CD47 and PD-L1 overexpression in proliferating human hepatocytes attenuated immune responses and ameliorated acute liver injury in mice.

Hepatocyte transplantation has the potential to treat acute liver failure and correct liver-based metabolic disorders. Proliferating human hepatocytes (ProliHHs) provide a large-scale source as an alternative to primary human hepatocytes. However, host rejection led to inefficient graft survival and function, which hindered the clinical application of cell therapy. Herein, we employed the lentiviral system to overexpress immunomodulatory factors programmed death-ligand 1 (cluster of differentiation 274) (CD274) and cluster of differentiation 47 (CD47) in ProliHHs. CD47+274 overexpression inhibited macrophage and T cell responses in vitro. After transplantation into mice via the spleen without immunosuppression, CD47+274 ProliHHs accumulation in the liver significantly increased for 48 hours compared with ProliHHs. Consistent with the in vitro results, CD47+274 ProliHHs were less aggregated and infiltrated by macrophages and also recruited fewer T cells in the liver. Seven days after transplantation, the human albumin level of engineered ProliHHs doubled compared with control group. CD47+274 ProliHHs further ameliorated the liver injury induced using concanavalin A. Overall, our results suggested CD47+274 overexpression reduced innate and adaptive immune responses during hepatocyte transplantation, and the survival rate and graft function of transplanted hepatocyte-like cells were all significantly improved.

High ligation of the inferior mesenteric artery and anastomotic leakage in anterior resection for rectal cancer: a systematic review and meta-analysis of randomized controlled trial studies.

AIM: Surgeons have concerns whether high ligation (HL) of the inferior mesenteric artery (IMA) increases the incidence of anastomotic leakage (AL). This meta-analysis aimed to evaluate the influence of HL of the IMA on AL compared with low ligation (LL). METHODS: PubMed, Embase, Web of Science, Cochrane Central Register of Controlled Trials and ClinicalTrials.gov databases were searched. Randomized controlled trial studies that compared HL with LL of the IMA in anterior resection for rectal cancer and reported AL outcomes were eligible for inclusion. The odds ratios and mean differences were analysed by a random-effects model. Trial sequential analysis was performed to minimize the risk of random errors. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to evaluate the quality of evidence for outcomes. RESULTS: Of the 531 records screened, five randomized controlled trials with 779 patients were selected for analysis. The pooled incidence of AL was 12.1% (95% Cl 7.77-18.26) in the HL group and 9.7% (95% Cl 5.79-15.82) in the LL group (OR 1.20, 95% CI 0.77-1.87, P = 0.42). In trial sequential analysis, the cumulative Z-score curve exceeded the futility boundary, although the required information size of 1060 had not been reached. The quality of evidence was judged to be high according to the GRADE approach. CONCLUSIONS: This meta-analysis shows that HL of the IMA does not increase the incidence of AL in anterior resection for rectal cancer.

A Pilot Study on Plasma and Urine Neurotransmitter Levels in Children with Tic Disorders.

BACKGROUND: Tic disorders (TDs), including Tourette syndrome, are childhood-onset neuropsychiatric disorders characterized by motor and/or vocal tics that commonly affect children's physical and mental health. The pathogenesis of TDs may be related to abnormal neurotransmitters in the cortico-striatal-thalamo-cortical circuitry, especially dopaminergic, glutamatergic, and serotonergic neurotransmitters. The purpose of this study was to preliminarily investigate the differences in the three types of neurotransmitters in plasma and urine between children with TD and healthy children. METHODS: We collected 94 samples of plasma and 69 samples of urine from 3-12-year-old Chinese Han children with TD before treatment. The plasma and urine of the same number of healthy Chinese Han children, matched for age and sex, participating in a physical examination, were collected. Ultra-performance liquid chromatography-tandem mass spectrometry was used to detect the three types of neurotransmitters in the above samples. RESULTS: The plasma levels of norepinephrine, glutamic acid, and γ-aminobutyric acid, and the urine levels of normetanephrine and 5-hydroxyindoleacetic acid were higher in the TD children than in healthy children. The area under the curve (AUC) values of the above neurotransmitters in plasma and urine analyzed by receiver operating characteristic curve analysis were all higher than 0.6, with significant differences. Among them, the combined AUC of dopamine, norepinephrine, normetanephrine, glutamic acid, and γ-aminobutyric acid in the 8-12-year-old subgroup was 0.930, and the sensitivity and specificity for TD were 0.821 and 0.974, respectively (p = 0.000). CONCLUSIONS: There are differences in plasma and urine neurotransmitters between TD children and healthy children, which lays a foundation for further research on the pathogenesis of TD.

Understanding inter-individual variability in pharmacokinetics/pharmacodynamics of aripiprazole in children with tic disorders: Individualized administration based on physiological development and CYP2D6 genotypes.

