[This corrects the article DOI: 10.3389/fimmu.2026.1822904.].

BACKGROUND:Tacrolimus is a widely used immunosuppressant in organ transplantation, but it is characterized by a narrow therapeutic index and high interindividual variations of its pharmacokinetics. Tacrolimus is a substrate for CYP3A. It has been conjectured that CYP3A5 polymorphism is associated with tacrolimus pharmacokinetic variations. The objective of this study was to evaluate the contribution of polymorphisms of the donor and recipient CYP3A5 gene on tacrolimus disposition in liver transplantation. METHODS:Fifty-three liver transplant recipients treated with tacrolimus were enrolled in this study. Tacrolimus dosage and blood trough concentration were investigated at 1 week, 2 weeks, and 1 month after transplantation. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis was applied to determine the genotype of CYP3A5 gene. RESULTS:The concentration/dose (C/D) ratios in patients with *1/*1(*1/*3) genotype donor were significantly lower than in patients with *3/*3 genotype donor at 2 weeks (P = 0.036) and 1 month (P = 0.021), but not at 1 week posttransplantation. Combination analysis showed that such significance still existed between CYP3A5 expressor group and nonexpressor group for both donor and recipient genotype. Also differences of C/D ratio between CYP3A5 expressor and nonexpressor donors in nonexpressor recipients were larger than those between recipients in nonexpressor donors. CONCLUSION:The large interindividual variation of tacrolimus dose requirement is influenced by the metabolic activity of CYP3A5. Polymorphisms of the donor CYP3A5 gene seem to contribute more to such variation than the recipient. A larger population and further studies are needed to explore the exact mechanisms for tacrolimus pharmacokinetics.

BackgroundPostoperative infection remains a major cause of morbidity after liver transplantation (LT) in patients with liver failure. Increasing evidence suggests that gut microbiota dysbiosis may contribute to infection risk, but its dynamic changes after LT are not fully understood.MethodsThis retrospective study included 60 patients with liver failure who underwent LT and developed postoperative infection-related risk. Patients were divided into a probiotic group and a non-probiotic group. Fecal samples were collected before transplantation and on postoperative days 7, 14, 21, and 28. Metagenomic sequencing was performed to analyze gut microbial composition, diversity, and antibiotic resistance genes.ResultsThe probiotic group showed a significantly lower rate of postoperative bacterial infection, especially intra-abdominal infection. After LT, gut microbiota gradually recovered in both groups, but restoration was faster in the probiotic group. The non-probiotic group showed persistent dysbiosis, characterized by enrichment of opportunistic pathogens such as Enterococcus and Klebsiella, whereas beneficial genera including Bifidobacterium and Lactobacillus were more abundant in the probiotic group. Antibiotic resistance genes were also more enriched in the non-probiotic group.ConclusionEarly postoperative gut microbiota reconstruction is closely associated with infectious complications after LT, and modulation of gut microbiota may help improve postoperative outcomes.

BACKGROUND:Intrahepatic cholangiocarcinoma (ICC) is a highly malignant liver cancer subtype with limited effective treatment options. Emerging evidence suggests that inflammatory factors play a critical role in ICC progression within the tumor microenvironment (TME). However, causal relationships between specific inflammatory factors and ICC risk remain unclear. AIM:To investigate the causal relationship between inflammatory factors and ICC. METHODS:This study used Mendelian randomization (MR) and Bayesian weighted MR (BWMR) analyses to investigate the causal impact of inflammatory factors on ICC risk. Genetic data from genome-wide association studies were utilized to identify and validate instrumental variables for 91 inflammatory factors, followed by sensitivity analyses to ensure robustness. RESULTS:MR analysis identified significant associations between elevated levels of artemin and matrix metalloproteinase (MMP)-10 and increased ICC risk. BWMR and meta-MR analysis results validated these associations. Sensitivity analyses confirmed the stability of these findings, indicating that specific inflammatory factors may contribute causally to ICC development. CONCLUSION:This study provides evidence that certain inflammatory factors, particularly artemin and MMP-10, are causally linked to ICC risk, identifying them as potential risk factors and therapeutic targeting. These findings enhance the understanding of the inflammatory components of the TME in ICC, supporting the development of targeted intervention strategies.

