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Tertiary lymphoid structure (TLS) can predict the prognosis and sensitivity of tumors to immune checkpoint inhibitors (ICIs) therapy, whether it can be noninvasively predicted by radiomics in hepatocellular carcinoma with liver transplantation (HCC‐LT) has not been explored. In this study, it is found that intra‐tumoral TLS abundance is significantly correlated with recurrence‐free survival (RFS) and overall survival (OS). Tumor tissues with TLS are characterized by inflammatory signatures and high infiltration of antitumor immune cells, while those without TLS exhibit uncontrolled cell cycle progression and activated mTOR signaling by bulk and single‐cell RNA‐seq analyses. The regulators involved in mTOR signaling (RHEB and LAMTOR4) and S‐phase (RFC2, PSMC2, and ORC5) are highly expressed in HCC with low TLS. In addition, the largest cohort of HCC patients is studied with available radiomics data, and a classifier is built to detect the presence of TLS in a non‐invasive manner. The classifier demonstrates remarkable performance in predicting intra‐tumoral TLS abundance in both training and test sets, achieving areas under receiver operating characteristic curve (AUCs) of 92.9% and 90.2% respectively. In summary, the absence of intra‐tumoral TLS abundance is associated with mTOR signaling activation and uncontrolled cell cycle progression in tumor cells, indicating unfavorable prognosis in HCC‐LT. [ABSTRACT FROM AUTHOR]

Purpose: Hepatocellular carcinoma (HCC) accounts for more than 80% of primary liver cancers and is one of the leading causes of cancer-related death in many countries. Cancer cell-derived exosomes are shown to mediate communications between cancer cells and the microenvironment, promoting tumorigenesis. Hedgehog signaling pathway plays important roles in cancer development of HCC. Methods: Exosomes were isolated from culture medium of HCC cell lines PLC/PRF/5 and MHCC-97H and were found to promote cancer cell growth measured with cell proliferation and colony formation assay. HCC cells cultured with cancer cell-derived exosome had increased cancer stem cell (CSC) population demonstrated by increased cell sphere formation CSC marker expressions. Hedgehog protein Shh was found to be highly expressed in these two HCC cell lines and preferably carried by exosomes. When Shh was knocked down with shRNA, the resulting exosomes had a reduced effect on promoting cancer cell growth or CSC population increase compared to normal cell-derived exosomes. Results: The ability of PLC/PRF/5 cells to form tumor in a xenograft model was increased by the addition of the exosomes from control cancer cells but not the exosomes from Shh knocked down cancer cells. Finally, the higher plasma Exo-Shh levels were associated with later tumor stages, higher histological grades, multiple tumors, and higher recurrence rates. Conclusion: This study demonstrated that HCC cells secreted Shh via exosome and promote tumorigenesis through the activated Hedgehog pathway. [ABSTRACT FROM AUTHOR]

The concept that inflammation serves a leading role in osteoclast-induced bone loss under pathological circumstances is now widely accepted. In the present study, it was observed that lipopolysaccharides (LPSs) demonstrated a synergic effect on receptor activator of nuclear factor κ-B ligand (RANKL)-induced osteoclast differentiation in Raw264.7 cells, with increasing levels of multiple pro-inflammatory cytokines including interleukin (IL)-6, tumor necrosis factor-α and IL-1β. Furthermore, microRNA (miR)-146a was highly induced by LPS and RANKL co-stimulation during the process of osteoclast differentiation. Overexpression of miR-146a inhibited osteoclast transformation by targeting the key regulators of nuclear factor (NF)-κβ signaling, TNF receptor-associated factor 6 and interleukin-1 receptor-associated kinase 1. The downstream activation of NF-κβ signaling was also inhibited by transfection with a miR-146a mimic. Altogether, the results of the present study demonstrated that miR-146a prevents osteoclast differentiation induced by LPS and RANKL co-stimulation, suggesting that miR-146a may be a promising therapeutic target for treatment of inflammation mediated bone loss. [ABSTRACT FROM AUTHOR]

