BACKGROUND: Pre-transplant exposure to immune checkpoint inhibitors (ICIs) significantly increases the risk of allograft rejection after liver transplantation (LT); however, whether ICI-related rejection leads to increased graft loss remains controversial. Therefore, this study aimed to investigate the association between ICI-related allograft rejection and perioperative graft loss. METHODS: This was a retrospective analysis of adult liver transplant recipients with early biopsy-proven T-cell-mediated rejection (TCMR) at Liver Transplantation Center of Sun Yat-sen Memorial Hospital from June 2019 to September 2024. The pathological features, clinical characteristics, and perioperative graft survival were analyzed. RESULTS: Twenty-eight patients who underwent early TCMR between June 2019 and September 2024 were included. Based on pre-LT ICI exposure, recipients were categorized into ICI-related TCMR (irTCMR, n = 12) and conventional TCMR (cTCMR, n = 16) groups. Recipients with irTCMR had a higher median Banff rejection activity index (RAI) (6 vs . 5, P = 0.012) and more aggressive tissue damage and inflammation. Recipients with irTCMR showed higher proportion of treatment resistance, achieving a complete resolution rate of only 8/12 compared to 16/16 for cTCMR. Graft loss occurred in 5/12 of irTCMR recipients within 90 days after LT, with no graft loss in cTCMRs recipients. Cox analysis demonstrated that irTCMR with an ICI washout period of <30 days was an independent risk factor for perioperative graft loss (hazard ratio [HR], 6.540; 95% confidence interval [CI], 1.067-40.067, P = 0.042). CONCLUSION IrTCMR is associated with severe pathological features, increased resistance to treatment, and higher graft loss in adult liver transplant recipients.
Humans ; Liver Transplantation/adverse effects* ; Male ; Female ; Middle Aged ; Retrospective Studies ; Graft Rejection/immunology* ; Immune Checkpoint Inhibitors/therapeutic use* ; Adult ; T-Lymphocytes/drug effects* ; Graft Survival/immunology* ; Aged

Cancer immunotherapy has emerged as a promising strategy. However, low response rates and immune-related side effects have plagued immunotherapy. Metallic nanoparticles, utilizing metals as their framework, are gaining prominence in cancer immunotherapy. Metal ions have shown the ability to modulate immune status by activating the cGAS-STING pathway and inducing immunogenic cell death (ICD), thereby enabling multidimensional activation of immunotherapy. Metallic nanoparticles offer significant advantages in cancer immunotherapy, leading to their increasing use in enhancing therapeutic outcomes. In view of the ever-increasing research on metallic nanoparticles, this review presents the construction, characterization, and enhanced cancer immunotherapeutic effects of different types of metal nanosystems from the perspective of the immunoregulatory mechanisms of metal ions. We delve into the current limitations and future directions of metallic nanoparticles in this rapidly evolving field. To the best of our knowledge, this review offers the most up-to-date and systematic analysis of metallic nanoparticles in immunotherapeutic applications. It is anticipated that this review of metallic nanoparticles will inspire a more refined and intelligent design of metallic nanoparticles for future research, paving the way for advancing their clinical applications.

An ideal dermal filler should integrate filling, repair, and anti-aging effects, with immediate tissue augmentation, slow degradation, and progressive stimulation of collagen regeneration. However, commonly used hyaluronic acid (HA) hydrogels, while effective for rapid filling, suffer from limited duration of support, weak cell adhesion, and an inability to promote collagen regeneration. Silk fibroin (SF), a natural protein from silkworm cocoons, is known for its excellent cell adhesion and collagen-stimulating abilities. However, its limited gelation capability restricts its potential application as a standalone injectable hydrogel. Based on a complementary strategy, this study combines the rapid gelling properties of HA with the collagen regenerative properties of SF to create a co-crosslinked HA-SF hydrogel. The composite hydrogel merges HA's rapid filling effect with SF's strong tissue adhesion and collagen-stimulating abilities. The formulation, physicochemical properties, degradation, biocompatibility, and filling effects of the HA-SF hydrogel were systematically investigated. HA-SF hydrogel exhibits excellent mechanical properties and ensures long-term support while maintaining injectability. Interestingly, after intradermal injection in the UVB-induced photoaging model, HA-SF hydrogel not only enhances hydrogel-cell interaction but also continues to stimulate collagen regeneration, especially type III collagen. This dual action achieves the biological effects of repair and anti-aging while maintaining the filling effect. Proteomic analysis confirms that repair and anti-aging effects are enhanced by the regulation of skin fibroblasts and modulation of amino acid and lipid metabolism. This composite hydrogel holds strong promise for clinical applications, offering a safer, long-lasting, and more natural injectable filler that combines filling, repair, and anti-aging into one system.

