Proteomics Profiling of Bilirubin Nanoparticle Treatment against Myocardial Ischemia-Reperfusion Injury.

In myocardial infarction, ischemia-reperfusion injury (IRI) poses a significant challenge due to a lack of effective treatments. Bilirubin, a natural compound known for its anti-inflammatory and antioxidant properties, has been identified as a potential therapeutic agent for IRI. Currently, there are no reports about proteomic studies related to IRI and bilirubin treatment. In this study, we explored the effects of bilirubin nanoparticles in a rat model of myocardial IRI. A total of 3616 protein groups comprising 76,681 distinct peptides were identified using LC-MS/MS, where we distinguished two kinds of protein groups: those showing increased expression in IRI and decreased expression in IRI with bilirubin treatment, and vice versa, accounting for 202 and 35 proteins, respectively. Our proteomic analysis identified significant upregulation in the Wnt and insulin signaling pathways and increased Golgi markers, indicating their role in mediating bilirubin nanoparticle's protective effects. This research contributes to the proteomic understanding of myocardial IRI and suggests bilirubin nanoparticles as a promising strategy for cardiac protection, warranting further investigation in human models.

Clinical Impact and Risk Factors of Seizure After Liver Transplantation: A Nested Case-Control Study.

Seizures are a frequent neurological consequence following liver transplantation (LT), however, research on their clinical impact and risk factors is lacking. Using a nested case-control design, patients diagnosed with seizures (seizure group) within 1-year post-transplantation were matched to controls who had not experienced seizures until the corresponding time points at a 1:5 ratio to perform survival and risk factor analyses. Seizures developed in 61 of 1,243 patients (4.9%) at median of 11 days after LT. Five-year graft survival was significantly lower in the seizure group than in the controls (50.6% vs. 78.2%, respectively, p < 0.001) and seizure was a significant risk factor for graft loss after adjusting for variables (HR 2.04, 95% CI 1.24-3.33). In multivariable logistic regression, body mass index <23 kg/m2, donor age ≥45 years, intraoperative continuous renal replacement therapy and delta sodium level ≥4 mmol/L emerged as independent risk factors for post-LT seizure. Delta sodium level ≥4 mmol/L was associated with seizures, regardless of the severity of preoperative hyponatremia. Identifying and controlling those risk factors are required to prevent post-LT seizures which could result in worse graft outcome.

Self-Management Using eHealth Technologies for Liver Transplant Recipients: Scoping Review.

BACKGROUND: Liver transplantation has become increasingly common as a last-resort treatment for end-stage liver diseases and liver cancer, with continually improving success rates and long-term survival rates. Nevertheless, liver transplant recipients face lifelong challenges in self-management, including immunosuppressant therapy, lifestyle adjustments, and navigating complex health care systems. eHealth technologies hold the potential to aid and optimize self-management outcomes, but their adoption has been slow in this population due to the complexity of post-liver transplant management. OBJECTIVE: This study aims to examine the use of eHealth technologies in supporting self-management for liver transplant recipients and identify their benefits and challenges to suggest areas for further research. METHODS: Following the Arksey and O'Malley methodology for scoping reviews, we conducted a systematic search of 5 electronic databases: PubMed, CINAHL, Embase, PsycINFO, and Web of Science. We included studies that (1) examined or implemented eHealth-based self-management, (2) included liver transplant recipients aged ≥18 years, and (3) were published in a peer-reviewed journal. We excluded studies that (1) were case reports, conference abstracts, editorials, or letters; (2) did not focus on the posttransplantation phase; (3) did not focus on self-management; and (4) did not incorporate the concept of eHealth or used technology solely for data collection. The quality of the selected eHealth interventions was evaluated using (1) the Template for Intervention Description and Replication guidelines and checklist and (2) the 5 core self-management skills identified by Lorig and Holman. RESULTS: Of 1461 articles, 15 (1.03%) studies were included in the final analysis. Our findings indicate that eHealth-based self-management strategies for adult liver transplant recipients primarily address lifestyle management, medication adherence, and remote monitoring, highlighting a notable gap in alcohol relapse interventions. The studies used diverse technologies, including mobile apps, videoconferencing, and telehealth platforms, but showed limited integration of decision-making or resource use skills essential for comprehensive self-management. The reviewed studies highlighted the potential of eHealth in enhancing individualized health care, but only a few included collaborative features such as 2-way communication or tailored goal setting. While adherence and feasibility were generally high in many interventions, their effectiveness varied due to diverse methodologies and outcome measures. CONCLUSIONS: This scoping review maps the current literature on eHealth-based self-management support for liver transplant recipients, assessing its potential and challenges. Future studies should focus on developing predictive models and personalized eHealth interventions rooted in patient-generated data, incorporating digital human-to-human interactions to effectively address the complex needs of liver transplant recipients. This review emphasizes the need for future eHealth self-management research to address the digital divide, especially with the aging liver transplant recipient population, and ensure more inclusive studies across diverse ethnicities and regions.

