Heterogeneity-induced NGF-NGFR communication inefficiency promotes mitotic spindle disorganization in exhausted T cells through PREX1 suppression to impair the anti-tumor immunotherapy with PD-1 mAb in hepatocellular carcinoma.

BACKGROUND: The mechanism of decreased T cells infiltrating tumor tissues in hepatocellular carcinoma is poorly understood. METHODS: Cells were separated from the single-cell RNA-sequence dataset of hepatocellular carcinoma patients (GSE149614) for cell-cell communication. Flow cytometry, EDU staining, H3-Ser28 staining, confocal immunofluorescence staining, western blotting and naked microsubcutaneous tumors were performed for the mechanism of NGF-NGFR promoting proliferation. RESULTS: The present study has revealed that during the process of T-cell infiltration from adjacent tissues to tumor tissues, an inefficiency in NGF-NGFR communication occurs in the tumor tissues. Importantly, NGF secreted by tumor cells interacts with NGFR present on the membranes of the infiltrated T cells, thereby promoting the proliferation through the activation of mitotic spindle signals. Mechanistically, the mediation of mitotic spindle signal activation promoting proliferation is executed by HDAC1-mediated inhibition of unclear trans-localization of PREX1. Furthermore, PD-1 mAb acts synergistically with the NGF-NGFR communication to suppress tumor progression in both mouse models and HCC patients. Additionally, NGF-NGFR communication was positively correlates with the PD-1/PDL-1 expression. However, expressions of NGF and NGFR are low in tumor tissues, which is responsible for the invasive clinicopathological features and the disappointing prognosis in HCC patients. CONCLUSION: Inefficiency in NGF-NGFR communication impairs PD-1 mAb immunotherapy and could thus be utilized as a novel therapeutic target in the treatment of HCC patients in clinical practice.

Successful Liver Transplantation From a Deceased Donor With Congenital Extrahepatic Portosystemic Shunt: A Case Report.

Congenital extrahepatic portosystemic shunt belongs to a family of rare vascular abnormalities. We present a case of congenital extrahepatic portosystemic shunt occurring in a 42-year-old man who died of cerebral hemorrhage and donated his liver. His portal vein angiography revealed that the main portal vein communicated with the left renal vein, suggesting a portosystemic shunt. A liver biopsy showed that the liver tissue structure was normal. His liver was not involved, and the transplantation was carried out smoothly. The recipient recovered smoothly, and the function of the transplanted liver was good.

Marginal donor liver versus standard donor liver: A single-center observational study.

BACKGROUND: The effectiveness and safety of marginal donor livers remain controversial. This study aimed to investigate the clinical efficacy of marginal donor livers in patients with liver transplantation (LT). METHODS: This study included 199 liver donors (including 16 split donors) and 206 liver recipients from January 1, 2018 to January 27, 2020, with case follow-up until July 31, 2021. Clinical data of donors and recipients were retrospectively analyzed and were divided into the marginal donor and standard donor groups according to the criteria of marginal donor livers. Indices of liver and kidney functions, complications, and survival curves of the two groups were compared. RESULTS: Compared with the standard donor group, the blood creatinine levels were significantly higher in the marginal donor group in the first week after operation (P < 0.05); there were no significant differences in alanine aminotransferase, aspartate aminotransferase, and total bilirubin levels after LT (all P > 0.05); there was no significant difference in the incidence of complications after LT (P > 0.05); there was also no significant difference in the survival curve (P = 0.335). CONCLUSIONS: There were no significant differences in liver and kidney function and survival curve between the standard donor and marginal donor groups. The marginal donor liver appears safe and reliable for LT and may be an important strategy to expand the donor pool and solve the shortage of organs.

Development of a Novel Prognostic Nomogram for High Model for End-Stage Liver Disease Score Recipients Following Deceased Donor Liver Transplantation.

