5-Methoxytryptophan (5-MTP) is an endogenous tryptophan metabolite with anti-inflammatory and anti-fibrotic properties. Its clinical significance in acute myocardial infarction (AMI) and underlying mechanisms remain largely unknown. In a prospective cohort, 407 AMI patients undergoing successful percutaneous coronary intervention (PCI) were enrolled. Plasma 5-MTP was measured by ELISA. SYNTAX score was used to assess coronary artery disease complexity. In-hospital heart failure (HF) and 1-year major adverse cardiovascular events (MACE) were recorded. Associations were assessed using logistic/Cox regression, restricted cubic splines (RCS) and propensity score matching (PSM). In parallel, H9c2 cardiomyocytes were subjected to hypoxia/reoxygenation (H/R) and treated with 5-MTP (10 μM); cell viability, apoptosis and NF-κB pathway activation were evaluated. Primary rat cardiac fibroblasts were stimulated with TGF-β1 with or without 5-MTP; migration, α-SMA, collagen I and MMP-9 were measured. Plasma 5-MTP was inversely correlated with SYNTAX score (r = − 0.431, P < 0.001). Higher 5-MTP was independently associated with lower SYNTAX score (medium vs. low: OR 0.40, 95% CI 0.24–0.66, P < 0.001; high vs. low: OR 0.14, 95% CI 0.08–0.23, P < 0.001). Higher 5-MTP levels predicted reduced in-hospital HF (OR 0.20, 95% CI 0.08–0.52, P < 0.001) and 1-year MACE (HR 0.39, 95% CI 0.19–0.79, P = 0.009). RCS analyses confirmed a linear dose–response pattern across all outcomes (all P for nonlinear > 0.05). In vitro, 5-MTP attenuated H/R-induced cardiomyocyte apoptosis, suppressed IκBα phosphorylation, p65 nuclear translocation and reduced IL-1β, IL-6, TNF-α, MCP-1 and COX-2 expression. In fibroblasts, 5-MTP inhibited TGF-β1-induced migration, α-SMA/collagen I expression and MMP-9 secretion. Low plasma 5-MTP is independently associated with severe coronary artery disease, in-hospital HF and worse 1-year outcomes after AMI. Its cardioprotective effects may be mediated, at least in part, through inhibition of NF-κB-driven inflammation in cardiomyocytes and suppression of TGF-β1-induced fibroblast activation. These findings suggest that 5-MTP may serve as a prognostic biomarker and a potential therapeutic target in AMI, pending further validation.

Liver xenotransplantation has the potential to address the global shortage of donor organs; however, coagulation dysregulation remains a predominant barrier to long-term liver xenograft survival. In this study, orthotopic liver xenotransplantation was performed using a 10-gene-edited (GTKO/CMAHKO/β4GalNT2KO/hCD46/hCD55/hCD59/hTBM/hCD39/hEPCR/hCD47) porcine donor liver transplanted into a nonhuman primate recipient. Independent of graft function, which remained stable, an unexpected interruption of the oxygen supply on POD 3 triggered a terminal event, leading to death on POD 4. Despite technical success, rapid consumptive coagulopathy developed within 24 h, characterized by severe thrombocytopenia, fibrinogen depletion, and prolongation of coagulation times. Declining plasma von Willebrand factor activity (vWF) and reduced graft vWF expression accompanied these changes. Integrated longitudinal hematologic monitoring, histopathology, transcriptomics, and proteomics were used to define early graft injury. Histological analysis demonstrated microvascular injury with macrophage and B cell infiltration and immunoglobulin deposition, without T cell involvement. Molecular profiling revealed a dominant recipient innate immune response enriched for macrophage-mediated phagocytosis, adhesion, and proteasome pathways, alongside activation of complement and coagulation cascades. Concurrently, the donor graft showed downregulation of key metabolic enzymes, indicating early metabolic stress. These findings indicate that macrophage-driven innate immunity and systemic coagulation exhaustion represent principal early challenges in liver xenotransplantation, highlighting the complement-coagulation axis and macrophage activation as critical therapeutic targets for improving xenograft outcomes. However, given the intense induction immunosuppression and early severe systemic inflammation, these multi-omics findings reflect a complex interplay of graft injury and pharmacological intervention, requiring cautious interpretation.

