High intra-patient variability of tacrolimus within post-operative 1 month predicted worse 1-year outcomes in pediatric liver transplant recipients.

BACKGROUND: The pharmacokinetics of tacrolimus (TAC) show high intra-patient variability (IPV), which is associated with poor long-term outcomes following adult liver transplantation (LT). However, this relationship remains to be confirmed in pediatric liver transplant (PLT) recipients. The present study aimed to investigate the association between TAC IPV and grafts or patient outcomes after pediatric liver transplantion. METHODS: This retrospective study included 848 PLT recipients (including infants) between January, 2016, and June, 2021. The IPV of TAC concentrations was estimated by calculating the coefficient of variation (CV) of trough concentrations in whole blood within 1 month after transplantation. Patients were categorized into two groups, low IPV (CV < 45%) and high IPV (CV ≥ 45%), based on the third quartile of the CV distribution. RESULTS: A total of 848 patients were included in our study. The low CV group included 614 patients, with a mean TAC trough concentration of 8.59 ± 1.65 ng/ml and a median CV of 32.37%. In contrast, the high CV group included 214 patients, the mean TAC trough concentration and median CV were 8.81 ± 2.00 ng/ml and 54.88%, respectively. The median hospital duration was significantly higher in the high CV group (22 days vs. 20 days, P = 0.01). Univariate analysis was performed to evaluate the significant differences in 1-year recipient survival (P = 0.041) and 1-year graft survival (P = 0.005) between the high- and low-CV groups. Moreover, high CV (HR 2.316, 95%CI 1.026-5.231, P = 0.043) and persistent EBV viremia (HR 13.165, 95%CI 3.090-56.081, P < 0.001) were identified as independent risk factors for 1- year mortality after PLT. CONCLUSIONS: PLT recipients with high TAC trough concentration of CV in the first month were associated with poor 1-year outcomes. This CV calculation provides a valuable strategy to monitor TAC exposure.

Evaluation of the effectiveness and safety of sequential vaccination with inactivated SARS-CoV-2 vaccine and Ad5-nCoV booster in pediatric liver transplant recipients.

Amidst the COVID-19 pandemic, uncertainty persists among caregivers regarding the vaccination of pediatric liver transplant recipients (PLTRs). This study evaluates the immunogenicity and safety of COVID-19 vaccination in this vulnerable population. A cohort of 30 PLTRs underwent sequential vaccinations with an inactivated SARS-CoV-2 vaccine followed by an Ad5-nCoV booster. We collected and analyzed blood samples pre-vaccination and four weeks post-vaccination to quantify antibody and IGRA (IFN-γ Release Assay) levels. We also documented any adverse reactions occurring within seven days post-vaccination and monitored participants for infections over six months post-vaccination, culminating in a comprehensive statistical analysis. The Ad5-nCoV booster substantially elevated IgG (T1: 18.01, 20%; T2: 66.61, 55%) and nAb (T1: 119.29, 8%; T2: 3799.75, 80%) levels, as well as T-cell responses, in comparison to the initial dose. The first dose was associated with some common adverse reactions, such as injection site pain (13.3%) and fever (16.6%), but a low rate of systemic reactions (16.0%). There was no significant difference in Omicron infection rates or RTPCR conversion times between vaccinated and unvaccinated groups. Notably, following Omicron infection, vaccinated individuals exhibited significantly higher SARS-CoV-2 IgG and nAb titers (average IgG: 231.21 vs. 62.09 S/CO, p = 0.0003; nAb: 5246.11 vs. 2592.07 IU/mL, p = 0.0002). The use of inactivated vaccines followed by an Ad5-nCoV booster in PLTRs is generally safe and elicits a robust humoral response, albeit with limited T-cell responses.

Circ_0001825 promotes osteogenic differentiation in human-derived mesenchymal stem cells via miR-1270/SMAD5 axis.

