Protein arginine methyltransferase 5 (PRMT5) acts as an oncogene in liver cancer, yet its roles and in-depth molecular mechanisms within the liver cancer immune microenvironment remain mostly undefined. Here, we demonstrated that disruption of tumor-intrinsic PRMT5 enhances CD8⁺ T-cell-mediated antitumor immunity both in vivo and in vitro. Further experiments verified that this effect is achieved through downregulation of the inhibitory immune checkpoint molecule, fibrinogen-like protein 1 (FGL1). Mechanistically, PRMT5 catalyzed symmetric dimethylation of transcription factor 12 (TCF12) at arginine 554 (R554), prompting the binding of TCF12 to FGL1 promoter region, which transcriptionally activated FGL1 in tumor cells. Methylation deficiency at TCF12-R554 residue downregulated FGL1 expression, which promoted CD8⁺ T-cell-mediated antitumor immunity. Notably, combining the PRMT5 methyltransferase inhibitor GSK591 with PD-L1 blockade efficiently inhibited liver cancer growth and improved overall survival in mice. Collectively, our findings reveal the immunosuppressive role and mechanism of PRMT5 in liver cancer and highlight that targeting PRMT5 could boost checkpoint immunotherapy efficacy.

OBJECTIVES: To investigate the efficacy of Ag₂Se nanoparticles for eliminating intracellular Porphyromonas gingivalis (P. gingivalis) in esophageal cancer and examine the effect of P. gingivalis clearance on progression of esophageal cancer. METHODS: Ag₂Se nanoparticles were synthesized via a chemical synthesis method. The effects of Ag₂Se nanoparticles on P. gingivalis viability and colony-forming ability were assessed using fluorescence staining and colony formation assays. In a mouse model bearing subcutaneous murine esophageal cancer cell allograft with P. gingivalis infection, the effect of treatment with Ag₂Se nanoparticles on the abundance of P. gingivalis in the tumor tissues was quantified using RNAscope in situ hybridization and quantitative polymerase chain reaction (qPCR), and the changes in tumor volume were monitored. The biosafety of Ag₂Se nanoparticles was assessed by examining liver and kidney functions and pathological changes in the major organs of the mice. RESULTS: Transmission electron microscopy revealed that the synthesized Ag₂Se nanoparticles were uniformly dispersed spherical particles with a diameter around 50 nm. In vitro experiments demonstrated that exposure to Ag₂Se nanoparticles significantly reduced the viability and clonal proliferation capacity of P. gingivalis in a dose-dependent manner. In the tumor-bearing mice, treatment with Ag₂Se nanoparticles significantly reduced the abundance of P. gingivalis in tumor tissues and suppressed tumor cell proliferation. No significant damages to the liver and kidney functions or the major organs were observed in Ag₂Se nanoparticle-treated mice, demonstrating good biocompatibility of Ag₂Se nanoparticles. CONCLUSIONS Ag₂Se nanoparticles exhibit significant bactericidal and inhibitory effects against P. gingivalis, and can effectively eliminate intracellular P. gingivalis to suppress the growth of esophageal cancer allograft in mice, suggesting the potential of Ag₂Se nanoparticles in the treatment of esophageal cancer.
Animals ; Porphyromonas gingivalis/drug effects* ; Mice ; Esophageal Neoplasms/pathology* ; Nanoparticles ; Metal Nanoparticles ; Bacteroidaceae Infections ; Cell Line, Tumor