Objective: This study aims to develop a combined population pharmacokinetic (PPK) model for aripiprazole (ARI) and its main active metabolite dehydroaripiprazole (DARI) in pediatric patients with tic disorders (TD), to investigate the inter-individual variability caused by physiological and genetic factors in pharmacokinetics of ARI and optimize the dosing regimens for pediatric patients. Methods: A prospective PPK research was performed in Chinese children with TD. Totally 84 patients aged 4.83-17.33 years were obtained for the pharmacokinetic analysis. 27 CYP2D6 and ABCB1 gene alleles were detected. Moreover, the clinical efficacy was evaluated according to reduction rate of Yale Global Tic Severity Scale (YGTSS) score at the 12th week comparing with the baseline. Monte Carlo simulations were used to evaluate and optimize dosing regimens. Results: The PPK model was established to predict the concentrations of ARI and DARI. Body weight and CYP2D6 genotype were the significant covariates affecting the clearance of ARI. The DARI/ARI metabolic ratios (MRs) of AUC24h, Cmin and Cmax at the steady state of results were ultra-rapid metabolizers (UMs) > normal metabolizers (NMs) > intermediated metabolizers (IMs). MRs could be used to distinguish UMs or IMs from other patients. The best predictor of clinical efficacy for TD was the trough concentration of ARI and the cut-off point was 101.636 ng/ml. Conclusion: The pharmacokinetics of ARI and DARI in pediatric TD were significantly influenced by body weight and CYP2D6 genotype. Individualized dosing regimens were recommended for pediatric patients with TD to ensure clinical efficacy.

Association between R1 resection and oncological outcome in resectable gastrointestinal stromal tumors without tumor rupture: A systematic review and meta-analysis.

BACKGROUND: The influence of positive microscopic margin (R1) resection on the prognosis of gastrointestinal stromal tumors (GISTs) is controversial. Tumor rupture is significantly associated with the occurrence of R1 resection and may be a confounder of R1 resection in GISTs. The present meta-analysis evaluated the real influence of R1 resection on the prognosis of GISTs by excluding the confounding effect of tumor rupture. METHODS: The PubMed, Embase, Web of Science, Cochrane Central Register of Controlled Trials (CENTRAL), and ClinicalTrials.gov databases were searched. Studies that compared R1 with negative microscopic margin (R0) resection in GIST patients and reported the time-to-event data of recurrence-free survival (RFS) or disease-free survival (DFS) were eligible for inclusion. The quality of the observational studies was assessed using the Newcastle-Ottawa scale. RESULTS: Of the 4896 records screened, 23 retrospective studies with 6248 participants were selected. In the overall analysis, R1 resection resulted in a significantly shorter RFS/DFS than R0 resection for GISTs (HR = 1.80, 95% CI = 1.54-2.10, P < 0.001, I2 = 14%). However, the inferior RFS/DFS vanished when tumor rupture cases were excluded (HR = 1.34, 95% CI = 0.98-1.83, P = 0.07, I2 = 33%). Sensitivity analysis by high-quality studies brought about a more robust HR of 1.15 (95% CI = 0.88-1.50, P = 0.29), with low heterogeneity (I2 = 0%). The qualities of evidence for the outcomes were high. CONCLUSIONS: This meta-analysis shows that R1 resection did not influence the survival outcome of GISTs. Reresection may not be necessary when positive microscopic margins exist. This analysis could provide high-quality evidence for the development of guidelines.

Association between intraoperative application of microfibrillar collagen hemostat and anastomotic leakage after anterior resection for rectal cancer: A retrospective case-control study.

BACKGROUND: The purpose of the study was to evaluate the association between microfibrillar collagen hemostat and anastomotic leakage after anterior resection. METHOD: Between March 2015 and December 2019, a total of 203 consecutive rectal cancer patients who underwent elective anterior resection were included. Patient parameters were analyzed. The relevant risk factors were identified by univariate and multivariate analysis. Propensity score matching was performed to reduce the selection bias. RESULTS: In total, 26 (12.8%) of the 203 study patients developed clinical anastomotic leakage. The length of hospital stay was significantly prolonged by anastomotic leakage. In univariate analysis and multivariate analysis, male sex, low tumor location, and intraoperative application of microfibrillar collagen hemostat significantly increased the risk of anastomotic leakage. Furthermore, analysis after propensity score matching confirmed the independent role of microfibrillar collagen hemostat in anastomotic leakage. In addition, the median time of anastomotic leakage occurrence from the initial operation in patients with microfibrillar collagen hemostat was 9.00 days, which was significantly later than that in patients without microfibrillar collagen hemostat. CONCLUSION: In addition to male sex and low tumor location, intraoperative application of microfibrillar collagen hemostat was demonstrated to be a significant risk factor for anastomotic leakage. This finding suggested that surgeons should be fully aware of this potential risk in anterior resection. Because of the limitation of retrospective study, however, randomized controlled trials are needed to confirm this association in the future.