BACKGROUND: The implication of deregulated circular RNAs in osteoporosis (OP) has gradually been proposed. Herein, we aimed to study the function and mechanism of circ_0001825 in OP using osteogenic-induced human-derived mesenchymal stem cells (hMSCs). METHODS: The content of genes and proteins was tested by quantitative real-time polymerase chain reaction and Western blotting. The osteogenic differentiation in hMSCs were evaluated by ALP activity and Alizarin Red staining, as well as the detection of osteogenesis-related markers. Cell viability and apoptosis were measured by CCK-8 assay and flow cytometry. The binding between miR-1270 and circ_0001825 or SMAD5 (SMAD Family Member 5) was confirmed by using dual-luciferase reporter assay and pull-down assay. RESULTS: Circ_0001825 was lowly expressed in OP patients and osteogenic induced hMSCs. Knockdown of circ_0001825 suppressed hMSC viability and osteogenic differentiation, while circ_0001825 overexpression showed the exact opposite effects. Mechanistically, circ_0001825/miR-1270/SMAD5 formed a feedback loop. MiR-1270 was increased and SMAD5 was decreased in OP patients and osteogenic induced hMSCs. MiR-1270 up-regulation suppressed hMSC viability and osteogenic differentiation, which was reversed by SMAD5 overexpression. Moreover, miR-1270 deficiency abolished the effects of circ_0001825 knockdown on hMSCs. CONCLUSION: Circ_0001825 promoted hMSC viability and osteogenic differentiation via miR-1270/SMAD5 axis, suggesting the potential involvement of circ_0001825 in osteoporosis.

Knowledge, attitude, and practice regarding sarcopenia: a survey between orthopedic and geriatric professionals in China.

BACKGROUND: In elderly patients with fractures, sarcopenia impairs recovery and even increases mortality. Both orthopedic and geriatric professionals are at the forefront of treating sarcopenic patients with fractures. However, it is not clear to what extent they have knowledge and skills to diagnose and treat sarcopenia. AIMS: This study aimed to analyze and compare knowledge, attitude, and practice regarding sarcopenia between orthopedic and geriatric professionals. METHODS: An online cross-sectional survey was conducted in June 2022 targeting professionals in orthopedic and geriatric departments in two largest tertiary general hospitals in Taizhou, southeastern China. Results on knowledge, attitude, and practice of sarcopenia were analyzed. Variables with significance were then included in a stepwise multiple linear regression analysis. RESULTS: A total of 220 professionals, 176 from orthopedic departments and 44 from geriatric departments, participated in this study. Orthopedic professionals scored lower than geriatrics in knowledge, attitude and practice (P < 0.001). The attitude score was high in both orthopedic and geriatric professionals. Stepwise multiple linear regression analysis showed that participants who had contact with sarcopenia patients had higher knowledge score (ß = 1.941, P < 0.001); participants who had attended sarcopenia training in the past 6 months (ß = 4.305, P < 0.001) had higher practice score. DISCUSSION: Orthopedic professionals have deficiencies in the screening and diagnosis of sarcopenia. Improving the knowledge and training of professionals can strengthen practice. It is necessary to formulate diagnostic criteria and improve practice of sarcopenia through training. CONCLUSION: Orthopedic professionals had limited knowledge and practice regarding sarcopenia compared with geriatric professionals. To improve sarcopenia practice, the use of diagnostic tools to formally diagnose sarcopenia and regular training on sarcopenia should be encouraged.

EGFL6 promotes bone metastasis of lung adenocarcinoma by increasing cancer cell malignancy and bone resorption.

Lung adenocarcinoma is the most common and aggressive type of lung cancer with the highest incidence of bone metastasis. Epidermal growth factor-like domain multiple 6 (EGFL6) is an exocrine protein, and the expression of EGFL6 is correlated with survival of patient with lung adenocarcinoma. However, the association between EGFL6 expression in lung adenocarcinoma and bone metastasis has not been investigated. In this study, we found that EGFL6 levels in lung adenocarcinoma tissues correlate with bone metastasis and TNM stages in surgical patients. In vitro, overexpression of EGFL6 in lung adenocarcinoma cells promoted their proliferation, migration, and invasion ability compared with control by enhancing EMT process and activating Wnt/ß-catenin and PI3K/AKT/mTOR pathways. In the nude mouse model, overexpression of EGFL6 enhanced tumor growth and caused greater bone destruction. Moreover, the exocrine EGFL6 of human lung adenocarcinoma cells increased osteoclast differentiation of bone marrow mononuclear macrophages (BMMs) of mice via the NF-κB and c-Fos/NFATc1 signaling pathways. However, exocrine EGFL6 had no effect on osteoblast differentiation of bone marrow mesenchymal stem cells (BMSCs). In conclusion, high expression of EGFL6 in lung adenocarcinomas is associated with bone metastasis in surgical patients. The underlying mechanism may be the increased metastatic properties of lung adenocarcinoma cells with high EGFL6 level and the enhanced osteoclast differentiation and bone resorption by exocrine EGFL6 from tumors. Therefore, EGFL6 is a potential therapeutic target to reduce the ability of lung adenocarcinomas to grow and metastasize and to preserve bone mass in patients with bone metastases from lung adenocarcinomas.

