian rhythm type, shift work, age, the taste of diet, type of diet, smoking, overweight or obesity based on body mass index (BMI), concentration of urine creatinine (CREA), total cholesterol, triglyceride, and low-density lipoprotein cholesterol were found to be correlated with SUA abnormalities (P < 0.05). The risk of developing SUA abnormalities was found to be higher in individuals with an intermittent (OR = 1.34, 95% CI: 0.83-2.12, P < 0.05) or evening circadian rhythm type (OR = 1.45, 95% CI: 0.86-2.43, P > 0.05) compared to those with a morning type. Additionally, factors such as night shift work, a high-sodium diet, smoking, a diet high in meat and low in vegetables, being overweight or obese, and higher levels of CREA were also found to increase the risk of developing SUA abnormalities. The study also revealed a significant dose-response relationship between BMI and abnormal uric acid levels. After controlling for other factors, the risk of developing SUA abnormalities was found to be 1.18 times higher in the night shift work group than in the day work group (OR = 1.18, 95% CI:1.02-1.34, P = 0.01)., Conclusion: Shift work has been linked to a higher risk of developing SUA abnormalities, and there are several factors that may contribute to this risk. To prevent diseases, it is recommended that enterprises implement better health monitoring and management practices for shift workers., (© 2024. The Author(s).)

Background: The myeloblastosis (MYB) transcription factor (TF) family is one of the largest and most important TF families in plants, playing an important role in a life cycle and abiotic stress., Results: In this study, 268 Avena sativa MYB (AsMYB) TFs from Avena sativa were identified and named according to their order of location on the chromosomes, respectively. Phylogenetic analysis of the AsMYB and Arabidopsis MYB proteins were performed to determine their homology, the AsMYB1R proteins were classified into 5 subgroups, and the AsMYB2R proteins were classified into 34 subgroups. The conserved domains and gene structure were highly conserved among the subgroups. Eight differentially expressed AsMYB genes were screened in the transcriptome of transcriptional data and validated through RT-qPCR. Three genes in AsMYB2R subgroup, which are related to the shortened growth period, stomatal closure, and nutrient and water transport by PEG-induced drought stress, were investigated in more details. The AsMYB1R subgroup genes LHY and REV 1, together with GST, regulate ROS homeostasis to ensure ROS signal transduction and scavenge excess ROS to avoid oxidative damage., Conclusion: The results of this study confirmed that the AsMYB TFs family is involved in the homeostatic regulation of ROS under drought stress. This lays the foundation for further investigating the involvement of the AsMYB TFs family in regulating A. sativa drought response mechanisms., (© 2024. The Author(s).)

Background: High doses of long-acting opioids were used to facilitate off-pump coronary artery bypass grafting procedure, which may result in opioid-related adverse events after surgery. Transcutaneous electrical acupoint stimulation (TEAS) had been reported to be effective in reducing intraoperative opioids consumption during surgery. The aim of this study is to assess whether TEAS with difference acupoints can reduce the doses of opioid analgesics., Methods: This was a multicenter, randomized, controlled, double-blind trial. Patients underwent off-pump coronary artery bypass grafting under general anesthesia were enrolled. Eligible patients were randomly and equally grouped into sham acupuncture group (n = 105), regional acupoints combination group (n = 105), or distal-proximal acupoints combination group (n = 105) using a centralized computer-generated randomization system. Transcutaneous electrical acupoint stimulation was applied for 30 min before anesthesia induction. The primary outcome was the doses of sufentanil during anesthesia. Secondary outcomes included the highest postoperative vasoactive-inotropic scores within 24 h, intraoperative propofol consumption, length of mechanical ventilation, duration of cardiac care unit and postoperative hospital stay, incidence of postoperative complications, and mortality within 30 days after surgery., Results: Of the 315 randomized patients, 313 completed the trial. In the modified intention-to-treat analysis, the doses of sufentanil were 303.9 (10.8) μg in the distal-proximal acupoints group, significantly lower than the sham group, and the mean difference was - 34.9 (- 64.9 to - 4.9) μg, p = 0.023. The consumption of sufentanil was lower in distal-proximal group than regional group (303.9 vs. 339.5), and mean difference was - 35.5 (- 65.6 to - 5.5) μg, p = 0.020. The distal-proximal group showed 10% reduction in opioids consumption comparing to both regional and sham groups. Secondary outcomes were comparable among three groups., Conclusion: Transcutaneous electrical acupoint stimulation with distal-proximal acupoints combination, compared to regional acupoints combination and sham acupuncture, significantly reduced sufentanil consumption in patients who underwent off-pump coronary artery bypass grafting surgery., (© 2024. The Author(s).)

Background: In the tumor microenvironment (TME), a bidirectional relationship exists between hypoxia and lactate metabolism, with each component exerting a reciprocal influence on the other, forming an inextricable link. The aim of the present investigation was to develop a prognostic model by amalgamating genes associated with hypoxia and lactate metabolism. This model is intended to serve as a tool for predicting patient outcomes, including survival rates, the status of the immune microenvironment, and responsiveness to therapy in patients with lung adenocarcinoma (LUAD)., Methods: Transcriptomic sequencing data and patient clinical information specific to LUAD were obtained from comprehensive repositories of The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). A compendium of genes implicated in hypoxia and lactate metabolism was assembled from an array of accessible datasets. Univariate and multivariate Cox regression analyses were employed. Additional investigative procedures, including tumor mutational load (TMB), microsatellite instability (MSI), functional enrichment assessments and the ESTIMATE, CIBERSORT, and TIDE algorithms, were used to evaluate drug sensitivity and predict the efficacy of immune-based therapies., Results: A novel prognostic signature comprising five lactate and hypoxia-related genes (LHRGs), PKFP, SLC2A1, BCAN, CDKN3, and ANLN, was established. This model demonstrated that LUAD patients with elevated LHRG-related risk scores exhibited significantly reduced survival rates. Both univariate and multivariate Cox analyses confirmed that the risk score was a robust prognostic indicator of overall survival. Immunophenotyping revealed increased infiltration of memory CD4 + T cells, dendritic cells and NK cells in patients classified within the high-risk category compared to their low-risk counterparts. Higher probability of mutations in lung adenocarcinoma driver genes in high-risk groups, and the MSI was associated with the risk-score. Functional enrichment analyses indicated a predominance of cell cycle-related pathways in the high-risk group, whereas metabolic pathways were more prevalent in the low-risk group. Moreover, drug sensitivity analyses revealed increased sensitivity to a variety of drugs in the high-risk group, especially inhibitors of the PI3K-AKT, EGFR, and ELK pathways., Conclusions: This prognostic model integrates lactate metabolism and hypoxia parameters, offering predictive insights regarding survival, immune cell infiltration and functionality, as well as therapeutic responsiveness in LUAD patients. This model may facilitate personalized treatment strategies, tailoring interventions to the unique molecular profile of each patient's disease., (© 2024. The Author(s).)

Background: Irinotecan (CPT-11) is a first-line treatment for advanced colorectal cancer (CRC). Four components (baicalin, baicalein, wogonin, and glycyrrhizic acid) derived from Huangqin Decoction (HQD) have been proven to enhance the anticancer activity of CPT-11 in our previous study., Objective: This study aimed to determine the optimal combination of the four components for sensitizing CPT-11 as well as to explore the underlying mechanism., Methods: The orthogonal design method was applied to obtain candidate combinations (Cmb1-9) of the four components. The influence of different combinations on the anticancer effect of CPT-11 was first evaluated in vitro by cell viability, wound healing ability, cloning formation, apoptosis, and cell cycle arrest. Then, a CRC xenograft mice model was constructed to evaluate the anticancer effect of the optimal combination in vivo. Potential mechanisms of the optimal combination exerting a sensitization effect combined with CPT-11 against CRC were analyzed by targeted metabolomics., Results: In vitro experiments determined that Cmb8 comprised of baicalin, baicalein, wogonin, and glycyrrhizic acid at the concentrations of 17 μM, 47 μM, 46.5 μM and 9.8 μM respectively was the most effective combination. Importantly, the cell viability assay showed that Cmb8 exhibited synergistic anticancer activity in combination with CPT-11. In in vivo experiments, this combination (15 mg/kg of baicalin, 24 mg/kg of baicalein, 24 mg/kg of wogonin, and 15 mg/kg of glycyrrhizic acid) also showed a synergistic anticancer effect. Meanwhile, inflammatory factors and pathological examination of the colon showed that Cmb8 could alleviate the gastrointestinal damage induced by CPT-11. Metabolic profiling of the tumors suggested that the synergistic anticancer effect of Cmb8 might be related to the regulation of fatty acid metabolism., Conclusion: The optimal combination of four components derived from HQD for the synergistic sensitization of CPT-11 against CRC was identified., (© 2024. The Author(s).)