Background Gallstone disease (GSD), nonalcoholic fatty liver disease (NAFLD), metabolic dysfunction-associated fatty liver disease (MAFLD), and metabolic syndrome (MetS) are common medical disorders worldwide. This study aimed to ascertain how NAFLD, MAFLD, MetS, and other factors affect the development of GSD, and how the GSD-associated factors influence patient recovery after laparoscopic cholecystectomy (LC). Methods We included 200 patients who were diagnosed with GSD and underwent LC between January 2017 and February 2022. A total of 200 subjects without GSD and “non-calculous causes” during the same period were also included as controls. We compared the metabolic disorder differences between GSD patients and controls. Furthermore, we sub-grouped patients based on the comorbidities of preoperative NAFLD, MAFLD, and MetS, and compared the impacts of these comorbidities on short-term post-LC functional recovery of the patients. Results The prevalence of NAFLD and MetS were higher in GSD patients (P < 0.05). Based on multivariate logistic regression analysis, hyperglycemia [odds ratio (OR) = 2.2, 95% confidence interval (CI): 1.4–3.4, P = 0.001] and low high-density lipoprotein cholesterol (HDL-C) level (OR = 1.8, 95% CI: 1.1–3.1, P = 0.048) were linked to GSD. NAFLD and MetS linked to liver enzymes after LC (P < 0.05). MetS also linked to the levels of inflammatory indicators after LC (P < 0.05). The obesity, hyperlipidemia, low HDL-C level, and hyperglycemia linked to liver enzymes after LC (P < 0.05). Hyperlipidemia, low HDL-C level, and hypertension linked to inflammation after LC (P < 0.05). Conclusions The prevalence of GSD may be linked to NAFLD and MetS. Hyperglycemia and low HDL-C level were independent risk factors of GSD.

Objective: This study intended to evaluate the clinical efficacy and safety of colistin sulfate aerosol inhalation in combination with ceftazidime-avibactam for the treatment of pulmonary carbapenem-resistant Klebsiella pneumoniae (CRKP) infection during the peri-operative period of liver transplantation. Materials and Methods: A retrospective analysis was designed to investigate 52 patients who developed pulmonary CRKP infection after liver transplantation between December 1, 2019, and November 30, 2022. On the basis of whether they received colistin sulfate aerosol inhalation, the patients were divided into the treatment group (n = 29) and the control group (n = 23). The baseline information, infection status, CRKP enzyme type, inflammatory markers, liver and kidney function, and prognosis were compared and analyzed. Results: There were no significant differences in patient characteristics, infection status, and drug resistance enzyme type between the treatment group (treated with colistin sulfate aerosol inhalation and ceftazidime and avibactam sodium for injection) and the control group (treated with ceftazidime and avibactam sodium for injection alone). Colistin sulfate aerosol inhalation treatment reduced concentrations of inflammatory markers, with post-treatment white blood cell count, procalcitonin, and C-reactive protein significantly lower than pre-treatment levels (p < 0.05). Except for C-reactive protein at 14 days (p = 0.032), the two groups had no significant differences in other indicators. There were no significant differences in alanine aminotransferase, aspartate aminotransferase, total bilirubin, and glomerular filtration rate after treatment, indicating no discernible alteration in liver and kidney function. In addition, the treatment group took a significantly shorter time to normalize body temperature compared with the control group (p = 0.025), but there were no significant differences in the cure with no colonization rate and all-cause mortality rate between the two groups. Conclusions: The combination of colistin sulfate aerosol inhalation and ceftazidime and avibactam sodium for injection is effective in treating pulmonary CRKP infection during the peri-operative period of liver transplantation. It does not impose an additional burden on liver and kidney function, providing a new treatment option for this type of infection.

PDF file - 7K, Sequences of siRNA fragments used in this study

Hepatocellular carcinoma (HCC) is one of the most lethal malignant cancers across the world. It has a poor prognosis and lacks effective therapies, especially for patients with advanced-stage cancer, indicating an urgent need for new therapies and novel therapeutic targets. Here, by screening the U.S. Food and Drug Administration drug library against HCC cell lines, we identified that flubendazole, a traditional anthelmintic drug, could prominently suppress HCC cells in vivo and in vitro. RNA sequence analysis and cellular thermal shift assays showed that flubendazole reduced the expression of PCSK9 protein by direct targeting. The increased expression of PCSK9 in HCC tissues was demonstrated to be correlated with poor prognosis, and the inhibitory ability of flubendazole was selectively dependent on PCSK9 expression. PCSK9 knockdown abolished the antitumor effects of flubendazole in HCC. Mechanistically, flubendazole inhibited the Hedgehog signaling pathway induced by PCSK9, resulting in the downregulation of smoothened (SMO) and GLI Family Zinc Finger 1 (Gli1). Moreover, combining flubendazole with lenvatinib was found more effective than administering lenvatinib only for HCC treatment in vivo and in vitro. These findings reveal the therapeutic potential of flubendazole against HCC and provide clues on new repurposed drugs and targets for cancer treatment.