We investigated the overall situation of LT for BA in mainland China and analyzed their survival outcomes based on data from CLTR. Between January 1996 and December 2013, 509 liver transplants for BA were performed in mainland China and were included in this study. Patients' median age was 9.6 months (range: 4.8-175.2 months). KP was previously performed in 194 cases (38.1%). Grafts from living donors were used in 380 cases (74.7%). Era I (1996.1-2010.12) and era II (2011.1-2013.12) comprised 151 cases (29.7%) and 358 cases (70.3%), respectively. Twenty-five centers had performed at least one liver transplant for children with BA. Centers from Shanghai (197 cases), Tianjin (143 cases) and Beijing (81 cases) involved 82.7% of the 509 cases. One- and five-yr graft survival rates were 84.7% and 72.6%, respectively. Split grafts, center volume <20, GRWR ≥4.0%, and steroid-free immunosuppression regimen were independent risk factors for graft survival. In conclusion, the dramatic expansion of pediatric liver transplant programs in mainland China has enabled improved survival for those children affected by this devastating disease. However, screening of BA in neonates should be emphasized throughout the country to enhance early referrals for KP. [ABSTRACT FROM AUTHOR]

As a cytokine of the interleukin-6 family, cardiotrophin-1 (CT-1) has been shown to be an important endogenous protector in liver injury. Our study aimed to investigate the role of CT-1 in liver fibrosis in pediatric cholestatic liver disease (PCLD). CT-1 mRNA and protein expression levels were upregulated in PCLD liver biopsy tissues compared with controls. Immunohistochemistry and confocal microscopy of liver sections showed that CT-1 was predominantly expressed by biliary epithelium cells. Serum CT-1 was elevated significantly in the children with PCLD compared with controls. Serum CT-1 levels exhibited a moderate positive correlation with the Scheuer stage of hepatic fibrosis and serum TB levels and a weak correlation with serum ALP levels. In vitro analysis indicated that LX-2 cells preconditioned with CT-1 exhibited significant increments in proliferation and accumulation of extracellular matrix components, while also positively regulating the STAT3 and p38MAPK pathways. In conclusion, biliary epithelium-derived CT-1 may exert a profibrogenic potential in PCLD. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is a fatal malignancy which has insufficient treatment options. Long non-coding RNA (lncRNA) GASAL1 was discovered to be conspicuously up-regulated in HCC. However, the study on the role of GASAL1 in HCC reamins limited. Our study aimed at exploring the role and mechanism of GASAL1 in HCC. RT-qPCR or Western blot was conducted to examine the expression of RNAs or proteins. Functional assays were carried out to investigate the impact of GASAL1, USP10, and PCNA on HCC cells. Mechanism assays were performed to fathom out the relationship among GASAL1, miR-193b-5p, USP10, and PCNA. In vivo assays were also employed to determine the role of GASAL1 in HCC tumor growth and metastases. According to the data collected, GASAL1 displayed a high expression in HCC cells and GASAL1 knockdown led to impeded cell proliferation and migration, as well as tumor progression. A series of mechanism analysis demonstrated GASAL1 could sponge miR-193b-5p to raise the expression of USP10. Moreover, USP10 could induce PCNA deubiquitination to promote HCC cell growth. To conclude, GASAL1 plays an oncogenic role in HCC. GASAL1 could up-regulate USP10 via competitively binding to miR-193b-5p. And USP10 could strengthen cell proliferative and migratory abilities through deubiquitinating PCNA. [Display omitted] • This study first demonstrated GASAL1 could promote HCC cell proliferation and migration. • This study first revealed GASAL1 could up-regulate USP10 via acting as a ceRNA of miR-193b-5p in HCC cells. • This study first confirmed USP10 could modulate PCNA deubiquitination to stabilize PCNA protein. [ABSTRACT FROM AUTHOR]

Abstract: Cisplatin is one of the commonly used chemotherapeutic drugs for the treatment of patients with advanced liver cancer. However, acquisition of cisplatin resistance is common in patients with hepatocellular carcinoma (HCC), and the underlying mechanism of such resistance is not fully understood. In the study, we found that miR-130a levels were significantly increased in HCC patients treated with cisplatin-based chemotherapy. miR-130a levels were also higher in cisplatin-resistant Huh7 cells than in Huh7 cells. Overexpression of miR-130a contributed to cisplatin resistance in Huh7 cell, whereas knockdown of miR-130a overcame cisplatin resistance in cisplatin-resistant Huh7 cell. We further demonstrated that upregulated miR-130a directly inhibited expression of tumor suppressor gene RUNX3, which resulted in activation of Wnt/β-catenin signaling and increased drug resistance. These data suggest that miR-130a/RUNX3/Wnt signaling represents a novel pathway regulating chemoresistance, thus offering a new target for chemotherapy of HCC. [Copyright &y& Elsevier]