Background and Aims: The cardiotoxicity related to 5-Fluorouracil (5-FU) in cancer patients has garnered widespread attention. The systemic immune-inflammation index (SII) has recently been identified as a novel predictive marker for the development of cardiovascular illnesses in individuals without pre-existing health conditions. However, it remains unclear whether the levels of SII are linked to cardiotoxicity related to 5-FU. This retrospective study aims to fill this knowledge gap by examining the correlation between SII and cardiotoxicity related to 5-FU in a colorectal cancer cohort., Methods: The study comprised colorectal cancer patients who received 5-FU-based chemotherapy at the affiliated cancer hospital of Guizhou Medical University between January 1, 2018 and December 31, 2020. After adjustment for confounders and stratification by tertiles of the interactive factor, linear regression analyses, curve fitting and threshold effect analyses were conducted., Results: Of the 754 patients included final analysis, approximately 21% (n = 156) of them ultimately experienced cardiotoxicity related to 5-FU. Monocytes (M) was found as an influential element in the interaction between SII and cardiotoxicity related to 5-FU. In the low tertile of M (T1: M ≤ 0.38 × 10 9 /L), increasing log SII was positively correlated with cardiotoxicity related to 5-FU (Odds Ratio [OR], 8.04; 95% confidence interval [95%CI], 1.68 to 38.56). However, a curvilinear relationship between log SII and cardiotoxicity was observed in the middle tertile of M (T2: 0.38 < M ≤ 0.52 × 10 9 /L). An increase in log SII above 1.37 was shown to be associated with a decreased risk of cardiotoxicity (OR, 0.14; 95%CI, 0.02 to 0.88), indicating a threshold effect. In the high tertile of M (T3: M > 0.52 × 10 9 /L), there was a tendency towards a negative linear correlation between the log SII and cardiotoxicity was observed (OR, 0.85; 95%CI, 0.37 to 1.98)., Conclusion: Our findings suggest that SII may serve as a potential biomarker for predicting cardiotoxicity related to 5-FU in colorectal cancer patients. SII is an independent risk factor for cardiotoxicity related to 5-FU with low monocytes levels (T1). Conversely, in the middle monocytes levels (T2), SII is a protective factor for cardiotoxicity related to 5-FU but with a threshold effect., (© 2024. The Author(s).)

Background: Glycerophospholipids (GPLs) are essential for cell membrane structure and function. Sphingomyelin and its metabolites regulate cell growth, apoptosis, and stress responses. This study aimed to investigate lipid metabolism in patients experiencing sudden sensorineural hearing loss across all frequencies (AF-SSNHL)., Methods: The study included 60 patients diagnosed with unilateral AF-SSNHL, among whom 30 patients had a level of hearing improvement ≥ 15 dB after 6 months of follow-up. A propensity score-matched (2:1) control group was used. Liquid chromatography‒mass spectrometry based untargeted lipidomics analysis combined with multivariate statistics was performed to investigate the lipids change. The "lipidome" R package and weighted gene co-expression network analysis (WGCNA) were utilised to assess the lipids' structural features and the association between lipids and hearing., Results: Lipidomics successfully differentiated the AF-SSNHL group from the control group, identifying 17 risk factors, mainly including phosphatidylcholine (PC), phosphatidylethanolamine (PE), and related metabolites. The ratios of lysophosphatidylcholine/PC, lysophosphatidylethanolamine/PE, and lysodimethylphosphatidylethanolamine/PE were upregulated, while some glycerophospholipid (GPL)-plasmalogens were downregulated in the AF-SSNHL group, indicating abnormal metabolism of GPLs. Trihexosylceramide (d34:1), PE (18:1e&#95;22:5), and sphingomyelin (d40:3) were significantly different between responders and nonresponders, and positively correlated with hearing improvement. Additionally, the results of the WGCNA also suggested that partial GPL-plasmalogens were positively associated with hearing improvement., Conclusion: AF-SSNHL patients exhibited abnormally high blood lipids and pronounced GPLs metabolic abnormalities. Sphingolipids and GPL-plasmalogens had an association with the level of hearing improvement. By understanding the lipid changes, clinicians may be able to predict the prognosis of hearing recovery and personalize treatment approaches., (© 2024. The Author(s).)

Liver sinusoidal endothelial cells (LSECs) are highly specialized endothelial cells that represent the interface between blood cells on one side and hepatocytes on the other side. LSECs not only form a barrier within the hepatic sinus, but also play important physiological functions such as regulating hepatic vascular pressure, anti-inflammatory and anti-fibrotic. Pathologically, pathogenic factors can induce LSECs capillarization, that is, loss of fenestra and dysfunction, which are conducive to early steatosis, lay the foundation for the progression of metabolic dysfunction-associated fatty liver disease (MAFLD), and accelerate metabolic dysfunction-associated steatohepatitis (MASH) and liver fibrosis. The unique localization, phenotype, and function of LSECs make them potential candidates for reducing liver injury, inflammation, and preventing or reversing fibrosis in the future., (© 2024. The Author(s).)

Background: Dry eye is a chronic and multifactorial ocular surface disease caused by tear film instability or imbalance in the microenvironment of the ocular surface. It can lead to various discomforts such as inflammation of the ocular surface and visual issues. However, the mechanism of dry eye is not clear, which results in dry eye being only relieved but not cured in clinical practice. Finding multiple environmental pathways for dry eye and exploring the pathogenesis of dry eye have become the focus of research. Studies have found that changes in microbiota may be related to the occurrence and development of dry eye disease., Methods: Entered the keywords "Dry eye", "Microbiota", "Bacteria" through PUBMED, summarised the articles that meet the inclusion criteria and then filtered them while the publication time range of the literature was defined in the past 5 years, with a deadline of 2023.A total of 13 clinical and 1 animal-related research articles were screened out and included in the summary., Results: Study found that different components of bacteria can induce ocular immune responses through different receptors present on the ocular surface, thereby leading to an imbalance in the ocular surface microenvironment. Changes in the ocular surface microbiota and gut microbiota were also found when dry eye syndrome occurs, including changes in diversity, an increase in pro-inflammatory bacteria, and a decrease in short-chain fatty acid-related bacterial genera that produce anti-inflammatory effects. Fecal microbiota transplantation or probiotic intervention can alleviate signs of inflammation on the ocular surface of dry eye animal models., Conclusions: By summarizing the changes in the ocular surface and intestinal microbiota when dry eye occurs, it is speculated and concluded that the intestine may affect the occurrence of eye diseases such as dry eye through several pathways and mechanisms, such as the occurrence of abnormal immune responses, microbiota metabolites- intervention of short-chain fatty acids, imbalance of pro-inflammatory and anti-inflammatory factors, and release of neurotransmitters, etc. Analyzing the correlation between the intestinal tract and the eyes from the perspective of microbiota can provide a theoretical basis and a new idea for relieving dry eyes in multiple ways in the future., (© 2024. The Author(s).)