Purpose: To retrospectively analyze the data of 2 patients with hepatic angiosarcoma (HAS) who underwent liver transplantation in our hospital and to review the related literature. Case summary: Two patients were misdiagnosed before surgery (one was misdiagnosed with liver carcinoma, and the other was misdiagnosed with liver failure). Both patients received liver transplantation, and postoperative pathology confirmed the diagnosis of HAS. Both patients got recurrence after surgery. One patient had multiple tumor metastasis 3 months later and died 17 months after surgery due to tumor- induced multiple organ failure. The other suffered abdominal dissemination with bleeding 4 months after surgery, and died 7 months later. Conclusion: HAS is a tumor with a low incidence and high mortality. It is easily misdiagnosed or missed in diagnosis. Liver transplantation can be used as a salvage treatment, but the long- term prognosis is not ideal.

Background:Hepatoid adenocarcinoma (HAC) of the lung (HAL) is a rare and aggressive extrahepatic adenocarcinoma with an unknown etiology and unfavorable prognosis, which is similar to the pathophysiological characteristics of hepatocellular carcinoma (HCC).Methods:We first presented a 67-year-old patient diagnosed with HAC in the right middle lobe of the lung. Then, a systematic literature search was performed for HAL cases recorded between 1990 and 2020 based on three databases. The clinicopathological features, therapeutic method, and prognosis of this rare disease were reviewed, and corresponding prognostic factors were explored using Kaplan-Meier (K-M) curve and Cox proportional hazards regression model. Additionally, the potential biological mechanisms of HAL were further explored and compared with HCC and lung adenocarcinoma (LUAD) based on online databases.Results:In the present study, we reported an HAL patient who underwent surgical resection combined with chemotherapy and succumbed to disease 13 months after surgery. Additionally, a total of 43 experimental studies with 49 HAL patients, including the present case, met the inclusion criteria and were included in the present review. We found that HAL is characterized by a male-dominated incidence and is more common in the right lung. Patients in the surgical subgroup have a better prognosis than those in the non-surgical subgroup (p = 0.034). Moreover, the Cox proportional hazards regression model demonstrated that surgical resection can significantly improve the prognosis of HAL patients (p = 0.016). HAL is a rare disease associated with gene mutations that has a distinctive cause and unique pathogenesis. Additionally, Afatinib and Gefitinib may be new effective agents to better combat HAL.Conclusion:In conclusion, males may exhibit an increased risk of developing HAL and poorer prognosis than females. Surgical resection combined with chemotherapy may prolong the survival of patients with HAL. HAL has its unique clinicopathological characteristics and biological mechanisms.

Abstract Objectives Liver transplantation (LT) can benefit the long-term survival of hepatocellular carcinoma (HCC) patients. We hypothesized that circulating tumor cell (CTC) levels and subtypes are intimately associated with metastasis status of HCC patients. This study was designed to test that compositive hematological indices including CTC can provide a prediction of post-LT metastasis. Methods Between 2017 and 2018, 37 HCC patients within Hangzhou criteria receiving LT were included for analysis. The 24-month follow-up was mainly conducted by outpatient and telephone. Blood samples were collected, and hematological indices were examined. The outcomes such as PFS, recurrence, metastasis, location of recurrence/metastasis, and number of metastases were recorded. Results The follow-up analysis showed that microvascular invasion (MVI) classification at the baseline is associated with metastasis. Next, α-fetoprotein (AFP) level was another useful indicator of postoperative metastasis, especially at the third or fourth month; the protein induced by vitamin K absence or antagonist-II (PIVKA-II) level three months after LT was significantly higher for those who had later metastasis. The mesenchymal CTC level at the 45th day was increased for in the metastasis group. Using two-ends Logistic regression, the calculated value MP (metastasis predictor, by above factors). Had an AUC of 0.858 in the ROC curve, with a cutoff value of 0.328. Conclusions In conclusion, microvascular invasion, AFP level at the third or fourth month, PIVKA-II level at the third month, and mesenchymal CTC level at day 45 were associated with post-LT metastasis. Using Logistic regression based on above variables, the two-year metastasis can be predicted with satisfactory sensitivity and accuracy.