Abstract: Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. Systemic chemotherapy plays an important role in the treatment of patients with advanced liver cancer. However, chemoresistance to cisplatin is a major limitation of cisplatin-based chemotherapy in the clinic, and the underlying mechanism of such resistance is not fully understood. In the study, we found that miR-199a-5p levels were significantly reduced in HCC patients treated with cisplatin-based chemotherapy. Cisplatin treatment also resulted in decreased miR-199a-5p levels in human HCC cell lines. Forced expression of miR-199a-5p promoted cisplatin-induced inhibition of cell proliferation. Cisplatin treatment activated autophagy in Huh7 and HepG2 cells, which increased cell proliferation. We further demonstrated that downregulated miR-199a-5p enhanced autophagy activation by targeting autophagy-associated gene 7 (ATG7). More important, autophagy inhibition abrogated miR-199a-5p downregulation-induced cell proliferation. These data demonstrated that miR-199a-5p/autophagy signaling represents a novel pathway regulating chemoresistance, thus offering a new target for chemotherapy of HCC. [Copyright &y& Elsevier]

[Display omitted] • The influence of CYP3A polymorphisms on tacrolimus concentrations was investigated. • CYP3A polymorphisms of recipients affected tacrolimus concentrations. • CYP3A polymorphisms of donors did not influence tacrolimus concentrations. The purpose of this study was to investigate the effect of CYP3A7 , CYP3A4 , and CYP3A5 genetic polymorphisms in liver transplant recipients and donors on tacrolimus concentrations in the early stages after liver transplantation. One hundred and thirty-eight liver transplant recipients and matched donors were genotyped for CYP3A7 (rs10211 and rs2257401), CYP3A4 (rs4646437 and rs2242480), and CYP3A5 *3 (rs776746) polymorphisms. The relationships between dose-adjusted trough concentrations (C 0 /D) of tacrolimus and corresponding genotypes were investigated. Recipient CYP3A polymorphisms were associated with tacrolimus concentrations. The CYP3A7 rs10211 AA carriers (186.2 vs 90.5, p < 0.001), CYP3A4 rs4646437 CC carriers (184.0 vs 88.8, p < 0.001), CYP3A4 *1G rs2242480 CC carriers (189.8 vs 99.7, p < 0.001), and CYP3A5 *3 rs776746 GG carriers (197.3 vs 86.0, p < 0.001) had an almost twofold increase in the tacrolimus C 0 /D compared to that of the non-carriers. We further investigated the effect of the combination of recipient (intestinal) and donor (hepatic) genotypes on tacrolimus concentrations. Regardless of the genotype of the matched donor, CYP3A7 rs10211, CYP3A4*1G (rs2242480), and CYP3A5 *3 (rs776746) polymorphisms of recipients could affect tacrolimus concentrations. For the CYP3A4 rs4646437 polymorphisms, when the donor carried CYP3A4 rs4646437 CC, the recipient CYP3A4 rs4646437 polymorphism was associated with the C 0 /D of tacrolimus, and when the donor carried CYP3A4 rs4646437 CT/TT genotype, the recipient CYP3A4 rs4646437 polymorphism also affected on tacrolimus C 0 /D, although the effect was not significant. The large inter-individual variation in tacrolimus concentrations in the early stages after liver transplantation is influenced by genetic polymorphisms of CYP3A7 , CYP3A4 , and CYP3A5. Recipient (intestinal) CYP3A7 , CYP3A4 , and CYP3A5 polymorphisms seem to contribute more to such variation than donors. Therefore, the detection of CYP3A polymorphisms in recipients could help to predict the tacrolimus starting dose in the early stages after liver transplantation. [ABSTRACT FROM AUTHOR]