Osteoarthritis (OA) is the most common degenerative joint disorder that causes disability in aged individuals, caused by functional and structural alterations of the knee joint. To investigate whether metabolic drivers might be harnessed to promote cartilage repair, a liquid chromatography-mass spectrometry (LC-MS) untargeted metabolomics approach was carried out to screen serum biomarkers in osteoarthritic rats. Based on the correlation analyses, α-ketoglutarate (α-KG) has been demonstrated to have antioxidant and anti-inflammatory properties in various diseases. These properties make α-KG a prime candidate for further investigation of OA. Experimental results indicate that α-KG significantly inhibited H 2 O 2 -induced cartilage cell matrix degradation and apoptosis, reduced levels of reactive oxygen species (ROS) and malondialdehyde (MDA), increased superoxide dismutase (SOD) and glutathione (GSH)/glutathione disulfide (GSSG) levels, and upregulated the expression of ETV4, SLC7A11 and GPX4. Further mechanistic studies observed that α-KG, like Ferrostatin-1 (Fer-1), effectively alleviated Erastin-induced apoptosis and ECM degradation. α-KG and Fer-1 upregulated ETV4, SLC7A11, and GPX4 at the mRNA and protein levels, decreased ferrous ion (Fe 2+ ) accumulation, and preserved mitochondrial membrane potential (MMP) in ATDC5 cells. In vivo, α-KG treatment inhibited ferroptosis in OA rats by activating the ETV4/SLC7A11/GPX4 pathway. Thus, these findings indicate that α-KG inhibits ferroptosis via the ETV4/SLC7A11/GPX4 signaling pathway, thereby alleviating OA. These observations suggest that α-KG exhibits potential therapeutic properties for the treatment and prevention of OA, thereby having potential clinical applications in the future., (© 2024. The Author(s).)

Background: Legionella pneumonia is one of the most severe types of atypical pneumonia, impairing multiple organ systems, posing a threat to life. Diagnosing Legionella pneumonia is challenging due to difficulties in culturing the bacteria and limitations in immunoassay sensitivity and specificity., Case Presentation: This paper reports a rare case of sepsis caused by combined infection with Legionella pneumophila and Fusobacterium necrophorum, leading to respiratory failure, acute kidney injury, acute liver injury, myocardial damage, and electrolyte disorders. In addition, we systematically reviewed literature on patients with combined Legionella infections, analyzing their clinical features, laboratory results and diagnosis., Conclusions: For pathogens that require prolonged incubation periods and are less sensitive to conventional culturing methods, metagenomic next-generation sequencing (mNGS) can be a powerful supplement to pathogen screening and plays a significant role in the auxiliary diagnosis of complex infectious diseases., (© 2024. The Author(s).)

Background and Aims: To investigate the clinical features, ALDH5A1 gene variations, treatment, and prognosis of patients with succinic semialdehyde dehydrogenase (SSADH) deficiency., Materials and Methods: This retrospective study evaluated the findings in 13 Chinese patients with SSADH deficiency admitted to the Pediatric Department of Peking University First Hospital from September 2013 to September 2023., Results: Thirteen patients (seven male and six female patients; two sibling sisters) had the symptoms aged from 1 month to 1 year. Their urine 4-hydroxybutyrate acid levels were elevated and were accompanied by mildly increased serum lactate levels. Brain magnetic resonance imaging (MRI) showed symmetric abnormal signals in both sides of the globus pallidus and other areas. All 13 patients had psychomotor retardation, with seven showing epileptic seizures. Among the 18 variants of the ALDH5A1 gene identified in these 13 patients, six were previously reported, while 12 were novel variants. Among the 12 novel variants, three (c.85&#95;116del, c.206&#95;222dup, c.762C > G) were pathogenic variants; five (c.427delA, c.515G > A, c.637C > T, c.755G > T, c.1274T > C) were likely pathogenic; and the remaining four (c.454G > C, c.479C > T, c.1480G > A, c.1501G > C) were variants of uncertain significance. The patients received drugs such as L-carnitine, vigabatrin, and taurine, along with symptomatic treatment. Their urine 4-hydroxybutyric acid levels showed variable degrees of reduction., Conclusions: A cohort of 13 cases with early-onset SSADH deficiency was analyzed. Onset of symptoms occurred from 1 month to 1 year of age. Twelve novel variants of the ALDH5A1 gene were identified., (© 2024. The Author(s).)

Background: Tumor-associated macrophages (TAMs) constitute a substantial part of human hepatocellular carcinoma (HCC). The present study was devised to explore TAM diversity and their roles in HCC progression., Methods: Through the integration of multiple 10 × single-cell transcriptomic data derived from HCC samples and the use of consensus nonnegative matrix factorization (an unsupervised clustering algorithm), TAM molecular subtypes and expression programs were evaluated in detail. The roles played by these TAM subtypes in HCC were further probed through pseudotime, enrichment, and intercellular communication analyses. Lastly, vitro experiments were performed to validate the relationship between CD63, which is an inflammatory TAM expression program marker, and tumor cell lines., Results: We found that the inflammatory expression program in TAMs had a more obvious interaction with HCC cells, and CD63, as a marker gene of the inflammatory expression program, was associated with poor prognosis of HCC patients. Both bulk RNA-seq and vitro experiments confirmed that higher TAM CD63 expression was associated with the growth of HCC cells as well as their epithelial-mesenchymal transition, metastasis, invasion, and the reprogramming of lipid metabolism., Conclusions: These analyses revealed that the TAM inflammatory expression program in HCC is closely associated with malignant tumor cells, with the hub gene CD63 thus representing an ideal target for therapeutic intervention in this cancer type., (© 2024. The Author(s).)

Parkinson's disease (PD) is a prevalent neurodegenerative disorder with indistinct etiology and ill-defined pathophysiology. Intestinal inflammation involved in the pathogenesis of PD, but the underlying mechanism is not fully understood. Citrobacter rodentium (C.R) is a gram-negative bacterium that can be used to induce human inflammatory bowel disease in mice. Here, we investigated whether the proinflammatory effects caused by C.R infection initiate PD-like injury and/or exacerbate PD pathology and extensively studied the underlying mechanism. Mice were gavaged once with C.R and monitored for several pathological features at 9 days post infection. The results showed that C.R delivery in mice induced IBD-like symptoms, including significant weight loss, increased fecal water content, an impaired intestinal barrier, intestinal hyperpermeability and inflammation, and intestinal microbiota disturbances. Notably, C.R infection modified dopamine (DA) metabolism in the brains of both male and female mice. Subsequently, a single high dose of MPTP or normal saline was administered at 6 days post infection. At 3 days after MPTP administration, the feces were collected for 16 S rRNA analysis, and PD-like phenotypes and mechanisms were systemically analyzed. Compared with C.R or MPTP injection alone, the injection of C.R and MPTP combined worsened behavioral performance. Moreover, such combination triggered more severe dopaminergic degeneration and glial cell overactivation in the nigrostriatal pathway of mice. Mechanistically, the combination of C.R and MPTP increased the expression of TLR4 and NF-κB p65 in the colon and striatum and upregulated proinflammatory cytokine expression. Therefore, C.R infection-induced intestinal inflammation can impair dopamine metabolism and exacerbate PD pathological processes., (© 2024. The Author(s).)