OBJECTIVE:Keloids are pathological scars characterized by excessive collagen deposition that occurs during wound healing after skin injury. Keloid fibroblasts (KF) and keloid keratinocytes (KK) are key contributors to keloid pathogenesis. Although adipose-derived mesenchymal stromal cells (ASCs) have been investigated for keloid therapy, their therapeutic potential and underlying mechanisms require further elucidation. This study aimed to characterize the therapeutic potential of ASCs for human keloid management. METHODS:Molecular profiles associated with keloid pathogenesis were characterized through integrative analyses, including gene expression profiling, functional annotation, protein-protein interaction mapping, and hub gene identification. Single-cell RNA sequencing (scRNA-seq) was used to identify ASC subpopulations with inhibitory effects on keloid development. The therapeutic efficacy of these subpopulations was subsequently assessed in a miniature pig model of hypertrophic scar. RESULTS:Upregulation of hub genes such as NOG and IL6 was strongly associated with KF formation, whereas increased expression of APP and NOTCH1 was implicated in KK development. Functional scRNA-seq analysis identified ASC subpopulations capable of inhibiting the development of KF, KK, or both through molecular interactions with these hub genes. Administration of porcine ASCs enriched in the identified inhibitory subpopulations effectively prevented hypertrophic scar formation in the miniature pig model. CONCLUSION:This study delineated key molecular signatures underlying keloid formation and identified ASC subpopulations with targeted inhibitory activity against pathological cell types involved in keloid development. These findings support the potential application of ASC-based interventions for prophylaxis and treatment of hypertrophic scarring in humans.

Background Low-weight grafts from young pediatric donors are considered a risk factor for surgical complications. However, the limited availability of age- and size-matched organs has prompted a re-evaluation of low-weight grafts from young pediatric donors. Methods From January 1, 2019, to December 31, 2023, 52 pediatric liver transplants receiving young pediatric donors (<= 2 years old) with low body weight (<= 15 kg) were performed. According to graft weights (GW), recipients were divided into two groups: Group 1 (GW <= 150 g) and Group 2 (GW: 151-400 g), to compare donor and recipient characteristics, postoperative complications, and graft and recipient survival. Results Group 1 donors were younger (5.4 +/- 4.2 vs. 14.4 +/- 4.7 months, p < 0.001), smaller in body length (58.0 +/- 8.7 vs. 75.7 +/- 8.5 cm, p < 0.001), and lighter in weight (6.2 +/- 2.8 vs. 10.0 +/- 2.0 kg, p < 0.001) compared to Group 2. There were no significant differences in preoperative laboratory tests between groups, and the incidences of vascular complications were also similar between the groups. The 1- and 3-year patient survival rates were 100% and 100% in Group 1 vs. 97% and 97% in Group 2, respectively. The 1- and 3-year graft survival rates were 100% and 91% in Group 1 vs. 97% and 97% in Group 2, with no significant differences. The smallest graft, weighing 86 g, yielded an ideal outcome for the recipient. Conclusions Low-weight grafts from young pediatric donors can achieve excellent outcomes and represent a potential strategy to increase donor availability for well-selected pediatric recipients.