Objective:To evaluate the safety of neoadjuvant therapy with pembrolizumab combined with 5-fluorouracil (5-FU) and cisplatin in patients with advanced temporal bone squamous cell carcinoma (TBSCC), and its impact on tumor response rate and disease-free survival (DFS).Methods:This prospective, single-arm, open-label clinical study enrolled patients with advanced (Stage Ⅲ/Ⅳ) TBSCC from Sun Yat-sen Memorial Hospital. Patients received 2-3 cycles of neoadjuvant therapy with pembrolizumab, 5-FU, and cisplatin, followed by definitive surgery. Postoperatively, patients received 6 cycles of pembrolizumab combined with radiotherapy. The primary endpoint was the 2-year disease-free survival (DFS) rate. Secondary endpoints included objective response rate (ORR) and safety indicators. Survival analysis was performed using the Kaplan-Meier method. Adverse events (AE) were assessed using the National Cancer Institute′s Common Terminology Criteria for Adverse Events (CTCAE), version 5.0. Statistical analyses were conducted using SPSS software, version 22.0.Results:From August 2021 to April 2024, 16 patients with advanced TBSCC were enrolled (13 males and 3 females), with a median age of 54 years and a median follow-up time of 2.32 years. Following neoadjuvant therapy, the objective response rate (ORR) was 64.3% (9/14), and the disease control rate (DCR) was 92.9% (13/14). The 2-year DFS rate was 86.6%. Common treatment-related adverse events (TRAE) included leukopenia (56.3%, 9/16), nausea and vomiting (50.0%, 8/16), diarrhea, oral mucositis, and elevated liver function tests (25.0%, 4/16). One patient (6.25%) experienced a grade 3 adverse event.Conclusion:Neoadjuvant pembrolizumab-chemotherapy significantly enhances objective response rate and disease-free survival in advanced TBSCC.

Objective:To investigate the trends in insulin resistance, as represented by the triglyceride-glucose index (TyG index), among Chinese adult residents from 2010 to 2018 and to explore influencing factors.Methods:China Chronic Disease and Risk Factor Surveillance was conducted in 2010, 2013, and 2018, using a multi-stage stratified cluster random sampling method across all 31 provinces (autonomous regions and municipalities) in China. This study sampled 98 712 adults in 2010, 176 534 adults in 2013, and 184 876 adults in 2018, all aged ≥18 years, totaling 406 933 participants. Individuals with a TyG index > P75 were classified as having insulin resistance. The mean TyG index and the prevalence of insulin resistance were calculated for different years, sexes, age groups, provinces (autonomous regions and municipalities), and subgroups for 2018. Linear and logistic regression models were used to test trends in means and rates over time, and multivariate logistic regression models were conducted to analyze potential factors associated with insulin resistance. All analyses were adjusted for complex sampling weights based on the study design. Results:From 2010 to 2018, the mean TyG index among Chinese adults increased from 8.44±0.63 to 8.70±0.64, with significant upward trends observed across different age groups, sexes, and urban-rural residencies (all P<0.001). The mean TyG index was higher among males, urban residents, and those aged 45-59. There were significant differences in the mean TyG indices and prevalence of insulin resistance across provinces (autonomous regions and municipalities) (all P<0.05). Higher insulin resistance prevalence was independently associated with being male, aged ≥45 years, living in urban areas, excessive alcohol consumption, and insufficient physical activity (all P<0.05). Conclusions:From 2010 to 2018, the level of insulin resistance, as indicated by the TyG index, showed an increasing trend among Chinese adults. Males, individuals aged ≥45 years, urban residents, and individuals with unhealthy lifestyles such as excessive alcohol consumption or insufficient physical activity should be the focus of efforts to prevent and control metabolic diseases related to insulin resistance.