Background: Extracellular ATP-AMP-adenosine metabolism plays a pivotal role in modulating tumor immune responses. Previous studies have shown that the conversion of ATP to AMP is primarily catalysed by Ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD1/CD39), a widely studied ATPase, which is expressed in tumor-associated immune cells. However, the function of ATPases derived from tumor cells themselves remains poorly understood. The purpose of this study was to investigate the role of colon cancer cell-derived ATPases in the development and progression of colon cancer., Methods: Bioinformatic and tissue microarray analyses were performed to investigate the expression of ATPase family members in colon cancer. An ATP hydrolysis assay, high-performance liquid chromatography (HPLC), and CCK8 and colony formation assays were used to determine the effects of ENTPD2 on the biological functions of colon cancer cells. Flow cytometric and RNA-seq analyses were used to explore the function of CD8 + T cells. Immunoelectron microscopy and western blotting were used to evaluate the expression of ENTPD2 in exosomes. Double-labelling immunofluorescence and western blotting were used to examine the expression of ENTPD2 in serum exosomes and colon cancer tissues., Results: We found that ENTPD2, rather than the well-known ATPase CD39, is highly expressed in cancer cells and is significantly positively associated with poor patient prognosis in patients with colon cancer. The overexpression of ENTPD2 in cancer cells augmented tumor progression in immunocompetent mice by inhibiting the function of CD8 + T cells. Moreover, ENTPD2 is localized primarily within exosomes. On the one hand, exosomal ENTPD2 reduces extracellular ATP levels, thereby inhibiting P2X7R-mediated NFATc1 nuclear transcription; on the other hand, it facilitates the increased conversion of ATP to adenosine, hence promoting adenosine-A2AR pathway activity. In patients with colon cancer, the serum level of exosomal ENTPD2 is positively associated with advanced TNM stage and high tumor invasion depth. Moreover, the level of ENTPD2 in the serum exosomes of colon cancer patients is positively correlated with the ENTPD2 expression level in paired colon cancer tissues, and the ENTPD2 level in both serum exosomes and tissues is significantly negatively correlated with the ENTPD2 expression level in tumor-infiltrating CD8 + T cells., Conclusion: Our study suggests that exosomal ENTPD2, originated from colon cancer cells, contributes to the immunosuppressive microenvironment by promoting ATP-adenosine metabolism. These findings highlight the importance of exosome-derived hydrolytic enzymes as independent entities in shaping the tumor immune microenvironment., (© 2024. The Author(s).)

Purpose: To investigate the relationship between multi-dimensional aspects of screen exposure and autistic symptoms, as well as neuropsychological development in children with ASD., Methods: We compared the ScreenQ and Griffiths Development Scales-Chinese Language Edition (GDS-C) of 636 ASD children (40.79 ± 11.45 months) and 43 typically developing (TD) children (42.44 ± 9.61 months). Then, we analyzed the correlations between ScreenQ and Childhood Autism Rating Scale (CARS), and GDS-C. We further used linear regression model to analyze the risk factors associated with high CARS total scores and low development quotients (DQs) in children with ASD., Results: The CARS of children with ASD was positively correlated with the ScreenQ total scores and "access, frequency, co-viewing" items of ScreenQ. The personal social skills DQ was negatively correlated with the "access, frequency, content, co-viewing and total scores" of ScreenQ. The hearing-speech DQ was negatively correlated with the "frequency, content, co-viewing and total scores" of ScreenQ. The eye-hand coordination DQ was negatively correlated with the "frequency and total scores" of ScreenQ. The performance DQ was negatively correlated with the "frequency" item of ScreenQ., Conclusion: ScreenQ can be used in the study of screen exposure in children with ASD. The higher the ScreenQ scores, the more severe the autistic symptoms tend to be, and the more delayed the development of children with ASD in the domains of personal-social, hearing-speech and eye-hand coordination. In addition, "frequency" has the greatest impact on the domains of personal social skills, hearing-speech, eye-hand coordination and performance of children with ASD., (© 2024. The Author(s).)

Background: Previous research has extensively examined the role of interleukin 6 (IL-6) in sarcopenia. However, the presence of a causal relationship between IL-6, its receptor (IL-6R), and sarcopenia remains unclear., Method: In this study, we utilized summary-level data from genome-wide association studies (GWAS) focused on appendicular lean mass (ALM), hand grip strength, and walking pace. Single nucleotide polymorphisms (SNPs) were employed as genetic instruments for IL-6 and IL-6R to estimate the causal effect of sarcopenia traits. We adopted the Mendelian randomization (MR) approach to investigate these associations using the inverse variance weighted (IVW) method as the primary analytical approach. Additionally, we performed sensitivity analyses to validate the reliability of the MR results., Result: This study revealed a significant negative association between main IL-6R and eQTL IL-6R on the left grip strength were - 0.013 (SE = 0.004, p < 0.001) and -0.029 (SE = 0.007, p < 0.001), respectively. While for the right grip strength, the estimates were - 0.011 (SE = 0.001, p < 0.001) and - 0.021 (SE = 0.008, p = 0.005). However, no evidence of an association for IL-6R with ALM and walking pace. In addition, IL-6 did not affect sarcopenia traits., Conclusion: Our study findings suggest a negative association between IL-6R and hand grip strength. Additionally, targeting IL-6R may hold potential value as a therapeutic approach for the treatment of hand grip-related issues., (© 2024. The Author(s).)

Background: Clinicians traditionally aim to identify a singular explanation for the clinical presentation of a patient; however, in some cases, the diagnosis may remain elusive or fail to comprehensively explain the clinical findings. In recent years, advancements in next-generation sequencing, including whole-exome sequencing, have led to the incidental identification of dual diagnoses in patients. Herein we present the cases of five pediatric patients diagnosed with dual rare genetic diseases. Their natural history and diagnostic process were explored, and lessons learned from utilizing next-generation diagnostic technologies have been reported., Results: Five pediatric cases (3 boys, 2 girls) with dual diagnoses were reported. The age at diagnosis was from 3 months to 10 years. The main clinical presentations were psychomotor retardation and increased muscular tension, some accompanied with liver dysfunction, abnormal appearance, precocious puberty, dorsiflexion restriction and varus of both feet, etc. After whole-exome sequencing, nine diseases were confirmed in these patients: Angelman syndrome and Krabbe disease in case 1, Citrin deficiency and Kabuki syndrome in case 2, Homocysteinemia type 2 and Copy number variant in case 3, Isolated methylmalonic acidemia and Niemann-Pick disease type B in case 4, Isolated methylmalonic acidemia and 21-hydroxylase deficiency in case 5. Fifteen gene mutations and 2 CNVs were identified. Four novel mutations were observed, including c.15292de1A in KMT2D, c.159&#95;164inv and c.1427G > A in SLC25A13, and c.591 C > G in MTHFR., Conclusions: Our findings underscore the importance of clinicians being vigilant about the significance of historical and physical examination. Comprehensive clinical experience is crucial for identifying atypical clinical features, particularly in cases involving dual rare genetic diseases., (© 2024. The Author(s).)

Background: Patients with idiopathic scoliosis commonly present with an imbalance of the paraspinal muscles. However, it is unclear whether this muscle imbalance is an underlying cause or a result of idiopathic scoliosis. This study aimed to investigate the role of paraspinal muscles in the development of idiopathic scoliosis based on surface electromyography (sEMG) and radiographic analyses., Methods: This was a single-center prospective study of 27 patients with single-curve idiopathic scoliosis. Posteroanterior whole-spine radiographs and sEMG activity of the erector spinae muscles were obtained for all patients in the habitual standing position (HSP), relaxed prone position (RPP), and prone extension position (PEP). The Cobb angle, symmetrical index (SI) of the sEMG activity (convex/concave), and correlation between the two factors were analyzed., Results: In the total cohort, the mean Cobb angle in the HSP was significantly greater than the mean Cobb angle in the RPP (RPP-Cobb) (p < 0.001), whereas the mean Cobb angle in the PEP (PEP-Cobb) did not differ from the RPP-Cobb. Thirteen patients had a PEP-Cobb that was significantly smaller than their RPP-Cobb (p = 0.007), while 14 patients had a PEP-Cobb that was significantly larger than their RPP-Cobb (p < 0.001). In the total cohort and two subgroups, the SI of sEMG activity at the apex vertebra (AVSI) in the PEP was significantly greater than 1, revealing significant asymmetry, and was also significantly larger than the AVSI in the RPP. In the RPP, the AVSI was close to 1 in the total cohort and two subgroups, revealing no significant asymmetry., Conclusion: The coronal Cobb angle and the SI of paraspinal muscle activity in AIS patients vary with posture changes. Asymmetrical sEMG activity of the paraspinal muscles may be not an inherent feature of AIS patients, but is evident in the challenging tasks. The potential significance of asymmetric paraspinal muscle activity need to be explored in further research., (© 2024. The Author(s).)