Large language models (LLMs) hold great promise for assisting clinical interviews due to their fluent interactive capabilities and extensive medical knowledge. However, the lack of high-quality interview dialogue data and widely accepted evaluation methods has significantly impeded this process. So we propose CliniChat, a framework that integrates multi-source knowledge to enable LLMs to simulate real-world clinical interviews. It consists of two modules: Clini-Recon and Clini-Eval, each responsible for reconstructing and evaluating interview dialogues, respectively. By incorporating three sources of knowledge, Clini-Recon transforms clinical notes into systematic, professional, and empathetic interview dialogues. Clini-Eval combines a comprehensive evaluation metric system with a two-phase automatic evaluation approach, enabling LLMs to assess interview performance like experts. We contribute MedQA-Dialog, a high-quality synthetic interview dialogue dataset, and CliniChatGLM, a model specialized for clinical interviews. Experimental results demonstrate that CliniChatGLM's interview capabilities undergo a comprehensive upgrade, particularly in history-taking, achieving state-of-the-art performance.

4141 Background: Transarterial chemoembolization (TACE) combined with immunotherapy and anti-angiogenic therapy for advanced hepatocellular carcinoma (HCC) presents a promising first-line treatment option. Methods: We assessed overall survival (OS), progression-free survival (PFS), objective response rate, and adverse events between the TACE-ICI-Len group (n=160) and the TACE-ICI-Bev group (n=216) as first-line therapy for advanced HCC. Inverse probability of treatment weighting was employed to minimize bias. Efficacy was evaluated using RECIST 1.1 and mRECIST criteria. Results: The TACE-ICI-Bev group demonstrated significantly improved OS and PFS compared to the TACE-ICI-Len group, especially across BCLC-B and BCLC-C stages (Total: mOS 22.8 vs. 15.4 months, p<0.001; mPFS 12.4 vs. 8.3 months, p<0.001; BCLC-B: mOS 23.3 vs. 16.6 months, p=0.005; mPFS 14.0 vs. 8.2 months, p<0.0001; BCLC-C: mOS 22.3 vs. 15.1 months, p=0.002; mPFS 11.0 vs. 8.0 months, p<0.001). Within the TACE-Bev-Ate subgroup, OS and PFS were further enhanced (Total: mOS 26.3 months; mPFS 13.8 months; BCLC-B: mOS 27.7 months; mPFS 16.7 months; BCLC-C: mOS 24.2 months; mPFS 12.6 months). The incidence of gastrointestinal bleeding (GB) was significantly higher in the TACE-ICI-Bev group compared to the TACE-ICI-Len group (13.8% vs. 6.2%, p<0.001). Notably, GB was significantly more frequent in patients with portal hypertension (PHT) compared to those without, in both the TACE-ICI-Bev group (30.9% vs. 6.6%, p<0.001) and the TACE-ICI-Len group (20.2% vs. 0%, p<0.001). Conclusions: TACE-ICI-Bev demonstrated superior OS and PFS compared to TACE-ICI-Len as first-line treatment for advanced HCC, with an acceptable safety. Management of PHT in patients with advanced HCC is critical to optimizing patient outcomes. Patient baseline characteristics before and after applying IPTW. Before IPTW After IPTW Variable TACE-ICI-Bev TACE-ICI-Len p TACE-ICI-Bev TACE-ICI-Len p n N=216 N=160 N=223.64 N=153.48 Age (mean (SD)) 59.21 (9.81) 57.19 (10.81) 0.059 