• Predictive performance of nonlinear model was superior to linear models. • Nonlinear kinetics of tacrolimus may be attributed to the properties of the drug itself. • Published models performed inadequately in prediction- and simulation-based diagnostics. • Bayesian forecasting could improve the predictive performance of the models. Diverse tacrolimus population pharmacokinetic (popPK) models in adult liver transplant recipients have been established to describe the PK characteristics of tacrolimus in the last two decades. However, their extrapolated predictive performance remains unclear. Therefore, in this study, we aimed to evaluate their external predictability and identify their potential influencing factors. The external predictability of each selected popPK model was evaluated using an independent dataset of 84 patients with 572 trough concentrations prospectively collected from Huashan Hospital. Prediction- and simulation-based diagnostics and Bayesian forecasting were conducted to evaluate model predictability. Furthermore, the effect of model structure on the predictive performance was investigated. Sixteen published popPK models were assessed. In prediction-based diagnostics, the prediction error within ± 30% was below 50% in all the published models. The simulation-based normalised prediction distribution error test and prediction- and variability-corrected visual predictive check indicated large discrepancies between the observations and simulations in most of the models. Bayesian forecasting showed improvement in model predictability with two to three prior observations. Additionally, the predictive performance of the nonlinear Michaelis–Menten model was superior to that of linear one- and two-compartment models with first-order elimination, indicating the underlying nonlinear kinetics of tacrolimus in liver transplant recipients, which was consistent with the findings in adult kidney transplant recipients. The published models performed inadequately in prediction- and simulation-based diagnostics. Bayesian forecasting may improve the predictive performance of the models. Furthermore, nonlinear kinetics of tacrolimus may be mainly caused by the properties of the drug itself, and incorporating nonlinear kinetics may be considered to improve model predictability. Image, graphical abstract [ABSTRACT FROM AUTHOR]

Introduction: Proprotein convertase subtilisin/kexin-9 (PCSK9) has been primarily studied in the cardiovascular field however, its role in cancer pathophysiology remains incompletely defined. Recently, a pivotal role for PCSK9 in cancer immunotherapy was proposed based on the finding that PCSK9 inhibition was associated with enhancing the antigen presentation efficacy of target programmed cell death-1 (PD-1). Herein, we provide results of a comprehensive pan-cancer analysis of PCSK9 that assessed its prognostic and immunological functions in cancer., Methods: Using a variety of available online cancer-related databases including TIMER, cBioPortal, and GEPIA, we identified the abnormal expression of PCSK9 and its potential clinical associations in diverse cancer types including liver, brain and lung. We also validated its role in progression-free survival (PFS) and immune infiltration in neuroblastoma., Results: Overall, the pan-cancer survival analysis revealed an association between dysregulated PCSK9 and poor clinical outcomes in various cancer types. Specifically, PCSK9 was extensively genetically altered across most cancer types and was consistently found in different tumor types and substages when compared with adjacent normal tissues. Thus, aberrant DNA methylation may be responsible for PCSK9 expression in many cancer types. Focusing on liver hepatocellular carcinoma (LIHC), we found that PCSK9 expression correlated with clinicopathological characteristics following stratified prognostic analyses. PCSK9 expression was significantly associated with immune infiltrate since specific markers of CD8+ T cells, macrophage polarization, and exhausted T cells exhibited different PCSK9-related immune infiltration patterns in LIHC and lung squamous cell carcinoma. In addition, PCSK9 was connected with resistance of drugs such as erlotinib and docetaxel. Finally, we validated PCSK9 expression in clinical neuroblastoma samples and concluded that PCSK9 appeared to correlate with a poor PFS and natural killer cell infiltration in neuroblastoma patients., Conclusion: PCSK9 could serve as a robust prognostic pan-cancer biomarker given its correlation with immune infiltrates in different cancer types, thus potentially highlighting a new direction for targeted clinical therapy of cancers., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest, (Copyright © 2023 Sun, Zhu, Shen, Huang, Li, Li, Ma and Wang.)