Background: To investigate the value of a nomogram model based on the combination of clinical-CT features and multiphasic enhanced CT radiomics for the preoperative prediction of the microsatellite instability (MSI) status in colorectal cancer (CRC) patients., Methods: A total of 347 patients with a pathological diagnosis of colorectal adenocarcinoma, including 276 microsatellite stabilized (MSS) patients and 71 MSI patients (243 training and 104 testing), were included. Univariate and multivariate regression analyses were used to identify the clinical-CT features of CRC patients linked with MSI status to build a clinical model. Radiomics features were extracted from arterial phase (AP), venous phase (VP), and delayed phase (DP) CT images. Different radiomics models for the single phase and multiphase (three-phase combination) were developed to determine the optimal phase. A nomogram model that combines clinical-CT features and the optimal phasic radscore was also created., Results: Platelet (PLT), systemic immune inflammation index (SII), tumour location, enhancement pattern, and AP contrast ratio (ACR) were independent predictors of MSI status in CRC patients. Among the AP, VP, DP, and three-phase combination models, the three-phase combination model was selected as the best radiomics model. The best MSI prediction efficacy was demonstrated by the nomogram model built from the combination of clinical-CT features and the three-phase combination model, with AUCs of 0.894 and 0.839 in the training and testing datasets, respectively., Conclusion: The nomogram model based on the combination of clinical-CT features and three-phase combination radiomics features can be used as an auxiliary tool for the preoperative prediction of the MSI status in CRC patients., (© 2024. The Author(s).)

Neuroinflammation is one of the core pathological features of Parkinson's disease (PD). Innate immune cells play a crucial role in the progression of PD. Microglia, the major innate immune cells in the brain, exhibit innate immune memory effects and are recognized as key regulators of neuroinflammatory responses. Persistent modifications of microglia provoked by the first stimuli are pivotal for innate immune memory, resulting in an enhanced or suppressed immune response to second stimuli, which is known as innate immune training and innate immune tolerance, respectively. In this study, LPS was used to establish in vitro and in vivo models of innate immune memory. Microglia-specific Hif-1α knockout mice were further employed to elucidate the regulatory role of HIF-1α in innate immune memory and MPTP-induced PD pathology. Our results showed that different paradigms of LPS could induce innate immune training or tolerance in the nigrostriatal pathway of mice. We found that innate immune tolerance lasting for one month protected the dopaminergic system in PD mice, whereas the effect of innate immune training was limited. Deficiency of HIF-1α in microglia impeded the formation of innate immune memory and exerted protective effects in MPTP-intoxicated mice by suppressing neuroinflammation. Therefore, HIF-1α is essential for microglial innate immune memory and can promote neuroinflammation associated with PD., (© 2024. The Author(s).)

Objective: The current study used a composite outcome to investigate whether applying the ERAS protocol would enhance the recovery of patients undergoing laparoscopic total gastrectomy (LTG)., Exposures: Laparoscopic total gastrectomy and perioperative interventions were the exposure. An ERAS clinical pathway consisting of 14 items was implemented and assessed. Patients were divided into either ERAS-compliant or non-ERAS-compliant group according the adherence above 9/14 or not., Main Outcomes and Measures: The primary study outcome was a composite outcome called 'optimal postoperative recovery' with the definition as below: discharge within 6 days with no sever complications and no unplanned re-operation or readmission within 30 days postoperatively. Univariate logistic regression analysis and multivariate logistic regression analysis were used to model optimal postoperative recovery and compliance, adjusting for patient-related and disease-related characteristics., Results: A total of 252 patients were included in this retrospective study, 129 in the ERAS compliant group and 123 in the non-ERAS-compliant group. Of these, 79.07% of the patients in ERAS compliant group achieved optimal postoperative recovery, whereas 61.79% of patients in non-ERAS-compliant group did (P = 0.0026). The incidence of sever complications was lower in the ERAS-compliant group (1.55% vs. 6.5%, P = 0.0441). No patients in ERAS compliant group had unplanned re-operation, whereas 5.69% (7/123) of patients in non-ERAS-compliant group had (p = 0.006). The median length of the postoperative hospital stay was shorter in the in the ERAS compliant group (5.51 vs. 5.68 days, P = 0.01). Both logistic (OR 2.01, 95% CI 1.21-3.34) and stepwise regression (OR 2.07, 95% CI 1.25-3.41) analysis showed that high overall compliance with the ERAS protocol facilitated optimal recovery in such patients. In bivariate analysis of compliance for patients who had an optimal postoperative recovery, carbohydrate drinks (p = 0.0196), early oral feeding (P = 0.0043), early mobilization (P = 0.0340), and restrictive intravenous fluid administration (P < 0.0001) were significantly associated with optimal postoperative recovery., Conclusions and Relevance: Patients with higher ERAS compliance (almost 70% of the accomplishment) suffered less severe postoperative complications and were more likely to achieve optimal postoperative recovery., (© 2024. The Author(s).)

Background: Trans persons' physical and mental health is easily affected by the attitude of those around them. However, China currently lacks a valid psychometric instrument to investigate people's attitudes toward trans persons. Therefore, this study modifies the English version of the Transgender Attitudes and Beliefs Scale (TABS) to suit the Chinese context. It subsequently examines the reliability and validity of the Chinese version of the TABS., Methods: This study recruited 1164 university students, aged 18-25 years, from 7 regions of China. SPSS26.0 and AMOS24.0 were used for data statistical analysis. Critical ratio method and correlation coefficient method were used for item analysis. Exploratory factor analysis and confirmatory factor analysis were used to test the structural validity of the Chinese version of Transgender Beliefs and Attitudes Scale, and the internal consistency reliability of the scale was tested., Results: The TABS-C contains 26 items with 3 factors. The Cronbach's alpha was 0.957 for the total scale and 0.945, 0.888, and 0.885 for the 3 factors. The half-point reliability of the scale was 0.936, and the retest reliability was 0.877. The Pearson correlation coefficients for the 3 factors and the total scale score ranged from 0.768 to 0.946., Conclusion: The TABS-C has reliable psychometric properties and is suitable for usage among college students in the Chinese context., (© 2024. The Author(s).)

Background: Remnant cholesterol (RC) is recognized as a risk factor for diabetes mellitus (DM). Although iron status has been shown to be associated with cholesterol metabolism and DM, the association between RC, iron status, and DM remains unclear. We examined the relationship between RC and iron status and investigated the role of iron status in the association between RC and DM., Methods: A total of 7308 patients were enrolled from the China Health and Nutrition Survey. RC was calculated as total cholesterol minus low-density lipoprotein cholesterol and high-density lipoprotein cholesterol. Iron status was assessed as serum ferritin (SF) and total body iron (TBI). DM was ascertained by self-reported physician diagnosis and/or antidiabetic drug use and/or fasting plasma glucose ≥ 126 mg/dL and/or glycated haemoglobin ≥ 6.5%. General linear models were used to evaluate the relationships between RC and iron status. Restricted cubic splines were used to assess the association between RC and DM. Mediation analysis was used to clarified the mediating role of iron status in the association between the RC and DM., Results: The average age of the participants was 50.6 (standard deviation = 15.1) years. Higher RC was significantly associated with increased SF (β = 73.14, SE = 3.75, 95% confidence interval [CI] 65.79-80.49) and TBI (β = 1.61, SE = 0.08, 95% CI 1.44-1.78). J-shape relationships were found in the association between RC levels with DM, as well as iron status with DM. Significant indirect effects of SF and TBI in the association between RC and DM were found, with the index mediated at 9.58% and 6.37%, respectively., Conclusions: RC has a dose-response relationship with iron status. The association between RC and DM was mediated in part by iron status. Future studies are needed to confirm these findings and further clarify the underlying mechanism., (© 2024. The Author(s).)

