SOD1 inhibition enhances sorafenib efficacy in HBV-related hepatocellular carcinoma by modulating PI3K/Akt/mTOR pathway and ROS-mediated cell death.

Hepatitis B Virus (HBV) infection significantly elevates the risk of hepatocellular carcinoma (HCC), with the HBV X protein (HBx) playing a crucial role in cancer progression. Sorafenib, the primary therapy for advanced HCC, shows limited effectiveness in HBV-infected patients due to HBx-related resistance. Numerous studies have explored combination therapies to overcome this resistance. Sodium diethyldithiocarbamate (DDC), known for its anticancer effects and its inhibition of superoxide dismutase 1 (SOD1), is hypothesized to counteract sorafenib (SF) resistance in HBV-positive HCCs. Our research demonstrates that combining DDC with SF significantly reduces HBx and SOD1 expressions in HBV-positive HCC cells and human tissues. This combination therapy disrupts the PI3K/Akt/mTOR signalling pathway and promotes apoptosis by increasing reactive oxygen species (ROS) levels. These cellular changes lead to reduced tumour viability and enhanced sensitivity to SF, as evidenced by the synergistic suppression of tumour growth in xenograft models. Additionally, DDC-mediated suppression of SOD1 further enhances SF sensitivity in HBV-positive HCC cells and xenografted animals, thereby inhibiting cancer progression more effectively. These findings suggest that the DDC-SF combination could serve as a promising strategy for overcoming SF resistance in HBV-related HCC, potentially optimizing therapy outcomes.

Recipient blood group does not affect hepatocellular carcinoma recurrence after living donor liver transplantation in Korea.

PURPOSE: This study assessed whether or not the ABO blood type affects the incidence of HCC recurrence after living donor liver transplantation (LDLT). METHODS: This retrospective observational study included 856 patients with hepatocellular carcinoma (HCC) who underwent LDLT between January 2006 and December 2016 at the Asan Medical Center. RESULTS: This study included 324 patients (37.9%) with blood type A, 215 (25.1%) with blood type B, 210 (24.5%) with blood type O, and 107 (12.5%) with blood type AB. ABO-incompatible LT was performed in 136 (15.9%) patients. The independent risk factors for the disease-free survival (DFS) were maximal tumor diameter, microvascular invasion, and Milan criteria. The only independent risk factor for the overall survival (OS) was microvascular invasion. The ABO blood group did not affect the DFS (P = 0.978) or OS (P = 0.261). The DFS according to the ABO blood group did not differ significantly between the ABO-compatible (p = 0.701) and ABO-incompatible LDLT recipients (p = 0.147). The DFS according to the ABO blood group did not differ significantly between patients within the Milan criteria (p = 0.934) and beyond the Milan criteria (p = 0.525). The DFS did not differ significantly between recipients with and without type A blood (p = 0.941). CONCLUSIONS: This study demonstrated that the ABO blood group system had no prognostic impact on the oncological outcomes of patients undergoing LT for HCC.

A novel scoring system to predict short-term mortality after living donor liver transplantation for acute liver failure.

Liver transplantation is often the only lifesaving option for acute liver failure (ALF); however, the predictors of short-term mortality (death within one year) after living donor liver transplantation (LDLT) for ALF have yet to be defined. We retrospectively collected patients ≥18 years old who underwent LDLT for ALF between 2010 and 2020 at 35 centers in Asia. Univariate and multivariate logistic regression analyses were conducted to identify the clinical variables related to short-term mortality and establish a novel scoring system. The Kaplan-Meier method was performed to explore the association between the score and overall survival. Of the 339 recipients, 46 (13.6%) died within 1 year after LDLT. Multivariate analyses revealed 4 independent risk factors for death: use of vasopressors or mechanical ventilation, the higher model for end-stage liver disease score, and a lower graft-to-recipient weight ratio. The internally validated c-statistic of the short-term mortality after transplant (SMT) score derived from these 4 variables was 0.80 (95% confidence interval: 0.74-0.87). The SMT score successfully stratified recipients into low-, intermediate-, and high-risk groups with 1-year overall survival rates of 96%, 80%, and 50%, respectively. In conclusion, our novel SMT score based on 4 predictors will guide ALF recipient and living donor selection.