Nucleolar HEAT Repeat Containing 1 Up-regulated by the Mechanistic Target of Rapamycin Complex 1 Signaling Promotes Hepatocellular Carcinoma Growth by Dominating Ribosome Biogenesis and Proteome Homeostasis.

BACKGROUND & AIMS: Hyperactivation of ribosome biogenesis leads to hepatocyte transformation and plays pivotal roles in hepatocellular carcinoma (HCC) development. We aimed to identify critical ribosome biogenesis proteins that are overexpressed and crucial in HCC progression. METHODS: HEAT repeat containing 1 (HEATR1) expression and clinical correlations were analyzed using The Cancer Genome Atlas and Gene Expression Omnibus databases and further evaluated by immunohistochemical analysis of an HCC tissue microarray. Gene expression was knocked down by small interfering RNA. HEATR1-knockdown cells were subjected to viability, cell cycle, and apoptosis assays and used to establish subcutaneous and orthotopic tumor models. Chromatin immunoprecipitation and quantitative polymerase chain reaction were performed to detect the association of candidate proteins with specific DNA sequences. Endogenous coimmunoprecipitation combined with mass spectrometry was used to identify protein interactions. We performed immunoblot and immunofluorescence assays to detect and localize proteins in cells. The nucleolus ultrastructure was detected by transmission electron microscopy. Click-iT (Thermo Fisher Scientific) RNA imaging and puromycin incorporation assays were used to measure nascent ribosomal RNA and protein synthesis, respectively. Proteasome activity, 20S proteasome foci formation, and protein stability were evaluated in HEATR1-knockdown HCC cells. RESULTS: HEATR1 was the most up-regulated gene in a set of ribosome biogenesis mediators in HCC samples. High expression of HEATR1 was associated with poor survival and malignant clinicopathologic features in patients with HCC and contributed to HCC growth in vitro and in vivo. HEATR1 expression was regulated by the transcription factor specificity protein 1, which can be activated by insulin-like growth factor 1-mammalian target of rapamycin complex 1 signaling in HCC cells. HEATR1 localized predominantly in the nucleolus, bound to ribosomal DNA, and was associated with RNA polymerase I transcription/processing factors. Knockdown of HEATR1 disrupted ribosomal RNA biogenesis and impaired nascent protein synthesis, leading to reduced cytoplasmic proteasome activity and inhibitory-κB/nuclear factor-κB signaling. Moreover, HEATR1 knockdown induced nucleolar stress with increased nuclear proteasome activity and inactivation of the nucleophosmin 1-MYC axis. CONCLUSIONS: Our study revealed that HEATR1 is up-regulated by insulin-like growth factor 1-mammalian target of rapamycin complex 1-specificity protein 1 signaling in HCC and functions as a crucial regulator of ribosome biogenesis and proteome homeostasis to promote HCC development.

SARS-CoV-2 BA.2 (Omicron) variant infection in pediatric liver transplanted recipients and cohabitants during 2022 Shanghai outbreak: a prospective cohort.

BACKGROUND: The Omicron variant BA.2 was the dominant variant in the COVID-19 outbreak in Shanghai since March 2022. We aim to investigate the characteristics of SARS-CoV-2 Omicron variant infection in pediatric liver-transplanted recipients. METHODS: We conducted a single-center, prospective, observational, single-arm study. We enrolled pediatric liver-transplanted patients infected with the Omicron variant BA.2 from March 19th to October 1st, 2022 and analyzed their demographic, clinical, laboratory, and outcome data. The management of COVID-19 was conducted according to the 9th trial edition of the Chinese guideline. The immunosuppressive therapy was tailored considering the patients' infection developments and liver functions. RESULTS: Five children were included. The primary diseases included Niemann-Pick disease, propionic acidemia, decompensated cirrhosis, biliary atresia, and Crigler-Najjar syndrome type I. All of the patients were onset with fever before or when getting RNA-positive results at the age of 3 (Range: 1-13) years. The infection duration was 29 (Range: 18-40) days. Three and two children were diagnosed with mild and moderate COVID-19 respectively. Two patients were tested RNA-positive within 14 days after having been tested negative. The immunosuppressants were paused or extenuated in four patients. Eight of all nine cohabitants were injected with at least two doses of inactivated SARS-CoV-2 vaccine. The disease courses were significantly longer than the patients (P < 0.05). CONCLUSIONS: Post-transplant immunosuppression slows down the virus clearance and increases the risk of relapse but does not affect symptom duration or infection severity in pediatric patients. Patients can usually gain a favorable outcome and prognosis by extenuating immunosuppressants.