Background: A high model of end-stage liver disease (MELD) score (>30) adversely affects outcomes even if patients receive prompt liver transplantation (LT). Therefore, balanced allocation of donor grafts is indispensable to avoid random combinations of donor and recipient risk factors, which often lead to graft or recipient loss. Predictive models aimed at avoiding donor risk factors in high-MELD score recipients are urgently required to obtain satisfactory outcomes. Method: Data of patients with MELD score >30 who underwent LT at three transplantation institutes between 2015 and 2018 were retrospectively reviewed. Early allograft dysfunction (EAD), length of intensive care unit (ICU) stay, and graft loss were recorded. Corresponding independent risk factors were analyzed using stepwise multivariable regression analysis. A prediction model of graft loss was developed, and discrimination and calibration were measured. Results: After applying the exclusion criteria, 778 patients were enrolled. The incidence of EAD was 34.8% (271/778). Donor graft macrovesicular steatosis, graft-to-recipient weight ratio (GRWR), warm ischemia time (WIT), cold ischemia time (CIT), and ABO blood incompatibility, together with donor serum albumins, were independent predictors of EAD. The incidence of ICU stay over 10 days was 64.7% (503/778). Donor age, recipient's MELD score, Child score, and CIT were independent predictors of ICU stay. The 3-year graft survival rates (GSRs) in the training and validation cohorts were 64.2 and 59.3%, respectively. The independent predictors of graft loss were recipient's Child score, ABO blood type incompatibility, donor serum total bilirubin over 17.1 µmol/L, and cold CIT. A nomogram based on these variables was internally and externally validated and showed good performance (area under the receiver operating characteristic curve = 70.8 and 66.0%, respectively). For a recipient with a high MELD score, the avoidance of ABO blood type incompatibility and CIT ≥6 h would achieve a 3-year GSR of up to 78.4%, whereas the presence of the aforementioned risk factors would decrease the GSR to 35.4%. Conclusion: The long-term prognosis of recipients with MELD scores >30 could be greatly improved by avoiding ABO blood type incompatibility and CIT ≥6 h.

Correlation Analysis of Pleural Effusion and Lung Infection After Liver Transplantation.

BACKGROUND: The aim was to probe the association of pleural effusion with lung infection in patients with liver transplantation and to provide a theoretical foundation for preventing, diagnosing, and remedying pulmonary complications after liver transplantation. METHODS: Our team harvested clinical data of patients undergoing orthotopic allogeneic liver transplantation complicated with pleural effusion after surgery in our institution from May 2018 to July 2019. Based on whether puncture drainage was needed, patients were allocated to either control group or observation group. The differences in pleural effusion depth, lung function, lung infection, serum inflammatory factor levels and 6-month survival before and after surgery were compared. Finally, ROC curves were constructed for dissecting the correlation of pleural effusion with lung infection. RESULTS: On day 3 after surgery, (1) pleural effusion depth of the observation group was 5.70 ± 1.20 cm, which was saliently greater than that of control group (p < 0.05); (2) in comparison to control group, lung function indexes FVC, FEV1.0, MVV, and PaO2 of observation group declined (all p < 0.05); (3) sputum culture evinced that the lung infection rates of the control group and observation group were 17.24% and 71.70%, respectively, and the observation group harbored brilliantly higher infection rate (p < 0.05); (4) in comparison to the control group, IL-6, IL-8, and TNF-α in observation group were increased (p < 0.05); (5) AUC of pleural effusion depth and lung infection was 0.849, 0.805, and 0.853, respectively on days 1, 2, and 3 after surgery. CONCLUSIONS: A positive correlation existed between pleural effusion and lung infection after liver transplantation. When patients have persistent pleural effusion, the incidence of lung infection should be prevented and reduced.

WITHDRAWN: Correlation analysis of pleural effusion and lung infection after liver transplantation.

Ahead of Print article withdrawn by publisher. The paper entitled "Correlation analysis of pleural effusion and lung infection after liver transplantation " by Chuanshen XU et al., which was published online on April 23, 2021, has been withdrawn by the Publisher due to double publication; the authors submitted for evaluation the same paper to more than one journal at the same time, which caused the double publication.

Transient elastography for assessment of fibrosis and steatosis of liver grafts from brain-death donors.