Background: Atherosclerosis (AS) is a persistent inflammatory condition triggered and exacerbated by several factors including lipid accumulation, endothelial dysfunction and macrophages infiltration. Nobiletin (NOB) has been reported to alleviate atherosclerosis; however, the underlying mechanism remains incompletely understood., Methods: This study involved comprehensive bioinformatic analysis, including multidatabase target prediction; GO and KEGG enrichment analyses for function and pathway exploration; DeepSite and AutoDock for drug binding site prediction; and CIBERSORT for immune cell involvement. In addition, target intervention was verified via cell scratch assays, oil red O staining, ELISA, flow cytometry, qRT‒PCR and Western blotting. In addition, by establishing a mouse model of AS, it was demonstrated that NOB attenuated lipid accumulation and the extent of atherosclerotic lesions., Results: (1) Altogether, 141 potentially targetable genes were identified through which NOB could intervene in atherosclerosis. (2) Lipid and atherosclerosis, fluid shear stress and atherosclerosis may be the dominant pathways and potential mechanisms. (3) ALB, AKT1, CASP3 and 7 other genes were identified as the top 10 target genes. (4) Six genes, including PPARG, MMP9, SRC and 3 other genes, were related to the M0 fraction. (5) CD36 and PPARG were upregulated in atherosclerosis samples compared to the normal control. (6) By inhibiting lipid uptake in RAW264.7 cells, NOB prevents the formation of foam cell. (7) In RAW264.7 cells, the inhibitory effect of oxidized low-density lipoprotein on foam cells formation and lipid accumulation was closely associated with the PPARG signaling pathway. (8) In vivo validation showed that NOB significantly attenuated intra-arterial lipid accumulation and macrophage infiltration and reduced CD36 expression., Conclusions: Nobiletin alleviates atherosclerosis by inhibiting lipid uptake via the PPARG/CD36 pathway., (© 2024. The Author(s).)

Background: Cardiovascular disease (CVD) caused by air pollution poses a considerable burden on public health. We aim to examine whether lifestyle factors mediate the associations of air pollutant exposure with the risk of CVD and the extent of the interaction between lifestyles and air pollutant exposure regarding CVD outcomes., Methods: We included 7000 participants in 2011-2012 and followed up until 2018. The lifestyle evaluation consists of six factors as proxies, including blood pressure, blood glucose, blood lipids, body mass index, tobacco exposure, and physical activity, and the participants were categorized into three lifestyle groups according to the number of ideal factors (unfavorable, 0-1; intermediate, 2-4; and favorable, 5-6). Satellite-based spatiotemporal models were used to estimate exposure to ambient air pollutants (including particles with diameters ≤ 1.0 μm [PM 1 ], ≤ 2.5 μm [PM 2.5 ], ≤ 10 μm [PM 10 ], nitrogen dioxide [NO 2 ], and ozone [O 3 ]). Cox regression models were used to examine the associations between air pollutant exposure, lifestyles and the risk of CVD. The mediation and modification effects of lifestyle categories on the association between air pollutant exposure and CVD were analyzed., Results: After adjusting for covariates, per 10 μg/m 3 increase in exposure to PM 1 (HR: 1.09, 95% CI: 1.05-1.14), PM 2.5 (HR: 1.04, 95% CI: 1.00-1.08), PM 10 (HR: 1.05, 95% CI: 1.03-1.08), and NO 2 (HR: 1.11, 95% CI: 1.05-1.18) was associated with an increased risk of CVD. Adherence to a healthy lifestyle was associated with a reduced risk of CVD compared to an unfavorable lifestyle (HR: 0.65, 95% CI: 0.56-0.76 for intermediate lifestyle and HR: 0.41, 95% CI: 0.32-0.53 for favorable lifestyle). Lifestyle played a significant partial mediating role in the contribution of air pollutant exposure to CVD, with the mediation proportion ranging from 7.4% for PM 10 to 14.3% for PM 2.5 . Compared to an unfavorable lifestyle, the relative excess risk due to interaction for a healthier lifestyle to reduce the effect on CVD risk was - 0.98 (- 1.52 to - 0.44) for PM 1 , - 0.60 (- 1.05 to - 0.14) for PM 2.5 , - 1.84 (- 2.59 to - 1.09) for PM 10 , - 1.44 (- 2.10 to - 0.79) for NO 2, and - 0.60 (- 1.08, - 0.12) for O 3 ., Conclusions: Lifestyle partially mediated the association of air pollution with CVD, and adherence to a healthy lifestyle could protect middle-aged and elderly people from the adverse effects of air pollution regarding CVD., (© 2024. The Author(s).)

Aims: Recent studies have indicated an association between intestinal flora and lipids. However, observational studies cannot indicate causality. In this study, we aimed to investigate the potentially causal relationships between the intestinal flora and blood lipids., Methods: We performed a bidirectional two-sample Mendelian Randomization (MR) analysis to investigate the causal relationship between intestinal flora and blood lipids. Summary statistics of genome-wide association studies (GWASs) for the 211 intestinal flora and blood lipid traits (n = 5) were obtained from public datasets. Five recognized MR methods were applied to assess the causal relationship with lipids, among which, the inverse-variance weighted (IVW) regression was used as the primary MR method. A series of sensitivity analyses were performed to test the robustness of the causal estimates., Results: The results indicated a potential causal association between 19 intestinal flora and dyslipidemia in humans. Genus Ruminococcaceae, Christensenellaceae, Parasutterella, Terrisporobacter, Parabacteroides, Class Erysipelotrichia, Family Erysipelotrichaceae, and order Erysipelotrichales were associated with higher dyslipidemia, whereas genus Oscillospira, Peptococcus, Ruminococcaceae UCG010, Ruminococcaceae UCG011, Dorea, and Family Desulfovibrionaceae were associated with lower dyslipidemia. After using the Bonferroni method for multiple testing correction, Only Desulfovibrionaceae [Estimate = -0.0418, 95% confidence interval [CI]: 0.9362-0.9826, P = 0.0007] exhibited stable and significant negative associations with ApoB levels. The inverse MR analysis did not find a significant causal effect of lipids on the intestinal flora. Additionally, no significant heterogeneity or horizontal pleiotropy for IVs was observed in the analysis., Conclusion: The study suggested a causal relationship between intestinal flora and dyslipidemia. These findings will provide a meaningful reference to discover dyslipidemia for intervention to address the problems in the clinic., (© 2024. The Author(s).)

Background: Xinjiang Mongolian cattle is an indigenous breed that inhabits the Taklimakan Desert and is characterized by its small body size. However, the genomic diversity, origin, and genetic basis underlying the adaptation to the desert environment have been poorly studied., Results: We analyzed patterns of Xinjiang Mongolian cattle genetic variation by sequencing 20 genomes together with seven previously sequenced genomes and comparing them to the 134 genomes of nine representative breeds worldwide. Among the breeds of Bos taurus, we found the highest nucleotide diversity (0.0024) associated with the lower inbreeding coefficient (2.0110 -6 ), the lowest linkage disequilibrium (r 2 = 0.3889 at distance of 10 kb), and the highest effective population size (181 at 20 generations ago) in Xinjiang Mongolian cattle. The genomic diversity pattern could be explained by a limited introgression of Bos indicus genes. More importantly, similarly to desert-adapted camel and same-habitat sheep, we also identified signatures of selection including genes, GO terms, and/or KEGG pathways controlling water reabsorption and osmoregulation, metabolic regulation and energy balance, as well as small body size in Xinjiang Mongolian cattle., Conclusions: Our results imply that Xinjiang Mongolian cattle might have acquired distinct genomic diversity by virtue of the introgression of Bos indicus, which helps understand the demographic history. The identification of selection signatures can provide novel insights into the genomic basis underlying the adaptation of Xinjiang Mongolian cattle to the desert environment., (© 2024. The Author(s).)