OBJECTIVE: To investigate the potential mechanisms of sepsis pathogenesis in intensive care unit (ICU), with a specific focus on the role of skin microbiota, and to evaluate the causal relationships between skin microbiota and ICU sepsis using Mendelian randomization (MR). METHODS: A two-sample MR analysis was performed using skin microbiota genome-wide association study (GWAS) summary data from German population cohorts as exposures, combined with ICU sepsis susceptibility and 28-day mortality GWAS summary data from the IEU OpenGWAS database as outcomes. The primary causal effect estimates were generated using the inverse variance weighted (IVW) method, supplemented by validation through MR-Egger and weighted median approaches. Heterogeneity and pleiotropy tests, along with sensitivity analyses, were conducted to evaluate the robustness of the results. RESULTS: Regarding risk of ICU sepsis, IVW analysis showed that order Pseudomonadales [odds ratio (OR) = 0.93, 95% confidence interval (95%CI) was 0.88-0.98], family Flavobacteriaceae (OR = 0.93, 95%CI was 0.90-0.96), and genus Acinetobacter (OR = 0.96, 95%CI was 0.93-0.99) were significantly negatively correlated with the risk of ICU sepsis (all P < 0.05). There was a significant positive correlation between the risk of ICU sepsis and the presence of β-Proteobacteria (OR = 1.05, 95%CI was 1.00-1.11) and Actinobacteria (OR = 1.05, 95%CI was 1.00-1.11), both P < 0.05. Regarding 28-day mortality of ICU sepsis, IVW analysis showed that phylum Bacteroidetes (OR = 0.92, 95%CI was 0.86-0.99), family Streptococcaceae (OR = 0.92, 95%CI was 0.85-0.98), family Flavobacteriaceae (OR = 0.90, 95%CI was 0.83-0.97), genus Streptococcus (OR = 0.92, 95%CI was 0.86-0.99), ASV016 [Enhydrobacter] (OR = 0.92, 95%CI was 0.87-0.98), and ASV042 [Acinetobacter] (OR = 0.92, 95%CI was 0.88-0.97) were significantly negatively correlated with the 28-day mortality of ICU sepsis (all P < 0.05); family Moraxellaceae (OR = 1.09, 95%CI was 1.00-1.18) and ASV008 [Staphylococcus] (OR = 1.08, 95%CI was 1.03-1.14) was significantly positively correlated with the 28-day mortality of ICU sepsis (both P < 0.05). Sensitivity analysis and MR-PRESSO showed no heterogeneity, pleiotropy, or horizontal pleiotropy between skin microbiota and ICU sepsis risk and 28-day mortality rate. Analysis of confounding factors showed that single nucleotide polymorphisms (SNPs) associated with relevant skin bacteria could independently and causally affect the risk of ICU sepsis or ICU sepsis related mortality rate, independent of other confounding factors. The Steiger test results indicated that the established causal relationship was not due to reverse causality. CONCLUSIONS Skin microbiota composition may influence both sepsis susceptibility and 28-day mortality in ICU settings. Family Flavobacteriaceae demonstrated protective effects against sepsis onset and mortality. These findings provide new perspectives for early detection and management strategies.
Humans ; Sepsis/mortality* ; Intensive Care Units ; Mendelian Randomization Analysis ; Microbiota ; Skin/microbiology* ; Genome-Wide Association Study ; Risk Factors ; Skin Microbiome

Bone grafting is a primary method for treating bone defects. Among various graft materials, xenogeneic bone substitutes are widely used in clinical practice due to their abundant sources, convenient processing and storage, and avoidance of secondary surgeries. With the advancement of domestic production and the limitations of imported products, an increasing number of bone filling or grafting substitute materials isentering clinical trials. Relevant experts have drafted this consensus to enhance the management of medical device clinical trials, protect the rights of participants, and ensure the scientific and effective execution of trials. It summarizes clinical experience in aspects, such as design principles, participant inclusion/exclusion criteria, observation periods, efficacy evaluation metrics, safety assessment indicators, and quality control, to provide guidance for professionals in the field.
Humans ; Bone Substitutes/therapeutic use* ; Randomized Controlled Trials as Topic/methods* ; Consensus ; Bone Transplantation ; Research Design

To analyze the effects of tooth brushing frequency on blood indicators among adolescents and to preliminarily explore the effects of tooth brushing frequency on general health.

Oral health is closely related to systemic health. Common chronic oral diseases, periodontitis and periapical inflammation for example, not only affect the health of oral soft and hard tissues including the alveolar bone and gums, but may also cause changes in systemic conditions such as chronic low-grade inflammation, elevated oxidative stress levels, and dysbiosis of the microbiota. These changes in systemic health can exacerbate the progression of obesity. Therefore, through proactive oral health interventions such as maintaining good oral hygiene habits, modifying dietary structures, and undergoing oral examinations, it is possible to effectively prevent and alleviate inflammatory oral diseases, and actively intervene in obesity. This article delves into the impact of inflammatory oral diseases on obesity and their underlying mechanisms, defines the concept of "oral proactive healthcare", and systematically summarizes their preventive and therapeutic effects on inflammatory oral diseases, thereby demonstrating the potential of improving obesity through proactive oral health strategies.