Outcomes of 6000 living donor liver transplantation procedures: a pioneering experience at ASAN Medical Center.

Living donor liver transplantation (LDLT) has emerged as a favorable alternative to deceased donor liver transplantation, significantly reducing waitlist mortality, particularly in Asian countries with very low deceased organ donation rates. Asan Medical Center (AMC) in South Korea has pioneered innovative LDLT surgical techniques and become established as an extremely high-volume center for LDLT. This retrospective study analyzed 6000 consecutive LDLT procedures, including 510 dual-graft procedures, performed at AMC between December 1994 and January 2021. Of these, 312 LDLT procedures were performed in children aged < 18 years. In adult recipients, liver cirrhosis (LC) related to viral hepatitis was the most common indication, occurring in 69.8% of cases. Biliary atresia (46.8%) was the most common indication for pediatric LDLT. This study demonstrated outstanding long-term outcomes, with patient survival rates at 1, 5, 10, and 20 years of 92.7%, 85.9%, 82.1%, and 70.9%, respectively, in LDLT group for adults aged 50 and under at the time of LDLT, and 92.9%, 89.0%, 88.1%, and 81.9%, respectively, in the pediatric group. The in-hospital mortality rate of adult recipients was 3.8% (n = 214/5688). This study demonstrates the importance of refined surgical techniques, selection of grafts tailored to the recipient, and comprehensive multidisciplinary perioperative patient care in expanding the scope of LDLT and improving recipient outcomes.

Probing Inherent Optical Anisotropy in Substrates via Direct Nanoimaging of Mie Scattering.

In this study, we investigated the optical properties of a transition metal dichalcogenide (TMD) substrate via Mie-scattering-induced surface analysis (MISA). Employing near-field optical microscopy and finite-difference time-domain (FDTD) simulations, we systemically prove and directly visualize the Mie scattering of superspherical gold nanoparticles (s-AuNPs) at the nanoscale. Molybdenum disulfide substrates exhibited optical isotropy, while rhenium disulfide (ReS2) substrates showed anisotropic behavior attributed to the interaction with incident light's electric field. Our study revealed substantial anisotropic trends in Mie scattering, particularly in the near-infrared energy range, with ReS2 exhibiting more pronounced spectral and angular responses in satellite peaks. Our results emphasize the application of Mie scattering, exploring the optical properties of substrates and contributing to a deeper understanding of nanoscale light-matter interactions.

Safety of right liver donation after improving steatosis through weight loss in living donors: a retrospective study.

BACKGROUND: Living donor liver transplantation using hepatic steatosis-improved grafts mitigates donor shortage. Herein, we aimed to evaluate the safety and feasibility of right-lobe adult-to-adult living donor liver transplantation using grafts improved through donor weight loss. METHODS: In this retrospective study conducted in a single institution in the Republic of Korea, we reviewed the medical records of living liver donors who lost ≥ 10% of their body weight to improve steatosis before right lobe donation between January 2015 and December 2020. Overall, 1040 right-lobe donors were included, with 150 and 890 donors in the weight loss and control (non-steatosis) groups, respectively. RESULTS: We performed 1:1 individual matching using the greedy matching method, by which 124 patients were included in each group. The median period from the date of the first visit to donation was 113 (interquartile range: 78-184) days in the weight loss group. As body weight changed from 82.8 ± 13.7 kg to 70.8 ± 11.8 kg (p < 0.0001), body mass index also improved from 27.8 ± 3.9 kg/m2 to 23.8 ± 3.1 kg/m2 (p < 0.0001). No significant between-group differences existed in the postoperative laboratory data for living donors and recipients. The incidence of postoperative complications in donors was comparable between the groups (control group, 9.7%; weight loss group, 13.7%; p = 0.3185). The graft and recipient survival rates were comparable between the groups (p = 1.000). CONCLUSION: Weight loss through diet and exercise significantly could improve hepatic steatosis in living donor candidates for liver transplantation, with the surgical outcomes in recipients and donors being equivalent to those in recipients and non-steatotic donors.