Background: Enterocytozoon bieneusi is a zoonotic pathogen widely distributed in animals and humans. It can cause diarrhea and even death in immunocompromised hosts. Approximately 800 internal transcribed spacer (ITS) genotypes have been identified in E. bieneusi. Farmed foxes and raccoon dogs are closely associated to humans and might be the reservoir of E. bieneusi which is known to have zoonotic potential. However, there are only a few studies about E. bieneusi genotype identification and epidemiological survey in foxes and raccoon dogs in Henan and Hebei province. Thus, the present study investigated the infection rates and genotypes of E. bieneusi in farmed foxes and raccoon dogs in the Henan and Hebei provinces., Result: A total of 704 and 884 fecal specimens were collected from foxes and raccoon dogs, respectively. Nested PCR was conducted based on ITS of ribosomal RNA (rRNA), and then multilocus sequence typing (MLST) was conducted to analyze the genotypes. The result showed that infection rates of E. bieneusi in foxes and raccoon dogs were 18.32% and 5.54%, respectively. Ten E. bieneusi genotypes with zoonotic potential (NCF2, NCF3, D, EbpC, CHN-DC1, SCF2, CHN-F1, Type IV, BEB4, and BEB6) were identified in foxes and raccoon dogs. Totally 178 ITS-positive DNA specimens were identified from foxes and raccoon dogs and these specimens were then subjected to MLST analysis. In the MLST analysis, 12, 2, 7 and 8 genotypes were identified in at the mini-/ micro-satellite loci MS1, MS3, MS4 and MS7, respectively. A total of 14 multilocus genotypes were generated using ClustalX 2.1 software. Overall, the present study evaluated the infection of E. bieneusi in foxes and raccoon dogs in the Henan and Hebei province, and investigated the zoonotic potential of the E. bieneusi in foxes and raccoon dogs., Conclusions: These findings expand the geographic distribution information of E. bieneusi' host in China and was helpful in preventing against the infection of E. bieneusi with zoonotic potential in foxes and raccoon dogs., (© 2024. The Author(s).)

Background: Enhanced agricultural production is urgently required to meet the food demands of the increasing global population. Abundant genetic diversity is expected to accelerate crop development. In particular, the development of the CRISPR/Cas genome editing technology has greatly enhanced our ability to improve crop's genetic diversity through direct artificial gene modification. However, recent studies have shown that most crop improvement efforts using CRISPR/Cas techniques have mainly focused on the coding regions, and there is a relatively lack of studies on the regulatory regions of gene expression., Results: This review briefly summarizes the development of CRISPR/Cas system in the beginning. Subsequently, the importance of gene regulatory regions in plants is discussed. The review focuses on recent developments and applications of mutations in regulatory regions via CRISPR/Cas techniques in crop breeding., Conclusion: Finally, an outline of perspectives for future crop breeding using genome editing technologies is provided. This review provides new research insights for crop improvement using genome editing techniques., (© 2024. The Author(s).)

Background: Sepsis-associated encephalopathy (SAE) is an acute cerebral dysfunction caused by sepsis. Neuroinflammation induced by sepsis is considered a potential mechanism of SAE; however, very little is known about the role of the meningeal lymphatic system in SAE., Methods: Sepsis was established in male C57BL/6J mice by intraperitoneal injection of 5 mg/kg lipopolysaccharide, and the function of meningeal lymphatic drainage was assessed. Adeno-associated virus 1-vascular endothelial growth factor C (AAV1-VEGF-C) was injected into the cisterna magna to induce meningeal lymphangiogenesis. Ligation of deep cervical lymph nodes (dCLNs) was performed to induce pre-existing meningeal lymphatic dysfunction. Cognitive function was evaluated by a fear conditioning test, and inflammatory factors were detected by enzyme-linked immunosorbent assay., Results: The aged mice with SAE showed a significant decrease in the drainage of OVA-647 into the dCLNs and the coverage of the Lyve-1 in the meningeal lymphatic, indicating that sepsis impaired meningeal lymphatic drainage and morphology. The meningeal lymphatic function of aged mice was more vulnerable to sepsis in comparison to young mice. Sepsis also decreased the protein levels of caspase-3 and PSD95, which was accompanied by reductions in the activity of hippocampal neurons. Microglia were significantly activated in the hippocampus of SAE mice, which was accompanied by an increase in neuroinflammation, as indicated by increases in interleukin-1 beta, interleukin-6 and Iba1 expression. Cognitive function was impaired in aged mice with SAE. However, the injection of AAV1-VEGF-C significantly increased coverage in the lymphatic system and tracer dye uptake in dCLNs, suggesting that AAV1-VEGF-C promotes meningeal lymphangiogenesis and drainage. Furthermore, AAV1-VEGF-C reduced microglial activation and neuroinflammation and improved cognitive dysfunction. Improvement of meningeal lymphatics also reduced sepsis-induced expression of disease-associated genes in aged mice. Pre-existing lymphatic dysfunction by ligating bilateral dCLNs aggravated sepsis-induced neuroinflammation and cognitive impairment., Conclusion: The meningeal lymphatic drainage is damaged in sepsis, and pre-existing defects in this drainage system exacerbate SAE-induced neuroinflammation and cognitive dysfunction. Promoting meningeal lymphatic drainage improves SAE. Manipulation of meningeal lymphangiogenesis could be a new strategy for the treatment of SAE., (© 2024. The Author(s).)

Background: The widespread utilization of chest High-resolution Computed Tomography (HRCT) has prompted detection of pulmonary ground-glass nodules (GGNs) in otherwise asymptomatic individuals. We aimed to establish a simple clinical risk score model for assessing GGNs based on HRCT., Methods: We retrospectively analyzed 574 GGNs in 574 patients undergoing HOOK-WIRE puncture and pulmonary nodule surgery from January 2014 to November 2018. Clinical characteristics and imaging features of the GGNs were assessed. We analyzed the differences between malignant and benign nodules using binary logistic regression analysis and constructed a simple risk score model, the VBV Score, for predicting the malignancy status of GGNs. Then, we validated this model via other 1200 GGNs in 1041 patients collected from three independent clinical centers in 2022., Results: For the exploratory phase of this study, out of the 574 GGNs, 481 were malignant and 93 were benign. Vacuole sign, air bronchogram, and intra-nodular vessel sign were important indicators of malignancy in GGNs. Then, we derived a VBV Score = vacuole sign + air bronchogram + intra-nodular vessel sign, to predict the malignancy of GGNs, with a sensitivity, specificity, and accuracy of 95.6%, 80.6%, and 93.2%, respectively. We also validated it on other 1200 GGNs, with a sensitivity, specificity, and accuracy of 96.0%, 82.6%, and 95.0%, respectively., Conclusions: Vacuole sign, air bronchogram, and intra-nodular vessel sign were important indicators of malignancy in GGNs. VBV Score showed good sensitivity, specificity, and accuracy for differentiating benign and malignant pulmonary GGNs., (© 2024. The Author(s).)