Pure laparoscopic versus open left lateral hepatectomy in pediatric living donor liver transplantation: a review and meta-analysis.

PURPOSE: The meta-analysis was conducted to evaluate the safety and feasibility of pure laparoscopic left lateral hepatectomy in comparison with open approach for pediatric living donor liver transplantation (LDLT). METHODS: A systemic literature survey was performed by searching the PubMed, EMBASE and Cochrane Library databases for articles that compared pure laparoscopic left lateral living donor hepatectomy (LLDH) and open left lateral living donor hepatectomy (OLDH) by November 2021. Meta-analysis was performed to assess donors' and recipients' perioperative outcomes using RevMan 5.3 software. RESULTS: A total of five studies involving 432 patients were included in the analysis. The results demonstrated that LLDH group had significantly less blood loss (WMD = -99.28 ml, 95%CI -152.68 to -45.88, p = 0.0003) and shorter length of hospital stay (WMD = -2.71d, 95%CI -3.78 to -1.64, p < 0.00001) compared with OLDH group. A reduced donor overall postoperative complication rate was observed in the LLDH group (OR = 0.29, 95%CI 0.13-0.64, p = 0.002). In the subgroup analysis, donor bile leakage, wound infection and pulmonary complications were similar between two groups (bile leakage: OR = 1.31, 95%CI 0.43-4.02, p = 0.63; wound infection: OR = 0.38, 95%CI 0.10-1.41, p = 0.15; pulmonary complications: OR = 0.24, 95%CI 0.04-1.41, p = 0.11). For recipients, there were no significant difference in perioperative outcomes between the LLDH and OLDH group, including mortality, overall complications, hepatic artery thrombosis, portal vein and biliary complications. CONCLUSION: LLDH is a safe and effective alternative to OLDH for pediatric LDLT, reducing invasiveness and benefiting postoperative recovery. Future large-scale multi-center studies are expected to confirm the advantages of LLDH in pediatric LDLT.

Single-cell transcriptomics uncovers cellular architecture and developmental trajectories in hepatoblastoma.

BACKGROUND AND AIMS: Hepatoblastoma (HB) is the predominant type of childhood liver cancer. Treatment options for the clinically advanced HB remain limited. We aimed to dissect the cellular and molecular basis underlying HB oncogenesis and heterogeneity at the single-cell level, which could facilitate a better understanding of HB at both the biological and clinical levels. APPROACH AND RESULTS: Single-cell transcriptome profiling of tumor and paired distal liver tissue samples from five patients with HB was performed. Deconvolution analysis was used for integrating the single-cell transcriptomic profiles with the bulk transcriptomes of our HB cohort of post-neoadjuvant chemotherapy tumor samples. A single-cell transcriptomic landscape of early human liver parenchymal development was established for exploring the cellular root and hierarchy of HB oncogenesis. As a result, seven distinct tumor cell subpopulations were annotated, and an effective HB subtyping method was established based on their compositions. A HB tumor cell hierarchy was further revealed to not only fit with the classical cancer stem cell (CSC) model but also mirror the early human liver parenchymal development. Moreover, FACT inhibition, which could disrupt the oncogenic positive feedback loop between MYC and SSRP1 in HB, was identified as a promising epigenetic-targeted therapeutic strategy against the CSC-like HB1-Pro-like1 subpopulation and its related high-risk "Pro-like1" subtype of HB. CONCLUSIONS: Our findings illustrate the cellular architecture and developmental trajectories of HB via integrative bulk and single-cell transcriptome analyses, thus establishing a resourceful framework for the development of targeted diagnostics and therapeutics in the future.

Low COVID-19 vaccine coverage and guardian acceptance among pediatric transplant recipients.