Outcomes and Risk Factors for Liver Transplantation Using graft-to-Recipient Weight Ratio Less than 0.8 Graft from Living Donors: Multicentric Cohort Study.

OBJECTIVE: To compare graft survival after LDLT in patients receiving GRWR<0.8 versus GRWR≥0.8 grafts and identify risk factors for graft loss using GRWR<0.8 grafts. SUMMARY BACKGROUND DATA: Favorable outcomes after living donor liver transplantation (LDLT) using graft-to-recipient weight ratio (GRWR)<0.8 grafts were recently reported; however, these results have not been validated using multicenter data. METHODS: This multicentric cohort study included 3450 LDLT patients. Graft survival was compared between 1:3 propensity score-matched groups and evaluated using various Cox models in the entire population. Risk factors for graft loss with GRWR<0.8 versus GRWR≥0.8 grafts were explored within various subgroups using interaction analyses, and outcomes were stratified according to the number of risk factors. RESULTS: In total, 368 patients (10.7%) received GRWR<0.8 grafts (GRWR<0.8 group), whereas 3082 (89.3%) received GRWR≥0.8 grafts (GRWR≥0.8 group). The 5-y graft survival rate was significantly lower with GRWR<0.8 grafts than with GRWR≥0.8 grafts (85.2% vs. 90.1%, P=0.013). Adjusted hazard ratio (HR) for graft loss using GRWR<0.8 grafts in the entire population was 1.66 (95% confidence interval [CI] 1.17-2.35, P=0.004). Risk factors exhibiting significant interactions with GRWR<0.8 for graft survival were age ≥60 y, MELD score ≥15, and male donor. When ≥2 risk factors were present, GRWR<0.8 grafts showed higher risk of graft loss compared to GRWR≥0.8 graft in LDLT (HR 2.98, 95% CI 1.79-4.88, P<0.001). CONCLUSIONS: GRWR<0.8 graft showed inferior graft survival than controls (85.2% vs. 90.1%), especially when ≥2 risk factors for graft loss (among age ≥60 y, MELD score ≥15, or male donor) were present.

Outcomes of sexagenarian living liver donors in Korea: A multicenter study.

The safety of elderly living liver donors and recipient outcomes are always of concern. In the present study, the effects of age in 2 donor groups, a 60+years old group and a 50-59 years old group (referred to as the 60s and 50s donor groups, respectively), on living donor liver transplantation were compared regarding donor safety and recipient outcomes. We retrospectively identified 209 patients 50 years and above of age at 9 centers from 2005 to 2017 in Korea. The 60s donor group represented 10% (n=21) of donor patients. One case in each group was a left liver graft, respectively, and the others were right liver grafts. Postoperative complications were more common in the 60s donor group, but the proportion of Clavien-Dindo grade III in the 60s donor group did not differ from that in the 50s donor group. In-hospital mortality did not occur among donors, and donor mortality was not reported during the observation period. Postoperative total bilirubin and hospitalization in recipients of the 60s donor group were higher and longer than in recipients of the 50s donor group, respectively. Although the cumulative overall survival of the recipients in the 60s donor group was significantly lower than that of the 50s donor group, a difference was not observed in graft survival. Multivariate analysis showed that increased living liver donors age, the coexistence of HCC, and increased intraoperative blood loss during the recipient operation were important predisposing factors for patient death. Present study suggests that highly selected elderly living donors (≥60 y) can safely donate with similar recipient graft survival rates though the recipient overall patient survival is inferior compared to the 50s donor group.

Entecavir versus tenofovir on the recurrence of hepatitis B-related HCC after liver transplantation: A multicenter observational study.