BACKGROUND:Liver transplantation is an effective therapy for end-stage liver diseases and acute liver failure. After the operation, however, recipients may suffer grafts loss induced by alloimmune reaction, which is termed as acute allograft rejection. The interaction between costimulatory molecules, CD276, and its ligand, TREML2, promotes T cell-mediated immune response, as well as acute or chronic allograft rejection. Our research aimed at correlating genetic polymorphisms of CD276/TREML2 with acute rejection, and evaluating its prognostic value of acute rejection after liver transplantation. METHODS:The study enrolled a total of 388 recipients. Among them, acute allograft rejection was observed in 54 cases. We performed single nucleotide polymorphism genotyping of CD276, including rs11072431, rs11574495, rs12593558, rs12594627, rs2127015, rs3816661 and rs7176654, and TREML2, including rs4714431, rs6915083, rs7754593, and rs9394767 from preoperative peripheral blood genome DNA. RESULTS:We found rs2127015 of CD276, rs6915083 and rs7754593 of TREML2, and HBV infection as well were associated with acute rejection. And, rs2127015 influences CD276 expression. Moreover, we established a risk assessment model, composited by statistically proved risk factors. CONCLUSION:By integrating both clinical and genetic variables, liver transplant recipients can be categorized into different risk groups, and might benefit from individualized therapies.

OBJECTIVES This study aimed to investigate the safety, feasibility and availability of doubly committed ventricular septal defect (DCVSD) closure via an ultraminimal intercostal incision under the guidance of transoesophageal echocardiography in children. METHODS From August 2014 to August 2016, 35 children with DCVSDs (≤5 mm in diameter) were enrolled in this study. A left parasternal ultraminimal intercostal incision (≤1 cm) and a pericardium hanging technique were employed without sternal incision. DCVSDs were closed through a short delivery sheath assembled with an eccentric occluder device. Transoesophageal echocardiography was used to guide and monitor the entire procedure. All patients were followed up. RESULTS All 35 children had complete closures with an operation success rate of 100%. The average size of DCVSDs was 3.50 ± 0.79 (range 2.2‐5.0) mm, and the average device size was 5 ± 2 (range 4‐9) mm. The average operation duration was 45.42 ± 11.77 (range 25‐70) min, and the average hospital stay was 8 ± 2 (range 7‐16) days. The median follow‐up period was 17 months (range 6 months‐2.5 years). Pre‐existing aortic regurgitation disappeared after surgery in 1 patient and remained the same in 4 patients. No other complications were found during the operation or during follow‐up. CONCLUSIONS Under transoesophageal echocardiography guidance, DCVSD closure using an eccentric occluder via an ultraminimal intercostal incision is feasible, safe and effective in children. The use of this approach is recommended.

Although the chemotactic cytokine CXCL3 is thought to play an important role in tumor initiation and invasion, little is known about its function in hepatocellular carcinoma (HCC). In our previous study, we found that Ikaros inhibited CD133 expression via the MAPK pathway in HCC. Here, we showed that Ikaros may indirectly down-regulate CXCL3 expression in HCC cells, which leads to better outcomes in patients with CD133(+) cancer stem cell (CSC) populations. CD133 overexpression induced CXCL3 expression, and silencing of CD133 down-regulated CXCL3 in HCC cells. Knockdown of CXCL3 inhibited CD133(+) HCC CSCs' self-renewal and tumorigenesis. The serum CXCL3 level was higher in HCC patients' samples than that in healthy individual. HCC patients with higher CXCL3 expression displayed a poor prognosis, and a high level of CXCL3 was significantly associated with vascular invasion and tumor capsule formation. Exogenous CXCL3 induced Erk1/2 and ETS1 phosphorylation and promoted CD133 expression, indicating a positive feedback loop between CXCL3 and CD133 gene expression in HCC cells via Erk1/2 activation. Together, our findings indicated that CXCL3 might be a potent therapeutic target for HCC.

Splenogonadal fusion (SGF) is a rare congenital abnormality. It is typically identified during orchiectomy for a suspected testicular tumor or during orchiopexy. We describe the sonographic findings in a case of SGF that could help with correct diagnosis preoperatively. © 2016 Wiley Periodicals, Inc. J Clin Ultrasound 45:179-182, 2017.

In our previous studies, we reported that CD133(+) cancer stem cells (CSCs) were chemoresistant in hepatocellular carcinoma (HCC) and that isocorydine treatment decreased the percentage of CD133(+) CSCs. Here, we found that a derivative of isocorydine (d-ICD) inhibited HCC cell growth, particularly among the CD133(+) subpopulation, and rendered HCC cells more sensitive to sorafenib treatment. d-ICD inhibited IGF2BP3 expression in a time-dependent manner, and IGF2BP3 expression negatively correlated with d-ICD-induced growth suppression. IGF2BP3 overexpression enriched the CD133(+) CSC subpopulation in HCC, enhanced tumor sphere formation and suppressed the cytotoxic effects of sorafenib and doxorubicin. The expression of drug resistance-related genes, including ABCB1 and ABCG2, and the CSC marker CD133 expression was increased after IGF2BP3 overexpression. The significance of these observations was underscored by our findings that high IGF2BP3 expression predicted poor survival in a cohort of 236 patients with HCC and positively correlated with ABCG2 and CD133 expression in vivo. These results suggested that the d-ICD may inhibit HCC cells growth by IGF2BP3 decrease and that IGF2BP3 may serve as a therapeutic target for HCC.