To investigate COVID-19 vaccine coverage in immunosuppressed children, assess guardians' intention to vaccinate children, and determine reasons and associated factors. In addition, we attempted to capture the characteristics of them with Omicron. We obtained the vaccination coverage and guardian vaccine acceptance among pediatric transplant recipients through a web-based questionnaire conducted from April 12 to 28, 2022, and performed the statistical analysis. Seven organ transplant recipient children with Omicron were also clinically analyzed. The three-dose vaccine coverage for liver transplant (n = 563) and hematopoietic stem cell transplantation (n = 122) recipient children was 0.9% and 4.9%, and guardian vaccine acceptance was 63.8%. Independent risk factors for vaccine acceptance were the child's age, geographic location, type of transplant, guardian's vaccination status, guardian's level of distress about epidemic events, guardian's risk perception ability, anxiety, and knowledge of epidemic control. The main reasons for vaccine hesitancy were fear of vaccine-induced adverse events and doubts about efficacy. Ultimately, most children infected with Omicron have mild or no symptoms and are infected by intra-family. Since vaccine coverage and guardian acceptance are lowest among liver transplant children, and the infected are mainly intra-family, we should devise more targeted education and vaccination instructions for their guardians.

GRWR Correlates with the Metabolism of Tacrolimus after Pediatric Living Donor Liver Transplantation According to Donor CYP3A5 Polymorphism.

Objectives: Tacrolimus is characterized by high pharmacokinetic variability in combination with a narrow therapeutic range. However, influence of donor CYP3A5 genotype and graft-to-recipient body weight ratio (GRWR) on tacrolimus' pharmacokinetics after pediatric living donor liver transplantation (LDLT) remains unclear. Methods: A total of 174 LDLT recipients (<6 y) were grouped according to donor CYP3A5 genotypes (nonexpressor (NEX) or expressor (EX)) and GRWR (<3.0% (SS, small-size) or ≥3.0% (LS, large-size)): SS/NEX (n = 40), SS/EX (n = 38), LS/NEX (n = 48), and LS/EX (n = 48). Pharmacokinetics of tacrolimus and clinical outcomes were analyzed. Results: The relationships between the concentration-dose ratio and donor CYP3A5 genotypes and graft size were examined 3, 7, 14, and 30 days after the transplantation. Tacrolimus C0 levels varied greatly among groups, although recipients started with the same initial dosage. LS/EX recipients had significantly lower C0 levels in comparison with those of other groups. The use of CYP3A5-EX-grafts and a greater GRWR both resulted in significantly higher TAC dose requirements and lower C/D ratios. However, the significance of GRWR no longer exists 3 months after transplantation. The multivariate generalized linear mixed model analysis showed that donor CYP3A5 genotypes (F = 11.876; P = 0.01) and GRWR (F = 4.631; P = 0.033) were independent impact factors for C/D ratios 3, 7, 14, and 30 days after transplantation. Donor CYP3A5-EX genotype was associated with significantly increasing risks of infectious complications and significantly lower Cylex ATP values. However, no significant difference was observed in acute rejections among 4 groups. Conclusions: Monitoring of C0 levels alone is not reliable to guide tacrolimus administration. Donor CYP3A5 and GRWR both significantly affect tacrolimus pharmacokinetics after pediatric LDLT. The use of Cylex ATP tests would be helpful to avoid overimmunosuppression.

Association between Metabolic Dysfunction-associated Fatty Liver Disease and Cognitive Impairment.

Background and Aims: Metabolic dysfunction-associated fatty liver disease (MAFLD) is a newly proposed term based on modified criteria. Although nonalcoholic fatty liver disease (NAFLD) has been well-documented as a multisystem disease, research on the correlation of MAFLD and extra-hepatic diseases is limited. This study aimed to clarify the association of MAFLD, as well as NAFLD status with cognitive function. Methods: A total of 5,662 participants 20-59 years of age who underwent cognitive tests and liver ultrasonography in the Third National Health and Nutrition Examination Survey were included in the analysis. Cognitive function was evaluated using three computer-administered tests, the serial digit learning test (SDLT), the simple reaction time test (SRTT) and the symbol digit substitution test (SDST). Results: Participants with MAFLD had significantly poorer performance on the SRTT [odds ratio (OR) 1.47, 95% confidence interval (CI): 1.14-1.89)]. MAFLD with moderate-severe liver steatosis was associated with higher risks of scoring low in the SDLT (OR 1.37, 95% CI: 1.04-1.82) and SRTT (OR 1.55, 95% CI: 1.19-2.02). NAFLD combined with metabolic dysfunction, instead of NAFLD without metabolic disorders, was associated an increased risk of a low SRTT score (OR 1.44, 95% CI: 1.10-1.82). MAFLD patients had a high probability of fibrosis, prediabetes, and diabetes and were also significantly associated with increased risks based on the SDST or SRTT score. Conclusions: MAFLD was significantly associated with increased risk of cognitive impairment, especially among MAFLD patients with a high degree of liver fibrosis, moderate-severe steatosis, or hyperglycemia.