Considerable controversy exists regarding the superiority of tenofovir disoproxil fumarate (TDF) over entecavir (ETV) for reducing the risk of HCC. This study aimed to compare outcomes of ETV versus TDF after liver transplantation (LT) in patients with HBV-related HCC. We performed a multicenter observational study using data from the Korean Organ Transplantation Registry. A total of 845 patients who underwent LT for HBV-related HCC were divided into 2 groups according to oral nucleos(t)ide analogue used for HBV prophylaxis post-LT: ETV group (n = 393) and TDF group (n = 452). HCC recurrence and overall death were compared in naïve and propensity score (PS)-weighted populations, and the likelihood of these outcomes according to the use of ETV or TDF were analyzed with various Cox models. At 1, 3, and 5 years, the ETV and TDF groups had similar HCC recurrence-free survival (90.7%, 85.6%, and 84.1% vs. 90.9%, 84.6%, and 84.2%, respectively, p = 0.98) and overall survival (98.4%, 94.7%, and 93.5% vs. 99.3%, 95.8%, and 94.9%, respectively, p = 0.48). The propensity score-weighted population showed similar results. In Cox models involving covariates adjustment, propensity score-weighting, competing risk regression, and time-dependent covariates adjustment, both groups showed a similar risk of HCC recurrence and overall death. In subgroup analyses stratified according to HCC burden (Milan criteria, Up-to-7 criteria, French alpha-fetoprotein risk score), pretransplantation locoregional therapy, and salvage LT, neither ETV nor TDF was superior. In conclusion, ETV and TDF showed mutual noninferiority for HCC outcomes when used for HBV prophylaxis after LT.

Inhibition of Dickkopf-1 enhances the anti-tumor efficacy of sorafenib via inhibition of the PI3K/Akt and Wnt/ß-catenin pathways in hepatocellular carcinoma.

BACKGROUND: Sorafenib improves the overall survival in patients with advanced hepatocellular carcinoma (HCC). Dickkopf-1 (DKK1) is commonly overexpressed in HCC. In this study, we investigated whether the inhibition of DKK1 enhances the anti-tumor efficacy of sorafenib in HCC. METHODS: HCC cells were treated with sorafenib and WAY-262611, which is an inhibitor of DKK1. Transgenic mouse models were also developed using hydrodynamic tail vein injection. Mice were orally administered with sorafenib (32 mg/kg), WAY-262611 (16 mg/kg), or sorafenib + WAY-262611 for 10 days. Mechanisms of sorafenib and WAY-262611 were explored via western blotting, immunostaining, and RNA sequencing. RESULTS: DKK1 was significantly overexpressed in patients with HCC than in the healthy controls and patients with liver diseases except HCC (all P < 0.05). Compared with sorafenib alone, sorafenib + WAY-262611 significantly inhibited the cell viability, invasion, migration, and colony formation by promoting apoptosis and altering the cell cycles in HCC cells (all P < 0.05). Moreover, sorafenib + WAY-262611 decreased the p110α, phospho-Akt (all P < 0.05), active ß-catenin (all P < 0.05) and phospho-GSK-3ß (Ser9) expression levels, while increasing the phospho-GSK-3ß (Tyr216) expression levels compared with those in the sorafenib alone in vitro and in vivo. In addition, sorafenib + WAY-262611 inhibited tumor progression by regulating cell proliferation and apoptosis, significantly better than sorafenib alone in mouse models. CONCLUSIONS: Our results indicate that DKK1 inhibition significantly enhances the anti-tumor efficacy of sorafenib by inhibiting the PI3K/Akt and Wnt/ß-catenin pathways via regulation of GSK3ß activity, suggesting a novel therapeutic strategy for HCC. Video Abstract.

Effect of statins on the recurrence of hepatocellular carcinoma after liver transplantation: An illusion revealed by exposure density sampling.