Background: N 6 -methyladenosine (m 6 A) is the most abundant epitranscriptomic modification of RNA, which can affect RNA metabolism and protein translation. The m 6 A modification plays a critical role in cancer development, including hepatocellular carcinoma (HCC). Despite several m 6 A-related signatures in HCC, most of them lack the necessary validation and the reliability is still elusive., Methods: Differentially expressed genes (DEGs) in the Cancer Genome Atlas were comprehensively analyzed to identify m 6 A signature associated with HCC prognosis. Gene set enrichment analysis, tumor mutation burden (TMB), immune infiltration, and therapeutic response were evaluated. Importantly, mass spectrometry proteomics and multiplex immunofluorescence assays were performed for validation., Results: The m 6 A-related protein-coding gene signature was established, which can divide HCC into high-/low-risk subgroups with markedly different overall survival (OS) and clinical stages. Furthermore, we validated its reliability and robustness in our 101 independent HCC specimens using proteomic detection and confirmed that our signature readily identified high-risk HCC patients with 3-year survival rates of 44.1% vs. 71.8% in the low-risk group. Functional analysis indicated that the high-risk group might stimulate the cell cycle and activate oncogenic pathways such as MAPK, mTOR, and VEGF, whereas the low-risk group mainly regulated amino acid, fatty acid, and drug metabolism. Additionally, the high-risk group had more TMB, upregulated immune checkpoint molecule expression, including PD-1, CTLA4, TIM3, and LAG3, and preferentially formed an immunosuppressive microenvironment. Accordingly, potential therapeutic responses showed that high-risk patients were potentially sensitive to inhibitors targeting the cell cycle and MAPK signaling, with patients possibly benefiting from immunotherapy. Moreover, multiplex immunofluorescence assays indicated that high-risk HCC samples displayed distinct immunosuppressive features, with abundant M2-polarized macrophages and T-regulatory cell infiltration., Conclusion: The m 6 A signature had a prominent capacity to evaluate OS and characterize the tumor immune microenvironment of HCC, which may serve as a useful approach for risk stratification management and provide a valuable clue to choosing rational therapeutic strategies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Ma, Li, Shen, Gu, Zhang, Li, Zhao and Wang.)

Background: Ischemia-reperfusion injury (IRI) severely limits the efficacy and donor source of liver transplantation, and the crucial step in alleviating it is to control inflammation. Itaconic acid is a metabolite produced by intrinsic immune cells (especially macrophages) in the inflammatory state and can promote inflammation subsidence. However, its role in liver ischemia-reperfusion is insufficiently clarified., Methods: A mouse liver ischemia-reperfusion model was constructed, and blood and liver tissue samples were collected by sequential euthanasia of mice at pre-set time points. Liver function and inflammatory factor concentrations were measured, and HE staining was conducted. In the hypoxia-reoxygenation model, proteins were collected at pre-set time points, and the expression of NF-κB pathway-associated protein and its downstream inflammation-associated protein NLRP3 and caspase-1 were detected by Western blot, immunohistochemistry, and immunofluorescence. The level of P-P65 in the nucleus was detected by immunofluorescence., Results: In the liver ischemia-reperfusion model, liver function and inflammatory factors were dynamically varied with reperfusion time in mice, and itaconic acid significantly modified liver function and inflammatory status during this process. NF-κB pathway activity was dynamically varied during hypoxia-reoxygenation, and itaconic acid significantly inhibited the activity of the pathway and significantly suppressed the expression of its downstream inflammation-related proteins., Conclusions: Itaconic acid inhibits NF-κB pathway activation and reduces the accumulation of P-P65 in the nucleus. In turn, this reduces NLRP3 and caspase-1 expression of downstream inflammation-related proteins, promotes inflammation regression, and attenuates liver IRI., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://atm.amegroups.com/article/view/10.21037/atm-22-3388/coif). The authors have no conflicts of interest to declare., (2022 Annals of Translational Medicine. All rights reserved.)

Currently, chemokines and their receptors, CXCL12-CXCR4 and CCL21-CCR7 axes, are deemed vital factors in the modulation of angiogenesis and are crucial for the growth and development of liver cancer. Tumor-derived DNA can be recognized by immune cells to induce an autoimmune response. In this study, we demonstrated the mechanism of tumor-derived DNA on the CXCL12-CXCR4 and CCL21-CCR7 axes of hepatocellular carcinoma (HCC) cells and the regulatory effect of sinomenine hydrochloride. Tumor-derived DNA was separated from HCCLM cell lines. Tumor-derived DNA was transfected into SK-Hep1 cells by Lipofectamine 2000. We found that sinomenine hydrochloride reduced the expression of CXCR4, CXCR12, CCR7, and CCL21 in HCC cells, suppressed the growth and invasion of HCC cells, and increased apoptosis. In contrast to the controls, the protein expressions of CXCR4, CXCL12, CCR7, CCL21, P-ERK1/2, MMP-9, and MMP-2 in SK-Hep1 cells were significantly increased after transfection of tumor-derived DNA, while the increase was reversed by sinobine hydrochloride. Acid sinomenine interferes with tumor-derived DNA and affects ERK/MMP signaling via the CXCL12/CXCR4 axis in HCC cells. CXCR4 siRNA and CCR7 siRNA attenuated tumor-derived DNA activation of ERK1/2/MMP2/9 signaling pathways in HCC cells. CXCR4-oe and CCR7-OE enhance the stimulation of erK1/2/MMP2/9 signaling pathway by tumor-derived DNA in HCC cells. Tumor-derived DNA reduced apoptosis and increased invasion of SK-Hep1 cells by CXCL12-CXCR4 axis and CCL21-CCR7 axis, and sinobine hydrochloride reversed this regulation. These results strongly suggest that tumor-derived DNA can increase the growth and invasion of oncocytes via the upregulation of the expression of CXCL12-CXCR4 and CCL21-CCR7 axis and through ERK1/2/MMP2/9 signaling pathway in HCC cells, and sinobine hydrochloride can inhibit this signaling pathway, thus inhibiting HCC cells. These results provide new potential therapeutic targets for blocking the progression of HCC induced by CXCL12-CXCR4 axis and CCL21-CCR7., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Shen, Li, Li, Ma, Tao, Zhang and Wang.)