Acyloxyacyl hydrolase deficiency induces chronic inflammation and bone loss in male mice.

Hormonal homeostasis is essential in bone remodeling. Recent studies have shown that the treatment of intestinal inflammation can result in the regulation of bone resorption in distant bones. Increased intestinal permeability may lead to systemic inflammation and bone loss, also known as gut-bone axis. However, the underlying mechanism remains to be elucidated. Lipopolysaccharide (LPS) is a component of gram-negative bacteria that can increase osteoclastic differentiation in vitro. Acyloxyacyl hydrolase (AOAH) is a specific degrading enzyme of LPS, but little is known about the role of AOAH in bone metabolism. In this study, adult Aoah-/- mice showed a chronic inflammatory state and osteopenic phenotype analyzed by micro-CT and HE staining. Tartrate-resistant acid phosphatase (TRAP) staining of femurs showed an increase in TRAP-positive cells from Aoah-/- mice. AOAH depletion enhanced the osteoclast differentiation and bone resorption capacity of bone marrow-derived macrophages (BMMs). The enhanced osteoclast differentiation and bone resorption capacity of Aoah-/- BMMs were reversed by rAOAH. In conclusion, the chronic inflammatory state of adult Aoah-/- mice promotes bone resorption. AOAH participates in bone metabolism, which is mainly mediated by inhibiting osteoclast differentiation. LPS may be a key mediator of the gut-bone axis, and targeting AOAH may represent a feasible strategy for the treatment of chronic inflammatory bone resorption. KEY MESSAGES : AOAH knockout mice exhibited chronic inflammation mediated by LPS, and LPS may also serve as an important mediator in the regulation of bone metabolism in the gut-bone axis. AOAH regulated bone resorption by blocking the osteoclast differentiation via classical ERK and JNK pathways. rAOAH could rescue the enhanced osteoclast differentiation caused by AOAH deficiency.

Long-Term Results of Pediatric Liver Transplantation for Progressive Familial Intrahepatic Cholestasis.

We analyzed the long-term survival rate and development of progressive familial intrahepatic cholestasis (PFIC) patients after liver transplantation (LT). From October 2007 to May 2019, 41 patients were diagnosed as PFIC (type I-III) and received LT in Ren Ji Hospital due to end-stage liver diseases. The median age at LT was 2.93 years, with 75.6% of patients receiving living donor liver transplantation (LDLT). The 5- and 10-year patient survival rates after LT were 92.7% and 92.7%, respectively, and no difference was found among the three subtypes of PFIC. Two PFIC type II patients received re-transplantation due to vascular complications. Liver function and bile acid metabolism returned to normal levels in all living recipients. Catch-up growth was recorded as the height and weight Z scores increased from -2.53 and -1.54 to -0.55 and -0.27 with a median follow-up time of 5.55 years. Improved psychomotor ability and age-appropriate study ability was also observed. A total of 72.4% of school-aged recipients exhibited average academic performance. Diarrhea was reported in all PFIC type I recipients but resolved after resin absorptive treatment. However, allograft steatosis occurred in one PFIC type I patient and exhibited a "remission-relapse circle" under the treatment of cholestyramine. In conclusion, LT is an effective treatment for end-stage PFIC patients with encouraging long-term survival rate and development. However, allograft steatosis should be closely monitored in PFIC type I patients even if diarrhea has been well treated.

[Comparison of total hip arthroplasty with conventional instrument OCM approach and posterolateral approach in supine position].

OBJECTIVE: To compare the clinical efficacy of total hip arthroplasty with conventional instrument OCM approach and posterolateral approach in supine position. METHODS: From February 2017 to January 2019, 67 patients underwent hip arthroplasty due to hip diseases, including 21 patients in the minimally invasive group, 12 males and 9 females;there were 10 cases of femoral neck fracture, 5 cases of aseptic necrosis of femoral head and 6 cases of hip osteoarthritis. In the traditional group, 46 cases were treated by traditional posterolateral approach, including 28 males and 18 females;there were 24 cases of femoral neck fracture, 12 cases of aseptic necrosis of femoral head and 10 cases of hip osteoarthritis. All patientsused biological ceramic artificial joint prosthesis. The operation time, intraoperative bleeding, incision length, preoperative and postoperative creatine kinase (CK-NAC), underground activity time, hospital stay, abduction angle and anteversion angle of prosthesis were observed and compared between two groups. Harris scores before operation and 12 months after operation were compared between two groups. RESULTS: All cases were followed up for 14 to 26(18.4±3.6) months. There was no significant difference in intraoperative bleeding, postoperative anteversion and abduction angle between two groups (P>0.05). There were significant differences in operation time, incision length, postoperative creatine kinase, underground time and hospital stay between two groups (P<0.05). There was no significant difference in Harris function score between two groups before operation and 12 months after operation(P>0.05). CONCLUSION: The two approaches of total hip arthroplasty can obtain satisfactory results.OCM approach has less damage and rapid postoperative recovery. It is a reliable surgical approach and can be popularized and used.