Objective To investigate the effect of NK cells on the proliferation of four kinds of colorec-tal cancer(CRC)lines,and to explore the feasibility of adoptive NK cell immunotherapy in the treatment of CRC so as to provide an experimental basis for the diagnosis and treatment of CRC.Methods Peripheral blood mononuclear cells were isolated by the Ficoll density gradient centrifuge method,which were in vitro in-duced to activate as the NK cells and amplified.The CCK-8 method was used to detect the effect of NK cells on the proliferation of CRC cell lines RKO,HCT15,HCT116 and LoVo.The inhibition rate of NK cells on CRC cell lines was statistically analyzed and compared.Results The inhibitory rate of NK cells against the same target cells was significantly different at different effect target ratios(P＜0.05).Under different num-ber of target cells(5 × 103 vs.1 × 104),the inhibitory rate of NK cells against RKO(effect-target ratio 0.4∶1),HCT15(effect-target ratio 0.4∶1 and 0.2∶1),HCT116(effect-target ratio 3.2∶1,1.6∶1,0.8∶1,0.4∶1 and 0.2∶1)and LoVo(effect-target ratio 1.6∶1,0.8∶1,0.4∶1,0.2∶1 and 0.1∶1)were significantly different(P＜0.05),while no statistical differences were found among other groups(P＞0.05).The effect-target ratio corresponding to the maximum inhibitory rate of NK cells against four CRC cell lines was 12.8∶1 under different target cell numbers.Conclusion Adoptive NK cell immunotherapy has an impor-tant significance for the early intervention and treatment of CRC,moreover 12.8∶1 may be a safe and effec-tive effect-target ratio.

Background and aims:Despite growing evidence linking pretransplant exposure to immune checkpoint inhibitors(ICIs)to increased allograft rejection risk after liver transplantation(LT),a lack of comparative studies to definitively establish the correlation between ICI exposure and adverse short-term outcomes after LT exists.This study aimed to analyze the impact of preoperative ICI exposure on short-term post-LT prognosis and allograft rejection risk.Methods:This retrospective cohort study included 121 recipients who underwent LT for hepatocellular carcinoma(HCC)between June 2019 and March 2023.The recipients were categorized into ICI(n=35)and non-ICI(n=86)exposure groups based on pretransplant ICI exposure.Demographics,clinical characteristics,and short-term outcomes were compared between the cohorts.Kaplan-Meier analysis evaluated the impact of ICI exposure on graft survival.Univariate and multivariate logistic regression models assessed the impact of patient characteristics on allograft rejection.Results:Recipients with or without ICI exposure exhibited comparable demographic baseline charac-teristics.The incidences of early allograft dysfunction and biliary and vascular complications were similar between both groups.Post-transplant infection incidence was 37.1％and 20.9％in the ICI and non-ICI groups,respectively(P=0.064).Allograft rejection rates were significantly higher in the ICI group than in the non-ICI group(22.9％vs.5.8％,P=0.015).The ICI group exhibited a higher 90-day post-transplant mortality rate than that of the non-ICI group(14.3％vs.2.3％,P=0.034).Logistic regression analyses demonstrated that allograft rejection independently correlated with 90-day post-transplant mortality,with ICI exposure being an independent risk factor for allograft rejection.In recipients with ICI exposure,a shorter interval between ICIs and LT(washout period)was significantly associated with a higher allograft rejection risk,with the optimal washout period identified as 21 days for predicting 90-day rejection-free survival(P=0.0001).Moreover,in recipients with allograft rejection,the peripheral CD4+/CD8+T cell ratio was much lower in the ICI group than in the non-ICI group.Conclusions:Pretransplant ICI exposure was an independent risk factor for allograft rejection and was significantly associated with 90-day post-transplant mortality after LT for HCC.A ≤21-day washout period was significantly associated with allograft rejection.Future multicenter studies with larger cohorts and prospective designs are essential to validate these findings,confirm causality,and establish standardized clinical guidelines for ICI use before transplantation.Trail registration:ClinicalTrials.gov NCT05913583.

Objective:To explore the relationship between gut microbiota and giant cell arteritis (GCA), and to identifyits potential therapeutic strategies.Methods:Gut microbiota data were obtained from the MiBioGen consortium genome-wide association study (GWAS), and GCA data were obtained from the FinnGen consortium public GWAS. Causal associations between gut microbiota and GCA were assessed using two-sample Mendelian randomization (MR) analyses, including inverse-variance weighted (IVW), weighted median, MR-Egger regression, simple mode, and weighted mode methods. Heterogeneity and horizontal pleiotropy were evaluated, and false positive results were excluded by using the Benjamini-Hochberg (BH) method of multiple hypothesis testing. All analyses were completed using the TwoSampleMR and MRPRESSO software packages (version 4.3.0) in R language. The analysis of the intestinal flora data, followed by conducting network pharmacology analysis were carried out by Cytoscape 3.9.1 and perform molecular docking verification was performed with AutoDock Vina software.Results:IVW simulations revealed 13 gut microbiota taxa were associated with GCA, of which Lachnospiraceae was significantly negatively associated with GCA risk[nSNP=16, OR(95% CI)=0.32(0.16, 0.63), β=-1.15, Se=0.35, P=0.001, FDR<0.05], and there was no heterogeneity (Cochran′s Q test, Q=13.42, P=0.490) as well as horizontal pleiotropy ( P=0.370). Further literature search and computer simulation docking analysis showed that genistein binds to MMP2 with a binding energy of -43.1 kJ/mol. Conclusion:Lachnospiraceae in the gut microbiota was is negatively associated with GCA, and genistein may be able to regulate the abundance of Lachnospiraceae through the MMP2 target to treat GCA, providing a new therapeutic approach for giant cell arteritis.