Risk of Cerebral Aneurysm Rupture After Liver Transplantation: Development and Validation of a Hemorrhagic Stroke Scoring Model.

BACKGROUND: Liver transplantation (LT) patients appear to be more prone to neurological events compared to individuals undergoing other types of solid-organ transplantation. The aims of the present study were to analyze the prevalence of unruptured intracranial aneurysms (UIAs) in patients undergoing liver transplantation (LT) and to examine the perioperative occurrence of subarachnoid hemorrhage (SAH). Also, it intended to systematically identify the risk factors of SAH and hemorrhagic stroke (HS) within a year after LT and to develop a scoring system which involves distinct clinical features of LT patients. METHODS: Patients who underwent LT from January 2012 to March 2022 were analyzed. All included patients underwent neurovascular imaging within 6 months before LT. We conducted an analysis of prevalence and radiological features of UIA and SAH. The clinical factors that may have an impact on HS within one year of LT were also reviewed. RESULTS: Total of 3,487 patients were enrolled in our study after applying inclusion and exclusion criteria. The prevalence of UIA was 5.4%. The incidence of SAH and HS within one year following LT was 0.5% and 1.6%, respectively. We developed a scoring system based on multivariable analysis to predict the HS within 1-year after LT. The variables were a poor admission mental status, the diagnosis of UIA, serum ammonia levels, and Model for End-stage Liver Disease (MELD) scores. Our model showed good discrimination among the development (C index, 0.727; 95% confidence interval [CI], 0.635-0.820) and validation (C index, 0.719; 95% CI, 0.598-0.801) cohorts. CONCLUSION: The incidence of UIA and SAH was very low in LT patients. A poor admission mental status, diagnosis of UIA, serum ammonia levels, and MELD scores were significantly associated with the risk of HS within one year after LT. Our scoring system showed a good discrimination to predict the HS in LT patients.

Catalytic enhancements in cytochrome P450 2C19 by cytochrome b5.

Human cytochrome P450 2C19 catalyzes P450 enzyme reactions of various substrates, including steroids and clinical drugs. Recombinant P450 2C19 enzyme with histidine tag was successfully expressed in Escherichia coli and purified using affinity column chromatography. Ultra-performance liquid chromatography-tandem mass (UPLC-MS/MS) spectrometry showed that the purified P450 2C19 enzyme catalyzed 5-hydroxylation reaction of omeprazole. The purified enzyme displayed typical type I binding spectra to progesterone with a Kd value of 4.5 ± 0.2 µM, indicating a tight substrate binding. P450 2C19 catalyzed the hydroxylation of progesterone to produce 21-hydroxy (OH) as a major and 17-OH product as a minor product. Steady-state kinetic analysis of progesterone 21-hydroxylation indicated that the addition of cytochrome b5 stimulated a five-times catalytic turnover number of P450 2C19 with a kcat value of 1.07 ± 0.08 min-1. The molecular docking model of progesterone in the active site of P450 2C19 displayed that the 21-carbon of progesterone was located close to the heme with a distance of 4.7 Å, suggesting 21-hydroxylation of progesterone is the optimal reaction of P450 2C19 enzyme for a productive orientation of the substrate. Our findings will help investigate the extent to which cytochrome b5 affects the metabolism of P450 2C19 to drugs and steroids. Supplementary Information: The online version contains supplementary material available at 10.1007/s43188-023-00219-8.

No Prognostic Impact of Graft-to-Recipient Weight Ratio on Hepatocellular Carcinoma Recurrence Following Living Donor Liver Transplantation.