Background: Platelet count is associated with cardiovascular risk and mortality in several cardiovascular diseases, but the association of the nadir platelet counts post-septal myectomy with the cardiovascular complication risk in hypertrophic obstructive cardiomyopathy patients remains unclear., Methods: This retrospective cohort study reviewed all adult patients who underwent septal myectomy at a single tertiary referral center over a 5-year period. Postoperative nadir platelet count was defined as the lowest platelet count in the first 4 postoperative days or until hospital discharge. The composite outcome included cardiovascular death, myocardial infarction, heart failure, malignant arrhythmia, cardiac tamponade, and major bleeding events within 30 days postoperatively. Univariable and multivariable logistic regression and restricted cubic spline models were used to assess the association between postoperative nadir platelet count and the 30-day postoperative cardiovascular complication risk., Results: Among the 113 enrolled patients, 23 (20.4%) developed cardiovascular events within 30 days postoperatively. The incidence of postoperative cardiovascular complications was significantly higher in patients with a nadir platelet count ≤ 99 × 10 9 /L than in those with a nadir platelet count > 99 × 10 9 /L (33.3% vs. 7.1%, crude risk ratio: 4.67, 95% confidence interval: 1.69-12.85, P < 0.001). Multivariable logistic regression revealed that postoperative nadir platelet count was negatively associated with 30-day postoperative cardiovascular complications (adjusted odds ratio: 0.97; 95% confidence interval: 0.95-0.99; P = 0.005) and the association was linear (P nonlinearity = 0.058) after full adjustment. The association between nadir platelet count and cardiovascular complications within 30 days post-surgery was consistent in all predefined subgroups (P interaction > 0.05)., Conclusion: The postoperative nadir platelet count was significantly associated with the 30-day post-myectomy risk of cardiovascular complications in hypertrophic obstructive cardiomyopathy patients., Trial Registration: This trial was registered at ClinicalTrials.gov (NCT04275544)., (© 2024. The Author(s).)

Introduction: Several studies have proved that Polygenic Risk Score (PRS) is a potential candidate for realizing precision screening. The effectiveness of low-dose computed tomography (LDCT) screening for lung cancer has been proved to reduce lung cancer specific and overall mortality, but the cost-effectiveness of diverse screening strategies remained unclear., Methods: The comparative cost-effectiveness analysis used a Markov state-transition model to assess the potential effect and costs of the screening strategies incorporating PRS or not. A hypothetical cohort of 300,000 heavy smokers entered the study at age 50-74 years and were followed up until death or age 79 years. The model was run with a cycle length of 1 year. All the transition probabilities were validated and the performance value of PRS was extracted from published literature. A societal perspective was adopted and cost parameters were derived from databases of local medical insurance bureau. Sensitivity analyses and scenario analyses were conducted., Results: The strategy incorporating PRS was estimated to obtain an ICER of CNY 156,691.93 to CNY 221,741.84 per QALY gained compared with non-screening with the initial start age range across 50-74 years. The strategy that screened using LDCT alone from 70-74 years annually could obtain an ICER of CNY 80,880.85 per QALY gained, which was the most cost-effective strategy. The introduction of PRS as an extra eligible criteria was associated with making strategies cost-saving but also lose the capability of gaining more LYs compared with LDCT screening alone., Conclusion: The PRS-based conjunctive screening strategy for lung cancer screening in China was not cost-effective using the willingness-to-pay threshold of 1 time Gross Domestic Product (GDP) per capita, and the optimal screening strategy for lung cancer still remains to be LDCT screening for now. Further optimization of the screening modality can be useful to consider adoption of PRS and prospective evaluation remains a research priority., (© 2024. The Author(s).)

Background: The m6A modified demethylase FTO affects the progression of gastric cancer (GC), and the role mechanism of FTO in GC is still unclear. We, here, explored the role of FTO and unrevealed the mechanisms of its function in GC., Methods: The expression and clinical prognosis of FTO in GC were examined via UALCAN and GEPIA online databases. Effect of FTO shRNA on GC cellular malignant phenotype were proved by CCK-8, Transwell, Wound healing assay and Flow cytometric assay. RNA-sequencing data of FTO depleted AGS cells were downloaded to analyze differentially expressed genes of FTO downstream. The GO and KEGG pathway enrichment were performed for the DEGs by DAVID. RT-qPCR and RIP-qPCR assay were applied to verify the MOXD1 mRNA and methylated mRNA in FTO shRNA group. The expression and clinical prognosis of MOXD1 in GC were explored via UALCAN, GEPIA and Kaplan-Meier plotter. The role and mechanism and of MOXD1 in GC cell lines were detected and analyzed., Results: The expression of FTO was found to be elevated in GC tissues compared with normal tissues, and worse survival were strongly related to high expression of FTO in GC. FTO silencing suppressed the proliferation, migration and promoted apoptosis of GC cells. A total of 5856 DEGs were obtained in between NC and FTO depleted AGS cell groups, and involved in the cancer related pathways. Here, FTO targets MOXD1 mRNA and promotes its expression via m6A methylation. MOXD1 upregulation was associated to poor prognosis of GC. MOXD1 silencing suppressed the malignant phenotype of GC cells. MOXD1 activated cancer -related signaling pathway (MAPK, TGF-β, NOTCH and JAK/STAT)., Conclusions: Our study demonstrated that FTO silencing decreased MOXD1 expression to inhibit the progression of GC via m6A methylation modification. FTO/MOXD1 may be potential targets for the treatment and prognosis of GC., (© 2024. The Author(s).)

Background: The first local outbreak of Delta Variant B.1.617.2 COVID-19 of China occurred in Guangzhou city, south China, in May 2021. This study analyzed the transmission chains and local cluster characteristics of this outbreak, intended to provide information support for the development and adjustment of local prevention and control strategies., Methods: The transmission chains and local cluster characteristics of 161 local cases in the outbreak were described and analyzed. Incubation period, serial interval and generation time were calculated using the exact time of exposure and symptom onset date of the cases. The daily number of reported cases and the estimated generation time were used to estimate the effective reproduction number (Rt)., Results: We identified 7 superspreading events who had more than 5 next generation cases and their infected cases infected 70.81%(114/161) of all the cases transmission. Dining and family exposure were the main transmission routes in the outbreak, with 29.19% exposed through dining and 32.30% exposed through family places. Through further analysis of the outbreak, the estimated mean incubation period was 4.22 (95%CI: 3.66-4.94) days, the estimated mean generation time was 2.60 (95%CI: 1.96-3.11) days, and the estimated Rt was 3.29 (95%CI: 2.25-5.07)., Conclusions: Classification and dynamically adjusted prevention and control measures had been carried out according to analysis of transmission chains and epidemical risk levels, including promoting nucleic acid screening at different regions and different risk levels, dividing closed-off area, controlled area according to the risk of infection, raising the requirements of leaving Guangzhou. By the above control measures, Guangzhou effectively control the outbreak within 28 days without implementing a large-scale lockdown policy., (© 2023. The Author(s).)

Introduction: Recently, studies on behavioral tic suppression techniques have gained popularity as opposed to pharmacological alternatives that often have potentially dangerous side effects. Differential Reinforcement of Other Behaviors therapy (DRO) is one such behavioral technique whose efficacy in tic suppression has been experimentally demonstrated albeit in studies with very few patients, and lacking statistical power. Here, we conducted a meta-analysis of these studies to improve their overall power and explore whether DRO intervention is really effective for tic suppression., Materials and Methods: PubMed, Embase, PsycINFO, and Cochrane Library were searched from inception to August 30, 2023. Only original interventional studies that examined the efficacy of DRO for tic suppression were included., Results: A total of 8 no control interventional studies involving 79 children with tic disorders were recruited. Most of the children had moderate tic severity. The pooled mean Yale Global Tic Severity Scale (YGTSS) score was 24.64 (95% CI: 21.99 - 30.12, p =  < 0.00001, I 2  = 87%). In terms of efficacy of the DRO technique for tic suppression, the results showed that DRO was effective in reducing tic frequency among the children. The pooled standardized mean difference (SMD) was -10.25 (95% CI: -14.71 - -5.79, p =  < 0.00001) with I 2  = 94%., Conclusion: In conclusion, this study revealed that DRO is potentially an effective tic suppression technique for temporarily managing tic disorder. It also showed that DRO could be employed for both moderate and severe tic disorders. However, the technique bears crucial limitations that limit its implementation outside of experimental settings. More studies are needed to address these limitations and improve its applicability in the real world., (© 2023. The Author(s).)