Cancer metastasis is a complex process, and the incidence of metastasis is influenced by many biological factors. Orosomucoid 2 (ORM2) is an important glycoprotein that is mainly biosynthesized and secreted by hepatocytes. As an acute-phase protein, ORM2 likely plays important roles in anti-inflammation, immunomodulation and drug delivery. However, little is known regarding the function of ORM2 in hepatocellular carcinoma (HCC). In this study, we determined that ORM2 expression in HCC tissues was negatively associated with intrahepatic metastasis and histological grade. Moreover, the ectopic overexpression of ORM2 decreased HCC cell migration and invasion in vitro and intrahepatic metastasis in vivo, whereas silencing ORM2 expression resulted in increased tumor cell migration and invasion in vitro. The CCAAT/enhancer binding protein β (C/EBPβ) upregulated ORM2 expression, while only the LAP1/2 (C/EBPβ isoforms) possessed transcription-promoting activity on the ORM2 promoter. Subsequently, we found that LAP1 repressed HCC cell migration and invasion via the induction of ORM2 expression. Consistently, the protein expression of C/EBPβ was negatively associated with histological grade and positively correlated with ORM2 protein expression in HCC tissues. Collectively, our findings indicate that ORM2 is a functional downstream target of C/EBPβ and functions as a tumor suppressor in HCC.

Ribonucleotide reductase (RR)M2B is an enzyme belonging to the ribonucleotide reductase enzyme family, which is essential for DNA synthesis and repair. RRM2B plays an important role in tumor progression and metastasis; however, little is known about the expression and underlying molecular mechanisms of RRM2B in hepatocellular carcinoma (HCC). In the present study, we report that down-regulation of RRM2B in HCC is negatively associated with intrahepatic metastasis, regardless of p53 status. Moreover, the ectopic overexpression of RRM2B decreased HCC cell migration and invasion in vitro, whereas silencing RRM2B expression resulted in increased migration and invasion in vitro and intrahepatic and lung metastasis in vivo. Additionally, knockdown of RRM2B by short hairpin RNA (shRNA) in HCC cells was associated with epithelial-mesenchymal transition (EMT), including the down-regulation of E-cadherin, and the concomitant up-regulation of N-cadherin and slug. A further experiment showed that RRM2B inhibited cell migration and spreading through regulation of the early growth response protein 1 (Egr-1) / phosphatase and tensin homolog (PTEN) / Akt1 pathway. Consistently, we also detected a significant correlation between RRM2B and E-cadherin protein expression in HCC tissues. Furthermore, Egr-1 also directly bound to the RRM2B promoter and repressed RRM2B transcription, thereby establishing a negative regulatory feedback loop. Conclusion: These findings indicate that RRM2B suppresses cell migration and spreading by way of modulation of the Egr-1/PTEN/Akt1 pathway. (Hepatology 2014;59:1459-1470)

Background: Although liver transplantation is one of the most efficient curative therapies of end stage liver diseases, recipients may suffer liver graft loss opst-operation. IRF-5, a member of Interferon Regulatory Factors, functions as a key regulator in TLR4 cascade, and is capable of inducing inflammatory cytokines. Although TLR4 has been proved to contribute to acute allograft rejection, including after liver transplantation, the correlation between IRF5 gene and acute rejection has not been elucidated yet.Methods: The study enrolled a total of 289 recipients, including 39 females and 250 males, and 39 recipients developed acute allograft rejection within 6 months post-transplantation. The allograft rejections were diagnosed by liver biopsies. Genome DNA of recipients was extracted from pre-operative peripheral blood. Genotyping of IRF-5, including rs3757385, rs752637 and rs11761199, was performed, followed by SNP frequency and Hardy-Weinberg equilibrium analysis.Results: The genetic polymorphism of rs3757385 was found associated with acute rejection. G/G homozygous individuals were at higher risk of acute rejection, with a P value of 0.042 (OR = 2.34 (1.07-5.10)).Conclusions: IRF5, which transcriptionally activates inflammatory cytokines, is genetically associated with acute rejection and might function as a risk factor for acute rejection of liver transplantations.