57.59 (10.00) 57.23 (10.42) 0.780 Sex (%) 0.358 0.784 Female 37 (17.1) 21 (13.1) 33.1 (14.8) 24.6 (16.0) Male 179 (82.9) 139 (86.9) 190.6 (85.2) 128.9 (84.0) Hypertension (%) 0.46 0.928 No 152 (70.4) 106 (66.2) 150.8 (67.4) 104.3 (67.9) Yes 64 (29.6) 54 (33.8) 72.9 (32.6) 49.2 (32.1) DM (%) 0.176 0.981 No 147 (68.1) 120 (75.0) 164.3 (73.5) 112.5 (73.3) Yes 69 (31.9) 40 (25.0) 59.4 (26.5) 40.9 (26.7) ECOG_PS (%) <0.001 0.888 0 77 (35.6) 123 (76.9) 123.4 (55.2) 86.1 (56.1) 1 139 (64.4) 37 (23.1) 100.2 (44.8) 67.4 (43.9) TACE_number (%) 0.011 0.94 1~2 151 (69.9) 131 (81.9) 169.4 (75.7) 115.6 (75.3) >=3 65 (30.1) 29 (18.1) 54.3 (24.3) 37.9 (24.7) Child_Pugh_score (%) 0.125 0.629 <=6 117 (54.2) 73 (45.6) 109.7 (49.1) 70.6 (46.0) >6 99 (45.8) 87 (54.4) 113.9 (50.9) 82.9 (54.0) ALBI_grade (%) 0.367 0.536 I 94 (43.5) 78 (48.8) 102.7 (45.9) 64.6 (42.1) II-III 122 (56.5) 82 (51.2) 120.9 (54.1) 88.9 (57.9) BCLC_stage (%) 0.451 0.51 B 85 (39.4) 56 (35.0) 82.9 (37.1) 50.9 (33.1) C 131 (60.6) 104 (65.0) 140.7 (62.9) 102.6 (66.9) Lymphatic_metastasis (%) 0.001 0.845 No 126 (58.3) 65 (40.6) 107.1 (47.9) 75.4 (49.1) Yes 90 (41.7) 95 (59.4) 116.6 (52.1) 78.1 (50.9) Extrahepatic_metastasis (%) 0.11 0.536 No 179 (82.9) 121 (75.6) 172.1 (77.0) 123.2 (80.3) Yes 37 (17.1) 39 (24.4) 51.5 (23.0) 30.3 (19.7) Ascites (%) 0.298 0.35 No 146 (67.6) 99 (61.9) 150.5 (67.3) 94.8 (61.8) Yes 70 (32.4) 61 (38.1) 73.1 (32.7) 58.7 (38.2) Cirrhosis (%) 0.433 0.47 No 46 (21.3) 28 (17.5) 40.6 (18.2) 23.4 (15.2) Yes 170 (78.7) 132 (82.5) 183.0 (81.8) 130.1 (84.8) PHT (%) 0.425 0.698 No 106 (49.1) 71 (44.4) 111.6 (49.9) 72.8 (47.4) Yes 110 (50.9) 89 (55.6) 112.1 (50.1) 80.7 (52.6) Etiology_(%) 0.113 0.378 No/other 35(16.2) 16(10) 33.64 (12) 22.18 (14.6) HBV 181(83.8) 144(90) 190 (88) 131 (85.4) PVTT_classification_vp (%) 0.367 0.962 No 122 (56.5) 82 (51.2) 123.2 (55.1) 85.0 (55.4) VP1-VP4 94 (43.5) 78 (48.8) 100.5 (44.9) 68.5 (44.6) AFP_400 (%) 0.266 0.979 <400 119 (55.1) 78 (48.8) 112.8 (50.4) 77.1 (50.3) >=400 97 (44.9) 82 (51.2) 110.9 (49.6) 76.3 (49.7) Number_of_tumor (%) 0.979 0.678 <=3 62 (28.7) 47 (29.4) 66.0 (29.5) 41.7 (27.2) >3 154 (71.3) 113 (70.6) 157.6 (70.5) 111.7 (72.8) HCC_diameter_5 (%) 0.823 0.833 <5 60 (27.8) 47 (29.4) 65.8 (29.4) 47.1 (30.7) >=5 156 (72.2) 113 (70.6) 157.8 (70.6) 106.4 (69.3) NLR_grade (%) 0.902 0.884 <2.81 120 (55.6) 87 (54.4) 126.0 (56.4) 85.1 (55.5) >=2.81 96 (44.4) 73 (45.6) 97.6 (43.6) 68.4 (44.5) PLT (%) 0.082 0.901 <150 122 (56.5) 75 (46.9) 112.7 (50.4) 76.2 (49.6) >=150 94 (43.5) 85 (53.1) 110.9 (49.6) 77.3 (50.4)

Xenotransplantation has entered the clinical phase in an effort to address the global organ shortage. However, recent clinical studies have revealed that current xenografts from gene-edited (GE) pigs still pose a risk of immune rejection and biosafety concerns. In this study, we successfully produced a large batch of 582 GE cloned (GEC) pigs with 10-(GTKO/CMAHKO/β4GalNT2KO/hCD46/hCD55/hCD59/hTBM/hCD39/hEPCR/hCD47) gene edits via gene editing and somatic cell cloning technologies, and successfully obtained the F1 generation. Phenotypic characterization of 10-GEC pigs revealed the deletion of three xenoantigens and the expression of seven human transgenes across various tissues. Digital