BACKGROUND: An objective and accurate evaluation of liver grafts is required to improve the prognosis of liver transplant recipients and to increase the number of available liver grafts. AIM: To compare outcomes using FibroScan with that of pathology in liver grafts from brain-dead donors (DBD). METHODS: Liver grafts from 52 DBD were examined using ultrasound (US), FibroScan before liver transplantation (LT). Blood tested before LT and a biopsy was performed pre- or intra-operation to determine pathology. The diagnostic accuracy of the FibroScan results was compared with the pathology results, which is the gold standard for evaluating liver grafts. The donors enrolled were grouped by the stage of liver fibrosis (F0-F4) and steatosis (S0-S3), based on Kleiner's scoring system of nonalcoholic fatty liver disease, respectively. RESULTS: The liver stiffness (LS) value in group F1 was significantly increased compared with group F0 (8.74±1.32kPa and 5.93±1.64kPa, respectively, P<0.01). The LS value had a significant positive correlation with the liver graft fibrosis stage (r=0.73, P<0.01). The area under receiver operating characteristic curves (AUROC) for F1 stage fibrosis was 0.93 (P<0.01). Significant differences in the controlled attenuation parameter (CAP) were found among groups S0, S1, and S2 (173.30±38.36dB/m, 230.29±23.27dB/m, 250.00±57.01dB/m, respectively; F=12.41, P<0.01). The CAP was associated with the liver graft steatosis stage (r=0.64, P<0.01). The AUROC for S1 and S2 stage steatosis in liver grafts was 0.89 (P=0.002) and 0.83 (P=0.007), respectively. CONCLUSIONS: Transient elastography quantifies fibrosis and steatosis in liver grafts from 52 DBD with a high diagnostic accuracy and provides further imaging evidence for use in assessing liver grafts.

MicroRNA-370 functions as a tumor suppressor in hepatocellular carcinoma via inhibition of the MAPK/JNK signaling pathway by targeting BEX2.

Hepatocellular carcinoma (HCC) is a primary malignancy of the liver and occurs predominantly in patients with underlying chronic liver disease and cirrhosis. Accumulating studies have revealed that microRNAs (miRNAs) play a critical role in the development and progression of HCC. Through microarray-based gene expression profiling of HCC, miR-370, and BEX2 were identified in HCC. Hence, this study aimed to evaluate their abilities on the cellular processes in HCC. It was determined that BEX2 was highly expressed and miR-370 was poorly expressed in HCC cell lines and tissues. Then, the cell line presenting with the highest BEX2 expression and the lowest miR-370 expression was selected for subsequent gain- and loss-of-function experimentation. The antitumor effect of miR-370 on HCC cell proliferation, invasion, migration, and apoptosis, as well as the MAPK/JNK signaling pathway was examined. Meanwhile, the interaction among miR-370, BEX2, and MAPK/JNK signaling pathway was identified. BEX2 is verified to be a target of miR-370. Moreover, miR-370 exerted antitumor effect on HCC development through suppression of the MAPK/JNK signaling pathway by targeting BEX2. Later, it was further verified by in vivo experiment that overexpression of miR-370 inhibited tumor growth. Above results provide evidence that miR-370 could downregulate BEX2 gene and inhibit activation of MAPK/JNK signaling pathway, thus inhibiting the development of HCC. It provides a worth-trying novel therapeutic target for HCC treatment.

SnoN suppresses TGF-ß-induced epithelial-mesenchymal transition and invasion of bladder cancer in a TIF1γ-dependent manner.

The transcriptional regulator SnoN (also known as SKI-like proto-oncogene, SKIL), a member of the Ski family, has been reported to influence epithelial-mesenchymal transition (EMT) in response to TGF-ß. In the present study, we investigated the role of SnoN in bladder cancer (BC). Differential expression of SnoN was not detected in BC tissues compared with that noted in adjacent non-cancerous tissues. SnoN was upregulated in response to TGF-ß treatment, but had no effect on the TGF-ß pathway, which may be explained by the low level of SnoN SUMOylation. TIF1γ, which catalyzes the SUMOylation of SnoN, was downregulated in BC tissues. Overexpression of TIF1γ restored the ability of SnoN to suppress the TGF-ß pathway. Furthermore, TGF-ß-induced EMT and invasion of BC cells were suppressed by TIF1γ in the presence of SnoN. Collectirely, our data suggest that SnoN suppresses TGF-ß­induced EMT and invasion of BC cells in a TIF1γ­dependent manner and may serve as a novel therapeutic option for the treatment of BC.