BACKGROUND The effects of a low graft-to-recipient weight ratio (GRWR) on the prognosis of patients with hepatocellular carcinoma (HCC) are unclear. The present study examined whether the GRWR had an impact on the rate of HCC recurrence following living donor liver transplantation (LDLT). MATERIAL AND METHODS This retrospective observational single-center study included 856 patients who underwent LDLT for HCC between January 2006 and December 2016 at Asan Medical Center and evaluated the association between GRWR and post-transplant tumor recurrence. RESULTS Of the 856 patients who underwent LDLT for HCC, 54 (6.3%), 272 (31.8%), 274 (32.0%), and 256 (29.9%) had GRWR <0.8%, 0.8-0.99%, 1.0-1.19%, and ≥1.2%, respectively. Analysis of all patients revealed that the disease-free survival (DFS; P=0.545) and overall survival (OS; P=0.313) rates were not different in these 4 groups. Subgroups analyses also showed that GRWR did not influence survival rates in patients within (DFS: P=0.398; OS: P=0.676) and beyond (DFS: P=0.602; OS: P=0.649) the Milan criteria, or in patients with alpha-fetoprotein-des-γ-carboxyprothrombin-tumor volume scores <5log (DFS: P=0.633; OS: p=0.285) and ≥5log (DFS: P=0.674; OS: P=0.906). CONCLUSIONS GRWR less than 0.8% did not demonstrate a noteworthy prognostic influence on the oncological results among patients who had undergone LDLT for HCC. High-volume multi-center studies are necessary to validate these findings.

Reconstruction of all hepatic arteries in right lobe grafts with 2 hepatic arteries and zero percent hepatic artery thrombosis.

Hepatic artery thrombosis (HAT) is a common cause of graft loss in living-donor liver transplantation, occurring in ~2.5%-8% of patients. Some right lobe grafts have 2 hepatic arteries (HAs), and the optimal reconstruction technique remains controversial. This study aimed to identify risk factors for HAT and to evaluate the efficacy of reconstructing 2 HAs in right lobe grafts. This retrospective, single-center study analyzed 1601 living-donor liver transplantation recipients with a right liver graft and divided them into 1 HA (n = 1524) and 2 HA (n = 77) groups. The reconstruction of all HAs was performed using a microscope with an interrupted suture. The primary outcome was any HAT event. Of the 1601 patients, 37.8% had a history of transcatheter arterial chemoembolization, and 130 underwent pretransplant hepatectomy. Extra-anatomical arterial reconstruction was performed in 38 cases (2.4%). HAT occurred in 1.2% of patients (20/1601) who underwent surgical revascularization. In the multivariate analysis, undergoing pretransplant hepatectomy ( p = 0.008), having a female donor ( p = 0.02), having a smaller graft-to-recipient weight ratio ( p = 0.002), and undergoing extra-anatomical reconstruction ( p = 0.001) were identified as risk factors for HAT. However, having 2 HA openings in right liver grafts was not a risk factor for HAT in our series. Kaplan-Meier survival analysis showed no significant difference in graft survival and patient survival rates between the 1 HA and 2 HA groups ( p = 0.09, p = 0.97). In our series, although the smaller HA in the 2 HA group should increase the risk of HAT, HAT did not occur in this group. Therefore, reconstructing both HAs when possible may be a reasonable approach in living-donor liver transplantation using a right liver graft with 2 HA openings.

Safety and outcome of treatment of latent tuberculosis infection in liver transplant recipients.