Modified Dual Hepatic Vein Anastomosis in Pediatric Living-Donor Liver Transplantation Using Left Lateral Segment Grafts With Two Wide Orifices.

Background: The anatomic variation of hepatic vein in the left lateral segment (LLS) increases the risk of outflow complication in pediatric living liver transplantation (LDLT). Here, we share a modified method for dual hepatic vein reconstruction in pediatric LDLT using LLS with two wide orifices. Methods: From Sep 2018 to Dec 2019, 434 pediatric LDLTs using LLS were performed in our center. Hepatic veins of grafts were classified into three types with emphasis on the number, size, and location of orifices at the cut surface: a single opening (type I, n = 341, 78.57%); two adjacent orifices (type II, n = 66, 15.21%); two wide orifices with orifices distances <20 mm (type IIIa, n = 15, 3.46%); and two wide orifices with orifices distances >20 mm (type IIIb, n = 12, 2.76%). Rv was defined as the ratio of diameter of V2 and V3 (refer to hepatic vein drained segments II and III). We developed a modified dual hepatic vein anastomosis to reconstruct outflow for type IIIb grafts with Rv ≤1. Briefly, the hepatic vein of segment II was anastomosed to the common stump of middle hepatic vein (MHV) and left hepatic vein (LHV), followed by unification of V3 and the longitudinal incision orifice in inferior venous cave (IVC). Results: During median follow-up of 15.6 months (7.5-22.9 months), no hepatic vein complications occurred. Conclusion: This novel modified dual hepatic vein anastomosis could serve as a feasible surgical option for type IIIb LLS grafts with Rv ≤1 in pediatric LDLT.

Pediatric living-donor liver transplantation using right posterior segment grafts.

BACKGROUND: The right posterior segment (RPS) graft was introduced to overcome graft size discrepancy in living donor liver transplantation (LDLT). However, it was very rarely used in pediatric patients. Here we presented 4 pediatric LDLT cases receiving RPS graft between January 2015 and April 2020 in our center. A total of 1868 LDLT procedures were performed in this period. METHODS: Recipients included 1 boy and 3 girls with a median age of 45 months (range from 40 to 93 months). They were diagnosed with progressive familial intrahepatic cholestasis, propionic academia, ornithine transcarbamylase and biliary atresia, respectively. Four donors were all mothers with a median age of 32.5 years (31-38 years). Computer tomography angiography indicated posterior right branches branched off separately from main portal veins (type III variation). Three of these donor livers had 1 orifice of right hepatic veins (RHV). In the remaining 1 donor liver, the RHV showed 3 orifices and an outflow patch plastic was performed. Inferior right hepatic veins weren't found in four donor grafts. The median graft weight was 397.5 g (352-461 g) and the median graft-to-recipient weight ratio was 2.38% (1.44-2.80%). RESULTS: Postoperative complications occurred in neither donors nor recipients. Within the median follow-up duration of 29 months (14-64 months), four children are all alive with normal liver function. CONCLUSION: In summary, for older children weighed more than 15 kg with donors' variation of type III portal veins, the use of RPS grafts could be a feasible and favorable option.

Bile Acids Impair Vaccine Response in Children With Biliary Atresia.