Background: To evaluate the difference and efficacy of two donor liver procurement methods for treatment of pediatric acute liver failure (PALF) by living donor liver transplantation (LDLT)., Methods: A total of 17 patients (12 men, 5 women) with PALF who underwent LDLT in our hospital between October 2016 and October 2020, and prognostic efficacy of donors and recipients using two donor liver procurement methods were analyzed., Results: The donors and recipients were both divided into laparoscopic (7 cases) and open (10 cases) donor liver procurement groups. In the recipients, two deaths occurred in the laparoscopic group and one in the open group, and there were three postoperative complications in the laparoscopic group and six in the open group. The cumulative 1-year and 3-year survival rates in the laparoscopic group and the open group were 80.0% and 85.7% separately. There was no difference in the postoperative survival and complications rates between the two groups. In the donors, the operation time, postoperative hospital stay, and blood loss of the laparoscopic group was significantly reduced compared with the open group ( P ≤ 0.01). No death or serious complication occurred in either donor group., Conclusion: Laparoscopic donor liver procurement is worth recommending than open donor liver procurement for treatment of PALF combined with LDLT in qualified transplant centers., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Pei, Shen, Li, Tao, Lu, Chen, Xie and Wang.)

Background: An individual prognostic model that includes inflammation caused by the delayed recovery of liver function after surgery for the early recurrence of hepatocellular carcinoma (HCC) following liver transplantation (LT) has not been well determined. Our aim was to develop a nomogram model for predicting individual survival and early recurrence following LT for patients., Methods: Retrospective data, including clinical pathology and follow-up data, on HCC patients were collected between October 2016 and October 2019 at Huashan Hospital Affiliated to Fudan University. A nomogram estimating recurrence post-transplantation was constructed using multivariate Cox regression analysis., Results: A total of 210 patients were included in the present study. The multivariate estimators of recurrence consisted of age, maximum tumor diameter, tumor thrombus, microvascular invasion (MVI), alanine aminotransferase and alpha-fetoprotein on postoperative day 7. Nomogram of recurrence-free survival was developed. The calibration and discrimination of the novel model were assessed with the calibration curves and concordance index (C-index). Its reliability and advantages were evaluated by comparing it with the conventional American Joint Committee on Cancer (AJCC) 8th edition staging system using integrated discrimination improvement (IDI) and net reclassification improvement (NRI). In comparison to the AJCC 8th edition staging system, the C-index (development set: 0.796 vs. 0.643, validation set: 0.741 vs. 0.563), the area under the receiver operating characteristic curve (AUC) of the validation set (1-year AUC: 0.732 vs. 0.586, 2-year AUC: 0.705 vs. 0.504), the development set (1-year AUC: 0.799 vs. 0.551, 2-year AUC: 0.801 vs. 0.512), and this model's calibration plots all showed improved performance. In addition, NRI and IDI verified that the nomogram is an accurate prognostic tool. Subsequently, a web calculator was generated to assess the risk of tumor recurrence post-LT., Conclusions: The nomogram, based on clinical and pathological factors, showed good accuracy in estimating prognostic recurrence and can be used to guide individual patient follow-up and treatment., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/atm-21-334). The authors have no conflicts of interest to declare., (2021 Annals of Translational Medicine. All rights reserved.)