PURPOSE: Liver transplant (LT) recipients have an increased risk of tuberculosis (TB), which is associated with higher mortality rates. This retrospective cohort study assessed the outcome and tolerability of screening and treatment of latent tuberculosis infection (LTBI) in LT recipients. METHODS: Between March 2020 and February 2022, all adult LT candidates at our institution were screened for LTBI. The candidates who tested positive for interferon-γ-releasing assay or met epidemiological or clinical-radiological criteria for LTBI were treated and monitored. RESULTS: Among the 857 LT recipients, 199 (23.2%) were diagnosed with LTBI, of which 171 (85.9%) initiated LTBI treatment. The median duration of follow-up was 677 days. Adequate LTBI treatment occurred in 141/171 (82.5%) patients and was discontinued prematurely in 30/171 (17.5%) patients. The most common reason for discontinuation was liver enzyme elevation (11/30, 36.7%), although only five discontinued treatment due to suspicion of isoniazid-associated hepatotoxicity. None of the LTBI-treated patients developed active TB during the follow-up period, while 3.6% (1/28) of untreated LTBI patients and 0.6% (4/658) of patients without LTBI developed TB. CONCLUSION: These findings demonstrate that LTBI screening and treatment is a safe and effective strategy to prevent TB in LT recipients. However, monitoring for adverse events and liver enzyme elevation is recommended.

Achieving 400 Living Donor Liver Transplantations Annually During the COVID-19 Pandemic: A Single-Center Experience.

BACKGROUND: The COVID-19 pandemic has had a major impact on liver transplantation (LT) and living donor programs globally. PURPOSE: In this study, we aimed to present the principles and strategies of our LT program during the pandemic period and describe its achievements. BASIC PROCEDURES: We retrospectively reviewed the outcomes of 1417 LTs performed at Asan Medical Center, Seoul, Korea, from 2020 to 2022. Of these, 216 recipients who received transplants from deceased donors were excluded, and 1201 recipients who received transplants from 1268 live donors were included in the study, including 38 children <18 years old. MAIN FINDINGS: Among the 1201 living donor LT (LDLT) recipients, the most common indication for LT was unresectable hepatocellular carcinoma (315/1163, 27.1%) in adults and biliary atresia (29/38, 76.3%) in pediatric recipients. Emergency LDLT was performed in 40 patients (3.3%). The median model of end-stage liver disease and pediatric end-stage liver disease scores were 13.9 ± 7.2 and 13.8 ± 7.1, respectively. In-hospital mortality of recipients was higher than usual at 2.2%, but the cause of death was not related to COVID-19 infection. Of the 1268 live donors who underwent hepatectomy for liver donation, 660 (52.1%) underwent hepatectomy using a minimally invasive approach. Although 17 (1.3%) live donors experienced major complications, there were no serious life-threatening complications and no mortality. CONCLUSION: Even in a pandemic era, a team with well-established infection control protocols, patient-tailored surgical strategies, and thorough perioperative care can maintain LDLT at a similar quantitative and qualitative level as in a non-pandemic era.

Antioxidant, Antibacterial Properties of Novel Peptide CP by Enzymatic Hydrolysis of Chromis notata By-Products and Its Efficacy on Atopic Dermatitis.

This study investigated the antioxidant, antimicrobial, and anti-atopic dermatitis (AD) effects of a novel peptide (CP) derived from a Chromis notata by-product hydrolysate. Alcalase, Flavourzyme, Neutrase, and Protamex enzymes were used to hydrolyze the C. notata by-product protein, and the 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) radical-scavenging activity was measured. Alcalase hydrolysate exhibited the highest ABTS radical-scavenging activity, leading to the selection of Alcalase for further purification. The CHAO-1-I fraction, with the highest ABTS activity, was isolated and further purified, resulting in the identification of the peptide CP with the amino acid sequence Ala-Gln-Val-Met-Lys-Leu-Pro-His-Arg-Met-Gln-His-Ser-Gln-Ser. CP demonstrated antimicrobial activity against Staphylococcus aureus, inhibiting its growth. In a 2,4-dinitrochlorobenzene (DNCB)-induced AD-like skin model in mice, CP significantly alleviated skin lesions, reduced epidermal and dermal thickness, and inhibited mast cell infiltration. Moreover, CP suppressed the elevated levels of interleukin-6 (IL-6) in the plasma of DNCB-induced mice. These findings highlight the potential of CP as a therapeutic agent for AD and suggest a novel application of this C. notata by-product in the fish processing industry.