droplet polymerase chain reaction and whole-genome sequencing revealed two copies of hCD46/hCD55/hCD59/hTBM/hCD39 and one copy of hEPCR/hCD47 in the pig genome with minimal off-target effects or damage to the porcine functional genes. The validation results showed that 10-GEC pigs could effectively inhibit attacks from human antibodies, complement and macrophages on porcine endothelial cells, and alleviated coagulation abnormalities between pigs and humans. Large-scale screening of pathogens revealed no evidence of 47 pathogens, including cytomegalovirus, in our 10-GEC pigs. Kidney, heart and liver xenografts from these 10-GEC pigs were transplanted into nonhuman primates (NHPs), which worked normally without hyperacute rejection (HAR). Among NHPs, the heart and liver orthotopic transplant recipients survived for 3 and 4 days, respectively, while the two kidney transplant recipients survived for 23 and 16 days, respectively. Pathological analysis showed interstitial hemorrhage and fibrosis, cellular hyperplasia with minor antibodies and complement deposition, but significantly reduced infiltration of CD68+ macrophages in 10-GEC pig kidney xenografts. In summary, we successfully produced specific pathogen-free 10-GEC donor pigs that resulted in effective mitigation of immune rejection upon multiorgan transplantation to NHPs.

Purpose: This study aimed to investigate health-related quality of life (HRQOL) and related factors in Hangzhou, China, in patients with non-alcoholic fatty liver disease (NAFLD). Methods: The Chinese version of the EQ-5D-5L questionnaire was employed to assess HRQOL in 594 patients. A standardized questionnaire was employed to gather data regarding demographics, clinical characteristics, and lifestyle. This study employed Tobit regression models alongside multiple linear regression to examine the components influencing HRQOL, encompassing utility values and the EQ visual analogue scale (EQ-VAS). Results: This study included 594 participants with a mean age of 42.03 ± 13.83 years. The median utility index was 0.951 (P25-P75: 0.934-1.000), and the median EQ-VAS score was 76 (P25-P75: 66-82). Anxiety and depression were the predominant entry (31.9%) among the five health dimensions. Tobit regression models indicated that retirement (P = 0.011), monthly income >6000 (P = 0.002), alcohol consumption (P = 0.012), low-intensity activity (P = 0.002), obesity (P = 0.004), and cirrhosis (P = 0.038) were correlated with diminished HRQOL. The outcomes of multiple linear regression analyses indicated that regular exercise (β = 3.200; P = 0.003) and alcohol consumption (β = 2.466; P = 0.049) exhibited significant positive correlations with EQ-VAS scores, whereas obesity (β = -4.259; P = 0.005) and severe hepatic steatosis (β = -3.912; P = 0.036) demonstrated significant negative correlations. Conclusions: The anxiety/depression dimension was the most prevalent problem. The current investigation identified a notable correlation between HRQOL and low-intensity activity, obesity, and cirrhosis. Obesity and severe hepatic steatosis exhibited a substantial negative correlation with the EQ-VAS score. Future efforts should focus on enhancing the mental health and lifestyle of NAFLD patients.