Objective:To investigate the effects of backward walking observational training combined with Soundsory cognitive training based on PASS (P: planning; A: attention; S: simultaneous; S:successive) theory on cognitive function, balance function and self-efficacy in elderly patients with post-stroke mild cognitive impairment (MCI).Methods:A randomized controlled trial was conducted. Elderly patients with post-stroke MCI admitted to the Department of Neurology, Affiliated Hospital of Jiangnan University from December 2022 to November 2023 were selected as the study objects by convenience sampling method. The patients were divided into control group and observation group by random number table. The patients in the control group implemented routine care and rehabilitation training, while the observation group were implemented backward walking observational training combined with Soundsory cognitive training based on the PASS theory. The Montreal Cognitive Assessment (MoCA), the Brunel Balance, and the Stroke Self-Efficacy Questionnaire (SSEQ) were used to evaluate the intervention effect before intervention, 2 weeks and 4 weeks of intervention, respectively.Results:A total of 116 elderly patients with post-stroke MCI were included, comprising 58 patients in the observation group (32 males and 26 females), aged (73.47 ± 7.10) years, and 58 patients in the control group (33 males and 25 females), aged (72.72 ± 8.37) years. Before intervention, there were no significant differences in the total scores of MoCA, SSEQ and Brunel Balance Scale between the 2 groups (all P>0.05). At 2 and 4 weeks of intervention, the total score of MoCA in the observation group were (20.10 ± 2.73), (22.98 ± 2.98) points, which were higher than those of the control group (18.24 ± 2.84), (20.47 ± 3.29) points, the differences were statistically significant ( t=3.61, 4.32, both P<0.05). The total score of SSEQ in the observation group were (49.97 ± 7.73), (54.98 ± 7.88) points, which were higher than those in the control group (46.50 ± 8.69), (51.59 ± 6.10) points, the differences were statistically significant ( t=2.27, 2.60, both P<0.05). At 4 weeks of intervention, the Brunel Balance Scale score in the observation group was 11(9, 11) points, which was higher than 10(8, 11) points in the control group, the difference was statistically significant ( Z=-2.00, P<0.05). Conclusions:Backward walking observational training combined with Soundsory cognitive training based on PASS theory can effectively improve cognitive and balance functions, and enhance self-efficacy in elderly patients with post-stroke MCI.

Objective:To investigate the trends in insulin resistance, as represented by the triglyceride-glucose index (TyG index), among Chinese adult residents from 2010 to 2018 and to explore influencing factors.Methods:China Chronic Disease and Risk Factor Surveillance was conducted in 2010, 2013, and 2018, using a multi-stage stratified cluster random sampling method across all 31 provinces (autonomous regions and municipalities) in China. This study sampled 98 712 adults in 2010, 176 534 adults in 2013, and 184 876 adults in 2018, all aged ≥18 years, totaling 406 933 participants. Individuals with a TyG index > P75 were classified as having insulin resistance. The mean TyG index and the prevalence of insulin resistance were calculated for different years, sexes, age groups, provinces (autonomous regions and municipalities), and subgroups for 2018. Linear and logistic regression models were used to test trends in means and rates over time, and multivariate logistic regression models were conducted to analyze potential factors associated with insulin resistance. All analyses were adjusted for complex sampling weights based on the study design. Results:From 2010 to 2018, the mean TyG index among Chinese adults increased from 8.44±0.63 to 8.70±0.64, with significant upward trends observed across different age groups, sexes, and urban-rural residencies (all P<0.001). The mean TyG index was higher among males, urban residents, and those aged 45-59. There were significant differences in the mean TyG indices and prevalence of insulin resistance across provinces (autonomous regions and municipalities) (all P<0.05). Higher insulin resistance prevalence was independently associated with being male, aged ≥45 years, living in urban areas, excessive alcohol consumption, and insufficient physical activity (all P<0.05). Conclusions:From 2010 to 2018, the level of insulin resistance, as indicated by the TyG index, showed an increasing trend among Chinese adults. Males, individuals aged ≥45 years, urban residents, and individuals with unhealthy lifestyles such as excessive alcohol consumption or insufficient physical activity should be the focus of efforts to prevent and control metabolic diseases related to insulin resistance.