Objective:To analyze the distribution and genomic characteristics of SARS-CoV-2 variants isolated from imported cases of COVID-19 in Sichuan Province from December 2022 to January 2023.Methods:This study selected 108 nasal and throat swab samples with fluorescence threshold (Ct)≤32 that were collected from imported COVID-19 cases in Sichuan Province from December 2022 to January 2023. Targeted amplification and Illumina NextSeq? 2000 system were used for whole-genome sequencing. Nextclade and Pangolin online platforms were used to determine the virus genotypes and analyze the mutation loci. A phylogenetic tree was constructed using maximum likelihood.Results:A total of 55 SARS-CoV-2 whole genome sequences with coverage of >95% were obtained, and all of the strains were Omicron variants. Compared with the sequence of reference strain Wuhan-Hu-1, the median number of nucleotide mutation sites of 21L, 22B, 22D, 22E, and 22F genotypes were 93, 75, 92, 78, and 92, and the median number of amino acid mutation sites were 68, 53, 68, 69, and 65, respectively. From December 2022 to January 2023, the predominant circulating SARS-CoV-2 variants from imported cases in Sichuan Province were BA.5.2 (10.91%, 6/55), XBB.1.1 (9.10%, 5/55), BF.7.14 (7.23%, 4/55), and BQ.1.1 (7.23%, 4/55).Conclusions:The distribution of SARS-CoV-2 variants can reflect the global epidemic trend to a certain extent. However, it is different from the distribution of local circulating variants in the Chinese mainland. The XXB variants with transmission advantages can be detected in large numbers of inbound travelers before becoming the predominant circulating strains in the Chinese mainland.

Objective:To monitor the changes in donor gene chimerism ratio after allogeneic hematopoietic stem cell transplantation (allo-HSCT) in patients with severe beta-thalassemia using third-generation sequencing, and to explore the value of this technology in monitoring the proportion of donor genes chimerism in the early stage of postoperative allo-HSCT.Methods:Case analysis. Three beta-thalassemia patients at the First Affiliated Hospital of Guangxi Medical University during June-July 2022 who had undergone allo-HSCT with genotypes IVS-Ⅱ-654/CD41-42, IVS-Ⅱ-654/IVS-Ⅱ-654 and CD41-42/CD41-42 were included in this study. "Visual" analysis of the readouts of recipient DNA using third generation sequencing was used to monitor the genetic chimerism of the donor DNA and to compare with Sanger sequencing results. Post-transplantation follow-up was performed in the three patients to monitor the blood statistics and assess their implantation status and hematopoietic reconstitution.Results:The results of donor DNA chimerism status after allo-HSCT in the three patients detected by third generation sequencing were consistent with the Sanger sequencing results. The chimeric state of donor DNA gradually shifted to complete donor gene chimerism as the number of days after transplantation increased. Recipient 1 had 95.5% and 100% donor DNA chimerism at 10 and 20 d post-transplantation, respectively; recipient 2 had 100% donor DNA chimerism at 30 and 40 d post-transplantation; recipient 3 had 69.5% donor DNA chimerism at 1 d post-transplantation, and 100% donor DNA chimerism at 10 and 20 d post-transplantation. All patients achieved full donor gene chimerism within 30 d post-transplantation. Stable implantation of granulopoiesis, platelets, and erythropoiesis with hematopoietic reconstitution were obtained in all 3 patients within 1 month after transplantation.Conclusions:In this study, we developed a new method to detect the chimerism ratio of donor DNA using third-generation sequencing technology, enabling us to monitor the gene chimerism status of donor DNA at an early stage.