BACKGROUND Portal vein stenosis (PVS) is a prevalent complication following pediatric liver transplantation (pLT) and significantly impacts long-term graft outcomes. This study assessed the efficacy and safety of balloon angioplasty and stent placement, calculated rates of restenosis or reintervention, and determined optimal interventional strategies for managing PVS following pLT. MATERIAL AND METHODS We retrospectively analyzed 884 pLT recipients at our institution. PVS occurred in 67 patients; 64 successfully underwent interventional procedures. We comparatively analyzed patients who achieved satisfactory results following initial balloon angioplasty with those who required subsequent interventions. Factors, including history of portal vein bridging and donor-recipient portal vein discrepancy rate, were analyzed. Significant factors were used to develop a logistic regression-based risk prediction model. Kaplan-Meier curves estimated patient and graft survival rates. RESULTS Fifty-two patients (81.25%) demonstrated satisfactory recovery following initial balloon angioplasty among the 64 pLT recipients with PVS. Twelve patients had restenosis; 10 underwent subsequent interventions with successful outcomes. A comparative analysis between the initial balloon angioplasty success group and the reintervention group showed significant differences between the groups with respect to portal vein bridging history and portal vein discrepancy rate (P<0.05). A logistic regression-based prediction model for restenosis was established. Kaplan-Meier survival analysis indicated an overall patient survival rate of 98.5% and a graft survival rate of 92.5% during the study period. CONCLUSIONS Patients with portal vein bridging history or poor donor-recipient PV matching are more prone to restenosis after initial balloon angioplasty. For such cases, we recommend direct stent placement as the initial treatment strategy.

BACKGROUND:Intrahepatic cholangiocarcinoma (ICC) is a highly aggressive malignancy with limited treatment options and poor prognosis, especially for patients who failed standard therapies. OBJECTIVE:To explore the safety, efficacy and immunological mechanisms of the novel edition of oncolytic virus vaccination, VG161, a multiarmed oncolytic herpes simplex virus-1 expressing interleukin (IL)-12, IL-15 and a programmed death-ligand 1 antagonist, in patients with advanced ICC. DESIGN:This pooled analysis integrates data from two multicentre clinical studies: a Phase I dose-escalation study and a Phase IIa exploratory study. 24 patients with advanced ICC received ultrasound-guided intratumoral injections of VG161. Multiomics analyses were performed on longitudinal tumour biopsies to evaluate immune modulation. RESULTS:The oncolytic virus therapy VG161 was well tolerated and showed encouraging antitumour activity, including improved overall survival versus second-line FOLFOX chemotherapy, even though most patients received VG161 as third-line or later therapy. Notably, patients previously treated with immune checkpoint inhibitors (CPIs) experienced enhanced benefit. Multiomics profiling of longitudinal biopsies revealed significant remodelling of the immunosuppressive tumour microenvironment, with proliferated infiltration of antigen-presenting cells, CD8+ T cell activation and M2-like macrophage depletion. Single-cell and spatial transcriptomics identified epithelial and macrophage subpopulations (Epi-C2 and Macro-C1QC) as potential biomarkers of response and resistance. CONCLUSION:These early-phase findings suggest that VG161 elicits meaningful immune activation in ICC and supports further investigation. By inducing both direct oncolysis and multilayered immune activation, VG161 shows clinical benefit in a heavily pretreated population and holds promise for integration with CPI-based regimens. Validation in larger trials is warranted.