The cooperative roles of SENP1 and UBE2T in development and progression of hepatocellular carcinoma (HCC) are still unknown. The expression levels of SENP1 and UBE2T were evaluated in clinical specimens and HCC cells. The relationship between clinicopathological features and SENP1 were analyzed. We constructed the HepG2-SENP1 knockout cell model and explored the functions of SENP1 and UBE2T in HCC development. UBE2T was confirmed as a novel deSUMOylation target of SENP1. Upregulation of SENP1 and UBE2T were observed in HCC tissues and most hepatoma cell lines, and their expression levels were proved to be positively related. Knockout of SENP1 resulted in impaired growth, migration and invasion, and enhanced apoptosis in vitro, as well as inhibition of tumor growth in vivo. Furthermore, we demonstrated that SENP1 could directly deSUMOylate UBE2T thereby increasing its expression and activating Akt pathway. Functional studies showed that UBE2T overexpression or K8R mutation promoted cell growth, migration and invasion. In conclusion, our study demonstrated that SENP1 and UBE2T were positively related and functioned as tumor promoters. The carcinogenesis of SENP1 is mediated by deSUMOylation of UBE2T and the UBE2T/Akt pathway. Notably, UBE2T was identified as a novel deSUMOylation target of SENP1 in this study for the first time.

Cellular senescence, an irreversible growth arrest of cells, is involved in protection against cancer. Triptolide (TPL) plays an important role in immunosuppressive, anti-fertility, anti-cystogenesis and anticancer activities. However, effect and mechanism of TPL on cellular senescence-associated antitumor is rarely reported. Herein HepG2 cells were used to explore the effect of TPL on tumor growth and cellular senescence. We showed that TPL inhibited tumor cell proliferation and growth in vitro and in vivo, accelerated cellular senescence and arrested cells at G0/G1 phase. We further demonstrated that TPL accelerated HepG2 cell senescence by regulating the AKT pathway. In addition, TPL could also enhance cellular senescence and inhibit tumor growth by negatively regulating human telomerase reverse transcriptase (hTERT) signaling pathway. These findings reveal a regulatory mechanism of TPL on cellular senescence, indicating that TPL promotes HepG2 cell senescence through AKT pathway and hTERT pathway simultaneously. Altogether, TPL-induced senescence can be regarded as a promising strategy for anticancer therapy and drug development.

Objective: To summarize the clinical characteristics, early diagnosis, comprehensive treatment and prognosis of 6 cases of children with post-transplantation lymphoproliferative disorder (PTLD) after liver transplantation., Method: Data of 6 cases with PTLD seen between January 2011 and December 2013 were retrospectively analyzed. The anti-rejection drug dose adjustments, the effect of rituximab, antiviral therapy and comprehensive treatment program after surgery were explored., Result: (1) The diagnosis of PTLD was confirmed by histologic findings. Six cases of PTLD including 3 males and 3 females were diagnosed as congenital biliary atresia and underwent split liver transplantation. The occurrence rate of PTLD was 2.9%. (2) The median time to the development of PTLD was less than 6 months. The initial symptom of PTLD in all patients was fever and clinical manifestations of PTLD were non-specific, depending on the involving organs. Five cases of PTLD developed gastrointestinal symptoms, including diarrhea, abdominal pain, and abdominal distension. One case developed respiratory symptoms, including cough and tachypnea. Three cases had lymph node involvement. In 2 cases pathophysiology involved polymorphic lymphocyte proliferation and in 4 cases B lymphocyte proliferation. (3) Two cases died, in whom EBV DNA was not detected and were diagnosed as PTLD by surgical pathology before death. Four survived cases had high EBV-DNA load and then were diagnosed as PTLD by biopsy pathology. (4) Of the 6 cases of PTLD, 2 cases died and 4 cases survived. The overall mortality was 33%. The dead cases were only treated with laparotomy because of intestinal obstruction or perforation and the survived cases were treated with tacrolimus at reduced doses or discontinuation and rituximab. In 2 cases antiviral therapy (acyclovir) was continued, including 1 cases of intestinal obstruction treated with surgical repair. All the survived patients were followed up for 4 months to 1 year and no evidence has been found., Conclusion: EBV infection is the high risk factor for PTLD after liver transplantation. Close clinical surveillance of EBV DNA for pediatric liver transplantation was important for the early diagnosis of PTLD. Reducing doses of immunosuppressive agents and rituximab is the initial therapy for PTLD. A reduction in the dose of tacrolimus is suggested. Operation therapy can also play a role in the management of local complications.