AIM:To investigate the molecular mechanism of long noncoding RNA(lncRNA)SNHG1 in regu-lating ferroptosis to alleviate inflammation in CHME-5 human microglia induced by HIV-1 gp120 V3 loop.METHODS:CHME-5 human microglia were cultured in vitro,and were divided into 7 groups:blank group,random peptide group,gp120 V3 loop group(HIV-1 gp120 group),HIV-1 gp120+shCon group,HIV-1 gp120+SNHG1 sh2 group,HIV-1 gp120+SNHG1 sh2+ferrostatin-1(Fer-1;ferroptosis inhibitor)group,and HIV-1 gp120+SNHG1 sh2+EX527(Sirt1 in-hibitor)group.Normal CHME-5 cells were treated with random peptide or gp120 V3 loop for 24 h.After pretreatment of SNHG1 sh2 cells with inhibitors for 2 h,the cells were then treated with gp120 V3 loop for 24 h.The levels of inflammato-ry cytokines in the cell supernatants were detected by ELISA.Western blot was used to detect the protein expression levels of solute carrier family 7 member 11(SLC7A11),glutathione peroxidase 4(GPX4),Sirt1 and p53.Microplate reader was used to detect the levels of intracellular ferrous ion(Fe2+)and malondialdehyde(MDA).RESULTS:(1)The results of ELISA showed that the expression levels of tumor necrosis factor-α(TNF-α),interleukin-6(IL-6)and IL-1β in HIV-1 gp120 group were significantly higher than those in blank group(P<0.05).Compared with HIV-1 gp120 group,the ex-pression levels of inflammatory cytokines in HIV-1 gp120+SNHG1 sh2 group were significantly decreased(P<0.05).Compared with HIV-1 gp120+SNHG1 sh2 group,the expression levels of inflammatory factors in HIV-1 gp120+SNHG1 sh2+Fer-1 were significantly decreased(P<0.05),but those in HIV-1 gp120+SNHG1 sh2+EX527 group were significant-ly increased(P<0.01).(2)The results of Western blot showed that compared with blank group,the expression levels of ferroptosis-related proteins SLC7A11 and GPX4 in HIV-1 gp120 group were significantly down-regulated(P<0.01).Com-pared with HIV-1 gp120 group,the expression levels of SLC7A11 and GPX4 in HIV-1 gp120+SNHG1 sh2 group were sig-nificantly up-regulated(P<0.01).Compared with HIV-1 gp120+SNHG1 sh2 group,the expression levels of SLC7A11 and GPX4 in HIV-1 gp120+SNHG1 sh2+Fer-1 group were significantly up-regulated(P<0.05),but the expression levels of SLC7A11 and GPX4 in HIV-1 gp120+SNHG1 sh2+EX527 group were significantly down-regulated(P<0.01),and the expression level of p53 was significantly up-regulated(P<0.05).(3)Compared with blank group,the levels of Fe2+and MDA in HIV-1 gp120 group were significantly increased(P<0.05).Compared with HIV-1 gp120 group,the levels of Fe2+and MDA in HIV-1 gp120+SNHG1 sh2 group were significantly decreased(P<0.01).Compared with HIV-1 gp120+SNHG1 sh2 group,Fe2+and MDA in HIV-1 gp120+SNHG1 sh2+Fer-1 group were significantly decreased(P<0.05),but those in HIV-1 gp120+SNHG1 sh2+EX527 group was significantly increased(P<0.05).CONCLUSION:Knockdown of SNHG1 can attenuate the inflammation in microglia induced by HIV-1 gp120 V3 loop,which may be achieved by regulating ferrop-tosis-related signaling molecules through the Sirt1/p53 signaling pathway.

Objective To analyze the influencing factors of poor anal function after laparoscopic intersphincteric resection(Lap-ISR)for extremely low rectal cancer,and to construct and verify a prediction model based on this model,in order to provide guidance for improving the anal function of patients with extremely low rectal cancer after Lap-ISR.Method A total of 127 patients with extremely low rectal cancer who underwent Lap-ISR in Taizhou People's Hospital from June 2020 to June 2022 were retrospectively selected.Patients were followed up for 12 months after surgery,and postoperative anal function was evaluated by the anal incontinence score(Wexner).According to Wexner score,the patients were divided into good anal function group(106 cases)and poor anal function group(21 cases).The clinical data of patients were collected and the risk factors affecting postoperative poor anal dysfunction were analyzed,and a Nomogram model was constructed to predict the risk of postoperative anal dysfunction in patients after Lap-ISR,and the receiver operating characteristic curve(ROC)was drawn.The area under the curve(AUC)was used to analyze the predictive efficacy of the prediction model for poor anal dysfunction after Lap-ISR.Result The incidence of anal dysfunction after Lap-ISR in patients with extremely low rectal cancer was 16.54％(21/127).Univariate analysis showed that there was no significant difference in gender,age,body mass index,clinical stage,combined underlying diseases,operation time,intraoperative blood loss,anastomosis method,and the distance from the lower edge of the tumor to the dentate line between the two groups(P＞0.05).The proportion of tumor diameter≥5 cm,the proportion of neoadjuvant chemotherapy,the distance between anastomosis and anal verge＜2 cm,and the proportion of anastomotic leakage in the anal dysfunction group were higher than those in the good anal function group(P＜0.05).Cox multivariate regression analysis showed that tumor diameter≥5 cm(OR=5.124),neoadjuvant chemotherapy(OR=5.761)and anastomotic leakage(OR=6.881)were risk factors for postoperative anal function(P＜0.05).Wexner score of patients with tumor diameter ≥5 cm was higher than that of patients with tumor diameter＜5 cm,Wexner score of patients with neoadjuvant chemotherapy was higher than that of patients without neoadjuvant chemotherapy,and Wexner score of patients with anastomotic leakage was higher than that of patients without anastomotic leakage(P＜0.05).Internal validation of Bootstrap method showed that the C-index was 0.785(95％CI:0.692-0.851).The results of ROC curve showed that the sensitivity and specificity of the nomogram model in predicting postoperative poor anal function of patients were 85.70％and 88.70％,respectively,and the AUC was 0.895(95％CI:0.795-0.984).Conclusion Tumor diameter,neoadjuvant chemotherapy and anastomotic leakage are risk factors for poor anal function after Lap-ISR in patients with extremely low rectal cancer.The nomogram risk prediction model based on the above risk factors has a good risk efficiency in evaluating the risk of postoperative anal dysfunction in patients.