OBJECTIVE:Due to rapid economic development and the unique lifestyles, cultures and customs of Hangzhou, non-alcoholic fatty liver disease (NAFLD) has attracted widespread attention, with a prevalence rate of 35-45%. In this study, we used the Chinese version of the Chronic Liver Disease Questionnaire for NAFLD (CLDQ-NAFLD) to investigate the current health-related quality of life (HRQL) among patients with NAFLD and analyse the influencing factors, which provides a reference for improving the patients' HRQL. DESIGN:A cross-sectional design. SETTING:This study was conducted from March 2022 to March 2023 at a tertiary hospital in Hangzhou. PARTICIPANTS:All patients with NAFLD included in this study were diagnosed using FibroScan, with a controlled attenuation parameter ≥248 dB/m. PRIMARY OUTCOME MEASURES:The primary outcome of the study was the HRQL score, which was assessed using the Chinese version of the CLDQ-NAFLD. RESULTS:A total of 502 patients with NAFLD were enrolled in this study (mean age 1.79±13.49 years; 69.7% male). The overall HRQL score was 5.89 (5.33, 6.36), and the fatigue dimension score was the lowest at 5.17 (4.33, 6.00). Multiple linear regression analyses revealed that poor HRQL score was correlated with other marital status (β=-0.096, p=0.036), liver stiffness ≥10.3 (kPa) (β=-0.110, p=0.017), regular exercise (β=-0.121, p=0.006), sex (β=-0.114, p=0.012) and alanine transaminase (ALT) levels (β=-0.139, p=0.002). A monthly income >10 000 (renminbi) was associated with a significantly higher HRQL score. CONCLUSIONS:This cross-sectional survey conducted in Hangzhou, China, revealed that HRQL is impaired among patients with NAFLD. This study revealed a significant association between HRQL and sociodemographic factors, including sex, monthly income and marital status, alongside clinical factors such as liver stiffness, regular exercise and ALT level. Emphasising optimal care management is essential to improve HRQL in patients with NAFLD.

OBJECTIVE:This meta-analysis synthesizes preclinical evidence on the safety and efficacy of genetically modified pigs to nonhuman primates (NHPs) liver xenotransplantation. BACKGROUND:The outcomes of liver xenotransplantation from genetically modified pig-to-NHP remain suboptimal. METHODS:A systematic search of Embase, PubMed, and Scopus was conducted to identify and select relevant experimental studies. Data on survival rates and complications were extracted. Data on survival and complications were pooled using a random-effects model to generate summary effect sizes (ES) and 95% confidence intervals (CI). RESULTS:Eleven studies involving 59 pig-to-NHPs liver xenotransplantations were included. The pooled median survival time was 5 days [interquartile ranges (IQR): 1-9 days]. The 1-day, 3-day, 7-day, and 14-day pooled survival rates were 88.6% (95% CI: 0.682-0.999), 78.8% (95% CI: 0.526-0.976), 29.2% (95% CI: 0.133-0.473), and 4.2% (95% CI: 0.000-0.141), respectively. Coagulopathy was the leading cause of death (32.2%). The pooled incidence of acute rejection, coagulopathy, surgery-related complications, and infection-related complications was 0.034 (95% CI: 0.000-0.131), 0.522 (95% CI: 0.308-0.733), 0.134 (95% CI: 0.037-0.261), and 0.282 (95% CI: 0.111-0.482), respectively. Subgroup analysis revealed trends towards improved early survival with heterotopic transplantation over orthotopic, and immunosuppressive regimens including co-stimulation blockade were associated with significantly higher survival rates at day 7 ( P = 0.013) and day 14 ( P = 0.042) compared to blocker-free regimens. CONCLUSIONS:The results indicate that pig-to-NHP liver xenotransplantation has limited short-term survival, with coagulopathy being a major challenge. Further research is needed to optimize this procedure and facilitate its clinical translation.