Background: Vaccination is the best way to protect children under 5 years from death or disability. Children with biliary atresia (BA), which is the most common pediatric cholestatic end-stage liver disease (PELD), are more vulnerable to infectious diseases. However, the vaccination coverage and factors modulating vaccine responses in children with BA are largely unknown. Methods: In this study, 288 children (median age: 7 months) diagnosed with BA before liver transplantation were enrolled for the evaluation of vaccination status and the factors affecting the immune response to the hepatitis B (HBV) vaccine. Moreover, 49 BA children (median age: 4 months) were enrolled for flow cytometric analysis of CD4+ T cells and CD19+ B cell subsets and correlations with serum bile acid levels. Results: Generally, these children had very low routine vaccination rates for the meningococcal serogroup AC (Men AC) (41.2%), measles-mumps-rubella (MMR) (31.3%), poliomyelitis (Polio) (25.3%), hepatitis A (HAV) (25.0%), Japanese encephalitis (JE) (15.0%), diphtheria-tetanus-pertussis (DTP) (14.2%), meningococcal serogroup A (Men A) (13.5%) and varicella (VAR) (10.8%) vaccines, but not for the HBV (96.2%) and bacillus Calmette-Guérin (BCG) (84.7%) vaccines. Remarkably, 19.8% (57/288) of the patients had HBV infection. Out of 220 patients vaccinated for HBV, 113 (51.4%), 85 (38.6%) and 22 (10%) had one, two or three doses of the HBV vaccine, respectively. Furthermore, logistic regression analysis revealed that the bile acid level was an independent factor associated with poor HBV vaccine response (p = 0.03; OR = 0.394; 95% CI = 0.170-0.969). Immunophenotyping showed that bile acids were only negatively correlated with the CD19+CD27+IgG+ post-class-switched memory B cell ratio (p = 0.01). Conclusion: This study reveals the overall vaccination rates of routine vaccines in Chinese BA children are very low and the poor HBV vaccine responses are associated with bile acids, possibly via the inhibition of CD19+CD27+IgG+ post-class-switched memory B cell response. Clinical Trial Registration: http://www.chictr.org.cn, identifier ChiCTR1800019165.

XRCC2 repairs mitochondrial DNA damage and fuels malignant behavior in hepatocellular carcinoma.

The effects of DNA damage repair (DDR) and mitochondrial dysfunction associated with HCC have been investigated, but the functional role of mitochondrial DDR in HCC remains elusive. We studied the DDR genes and identified XRCC2 as a potential prognostic marker for HCC. XRCC2 overexpression was detected in HCC cells and shown to promote the malignant behavior of cancer cells. XRCC2 depletion in HCC cells led to DNA damage accumulation at the replication site in the nucleus. Additionally, XRCC2-depleted HCC cells exhibited impaired mitochondrial respiration and reduced complex I (CI) activity as XRCC2 was responsible for elimination of mitochondrial DNA (mtDNA) damage and maintenance of mtDNA-encoded CI-related genes' transcription in a RAD51-dependent manner. We showed that tunicamycin (Tm)-activated sXBP1 bound to the TGTCAT domain and suppressed XRCC2 expression. In HCC patients, we observed a negative correlation between XBP1 and XRCC2 expression. Moreover, XRCC2 inhibition by Tm led to genomic and mtDNA damage, which impaired the transcription of mtDNA-encoded CI-related genes and prevented tumor proliferation in vivo. We described the role of XRCC2 in mtDNA damage repair and HCC progression while unveiling the potential anti-tumor effect of Tm.

NEIL3 Prevents Senescence in Hepatocellular Carcinoma by Repairing Oxidative Lesions at Telomeres during Mitosis.

Patients with hepatocellular carcinoma (HCC) suffer from few treatment options and poor survival rates. Here we report that endonuclease VIII-like protein 3 (NEIL3) is overexpressed in HCC and correlates with poor survival. All six HCC cell lines investigated were dependent on NEIL3 catalytic activity for survival and prevention of senescence, while NEIL3 was dispensable for nontransformed cells. NEIL3-depleted HCC cell lines accumulated oxidative DNA lesions specifically at telomeres, resulting in telomere dysfunctional foci and 53BP1 foci formation. Following oxidative DNA damage during mitosis, NEIL3 relocated to telomeres and recruited apurinic endonuclease 1 (APE1), indicating activation of base excision repair. META-FISH revealed that NEIL3, but not NEIL1 or NEIL2, is required to initiate APE1 and polymerase beta (POLB)-dependent base excision repair at oxidized telomeres. Repeated exposure of NEIL3-depleted cells to oxidizing damage induced chromatin bridges and damaged telomeres. These results demonstrate a novel function for NEIL3 in repair of oxidative DNA damage at telomeres in mitosis, which is important to prevent senescence of HCC cells. Furthermore, these data suggest that NEIL3 could be a target for therapeutic intervention for HCC. SIGNIFICANCE: This study describes compartmentalization of base excision repair during mitosis that is dependent on NEIL3, APE1, and POLB to repair oxidative damage accumulating at telomeres in hepatocellular carcinoma.