BACKGROUND: Statins have been reported to reduce overall death and hepatocellular carcinoma (HCC) recurrence in liver transplantation (LT) recipients. However, previous retrospective studies have significant flaws in immortal time bias. METHODS: Using data from 658 patients who received LT for HCC, we matched 140 statin users with statin nonusers in a 1:2 ratio at the time of the first statin administration after LT using the exposure density sampling (EDS). The propensity score, calculated using baseline variables (including explant pathology), was used for EDS to equilibrate both groups. HCC recurrence and overall death were compared after adjusting for information at the time of sampling. RESULTS: Among statin users, the median time to statin start was 219 (IQR 98-570) days, and intensity of statins was mainly moderate (87.1%). Statin users and nonusers sampled using EDS showed well-balanced baseline characteristics, including detailed tumour pathology, and similar HCC recurrence with cumulative incidences of 11.3% and 11.8% at 5 years, respectively (p = .861). In multivariate Cox models (HR 1.04, p = .918) and subgroup analyses, statins did not affect HCC recurrence. Conversely, statin users showed a significantly lower risk of overall death than nonusers (HR 0.28, p < .001). There was no difference in the type and intensity of statin usage between statin users who experienced HCC recurrence and those who did not. CONCLUSION: Upon controlling immortal time bias by EDS, statins did not affect HCC recurrence but reduced mortality after LT. Statin usage is encouraged for survival benefits but not for preventing HCC recurrence in LT recipients.

Optimal imaging criteria and modality to determine Milan criteria for the prediction of post-transplant HCC recurrence after locoregional treatment.

OBJECTIVES: We aimed to investigate the optimal radiologic method to determine Milan criteria (MC) for the prediction of recurrence in patients who underwent locoregional treatment (LRT) for hepatocellular carcinoma (HCC) and subsequent liver transplantation (LT). METHODS: This retrospective study included 121 HCC patients who underwent LRT and had both liver dynamic CT and MRI. They were classified with MC using four cross combinations of two imaging modalities (CT and MRI) and two diagnostic criteria (modified Response Evaluation Criteria in Solid Tumors [mRECIST] and Liver Imaging Reporting and Data System treatment response algorithm [LI-RADS TRA]). Competing risk regression was performed to analyze the time to recurrence after LT. The predictive abilities of the four methods for recurrence were evaluated using the time-dependent area under the curve (AUC). RESULTS: Competing risk regression analyses found that beyond MC determined by MRI with mRECIST was independently associated with recurrence (hazard ratio, 6.926; p = 0.001). With mRECIST, MRI showed significantly higher AUCs than CT at 3 years and 5 years after LT (0.597 vs. 0.756, p = 0.012 at 3 years; and 0.588 vs. 0.733, p = 0.024 at 5 years). Using the pathologic reference standard, MRI with LI-RADS TRA showed higher sensitivity (61.5%) than CT with LI-RADS TRA (30.8%, p < 0.001) or MRI with mRECIST (38.5%, p < 0.001). CONCLUSIONS: MRI with mRECIST was the optimal radiologic method to determine MC for the prediction of post-LT recurrence in HCC patients with prior LRT. KEY POINTS: • MRI with modified RECIST (mRECIST) is the optimal preoperative method to determine Milan criteria for the prediction of post-transplant HCC recurrence in patients with prior locoregional treatment. • With mRECIST, MRI was better than CT for the prediction of post-transplant recurrence.

Incidence, mortality, and risk factors associated with carbapenem-resistant Acinetobacter baumannii bacteremia within 30 days after liver transplantation.

Carbapenem-resistant Acinetobacter baumannii bacteremia (CRAB-B) is a fatal infectious complication of liver transplantation (LT). This study investigated the incidence, effects, and risk factors associated with CRAB-B during the early post-LT period. Among 1051 eligible LT recipients, 29 patients experienced CRAB-B within 30 days of LT with a cumulative incidence of 2.7%. In the patients with CRAB-B (n = 29) and matched controls (n = 145) by nested-case control design, the cumulative incidence of death on days 5, 10, and 30 from the index date was 58.6%, 65.5%, and 65.5%, and 2.1%, 2.8%, and 4.2%, respectively (p < .001). Pre-transplant MELD (OR 1.11, 95% confidence interval [CI] 1.04-1.19, p = .002), severe encephalopathy (OR 4.62, 95% CI 1.24-18.61, p = .025), donor body mass index (OR .57, 95% CI .41-.75, p < .001), and reoperation (OR 6.40, 95% CI 1.19-36.82, p = .032) were independent risk factors for 30-day CRAB-B. CRAB-B showed extremely high mortality within 30 days after LT, especially within 5 days after its occurrence. Therefore, assessment of risk factors and early detection of CRAB, followed by proper treatment, are necessary to control CRAB-B after LT.