Lenvatinib, a multiple-receptor tyrosine kinase inhibitor, has gained recent approval for its use as a first-line treatment of hepatocellular carcinoma (HCC). While lenvatinib demonstrates notable therapeutic efficacy, the drug resistance undermines its sustained tumor control potential. The restricted clinical utility of lenvatinib underscores the imperative necessity to elucidate the mechanisms underpinning drug resistance. We established lenvatinib-resistant cell lines and investigated the changes in their biological characteristics. Next-generation sequencing was performed to identify genes associated with lenvatinib resistance. Western blots were utilized to confirm the involvement of these genes. Using lentiviral technology, we generated cell lines with lowered nuclear receptor coactivator 5 (NCOA5), a pivotal drug resistance-related gene, to explore the underlying resistance mechanism. Moreover, we developed a subcutaneous HCC xenograft tumor model to explore strategies for reversing drug resistance. Our study showed that HCC cells acquire resistance to lenvatinib through the activation of NCOA5, thereby stimulating the NCOA5-Protein Kinase B-mammalian target of rapamycin (AKT-mTOR) axis. Furthermore, the clinical evaluation of HCC specimens established a correlation between the activation of the NCOA5 pathway and the response to lenvatinib treatment. Everolimus, an mTOR inhibitor, in combination with lenvatinib and everolimus, exerted significant synergistic effects against HCC in vivo and in vitro . HCC cells develop resistance to lenvatinib by activating the NCOA5-AKT-mTOR pathway. The combination therapy of lenvatinib with everolimus is a promising strategy to overcome acquired resistance, thereby enhancing the clinical efficacy of lenvatinib.

Peri-operative respiratory virus (RV) infection is critical in paediatric liver transplantation. However, it has been inadequately studied, especially in terms of the clinical latency of infection (incubation period) and Omicron variant infection. Herein, we compared the infection profile of common RVs and Omicron variants in paediatric liver transplantation, aiming to identify the association of virus infection with outcomes. The Omicron cohort was designed prospectively, and the RV cohort was retrospective. Survival outcomes, medical resources, and major complications were compared. Risk factors associated with peri-operative mortality were investigated using regression analysis. We enrolled 649 paediatric liver transplantation patients, including 28 Omicron and 61 RV infections. The 1-y overall survival was 97.7 ± 0.6% for the non-infected group, and 93.4 ± 3.2% for the RV group (p = 0.092). No death occurred in the Omicron group. Mortality was higher in the clinical latency infection group compared with that in the non-infected group (13.8% vs. 1.4%, p = 0.002). Latent RV infection (hazard ratio (HR) = 6.323, 95% confidence interval (CI): 1.374-29.087), Multi‑drug resistance organism pneumonia (HR = 7.177, 95% CI: 1.817-28.350), infectious shock (HR = 4.284, 95% CI: 0.995-18.442) and blood loss (HR = 3.209, 95% CI: 1.166-8.833) were independent risk factors for peri-operative mortality. In conclusion, pre-transplant viral screening is fundamental to paediatric liver transplantation. Peri-operative Omicron infection might be controllable, while RV infection led to more complications compared with those in the non-infected group. Clinical latency infection is the key risk for paediatric liver transplantation mortality.

OBJECTIVES:There is a paucity of data regarding the long-term hemorrhage/progression outcomes of brain arteriovenous malformation (BAVM). The purpose of this study was to examine the outcomes of surgical treatment alone over a long follow-up period. MATERIALS AND METHODS:All patients (n = 356) harboring Grade I-III BAVMs who had been surgically treated alone between January 2010 and December 2019 were included. Univariate analysis and multivariate analysis with proportional hazard models were implemented to identify the predictors of hemorrhage-free survival (HFS) (n = 356) and progression-free survival (PFS) (n = 334). RESULTS:Of the 356 BAVM patients, 233 were male and 123 were female (male-to-female ratio of 1.89:1). Rehemorrhage was observed in 22 (6.2%) patients. The overall HFS rates at 5, 10, and 15 years in the entire cohort were 96.0%, 92.4%, and 91.1%, respectively. A 1 cm3 increase in lesion volume (hazard ratio [HR] = 1.049, 95% confidence interval [CI] = 1.013-1.085; P = 0.007) was a significant adverse factor for HFS. The probabilities of PFS at 5, 10, and 15 years were 94.9%, 90.6%, and 85.5%, respectively. With respect to clinical predictors of PFS, only male sex (HR = 3.146, 95% CI = 1.088-9.098; P = 0.034) was a significant predictor of PFS after surgical treatment in the univariate analysis. CONCLUSIONS:For the majority of patients, surgery remains the first-line treatment for BAVMs. Our study included a significant subset of patients who were successfully managed by surgery alone.