Late-stage modification of complex drug: Base-controlled Pd-catalyzed regioselective synthesis and bioactivity of arylated osimertinibs.

Achieving regioselective synthesis in complex molecules with multiple reactive sites remains a tremendous challenge in synthetic chemistry. Regiodivergent palladium-catalyzed C─H arylation of complex antitumor drug osimertinib with various aryl bromides via the late-stage functionalization strategy was demonstrated here. This reaction displayed a switch in regioselectivity under complete base control. Potassium carbonate (K2CO3) promoted the arylation of acrylamide terminal C(sp2)-H, affording 34 derivatives. Conversely, sodium tert-butoxide (t-BuONa) mediated the aryl C(sp2)-H arylation of the indole C2 position, providing 27 derivatives. The derivative 3r containing a 3-fluorophenyl group at the indole C2 position demonstrated similar inhibition of EGFRT790M/L858R and superior antiproliferative activity in H1975 cells compared to osimertinib, as well as similar antiproliferative activity in A549 cells and antitumor efficacy in xenograft mouse model bearing H1975 cells. This approach provides a "one substrate-multi reactions-multiple products" strategy for the structural modification of complex drug molecules, creating more opportunities for the fast screening of pharmaceutical molecules.

Tracking of Stem Cells in Chronic Liver Diseases: Current Trends and Developments.

Stem cell therapy holds great promise for future clinical practice for treatment of advanced liver diseases. However, the fate of stem cells after transplantation, including the distribution, viability, and the cell clearance, has not been fully elucidated. Herein, recent advances regarding the imaging tools for stem cells tracking mainly in chronic liver diseases with the advantages and disadvantages of each approach have been described. Magnetic resonance imaging is a promising clinical imaging modality due to non-radioactivity, excellent penetrability, and high spatial resolution. Fluorescence imaging and radionuclide imaging demonstrate relatively increased sensitivity, with the latter excelling in real-time monitoring. Reporter genes specialize in long-term tracing. Nevertheless, the disadvantages of low sensitivity, radiation, exogenous gene risk are inevitably present in each of these means, respectively. In this review, we aim to comprehensively evaluate the current state of methods for tracking of stem cell, highlighting their strengths and weaknesses, and providing insights into their future potential. Multimodality imaging strategies may overcome the inherent limitations of single-modality imaging by combining the strengths of different imaging techniques to provide more comprehensive information in the clinical setting.

TRIM24 is critical for the cellular response to DNA double-strand breaks through regulating the recruitment of MRN complex.

The MRE11-RAD50-NBS1 (MRN) complex plays a crucial role in DNA double-strand breaks (DSBs) sensing and initiation of signaling cascades. However, the precise mechanisms by which the recruitment of MRN complex is regulated has yet to be elucidated. Here, we identified TRIpartite motif-containing protein 24 (TRIM24), a protein considered as an oncogene overexpressed in cancers, as a novel signaling molecule in response to DSBs. TRIM24 is essential for DSBs-induced recruitment of MRN complex and activation of downstream signaling. In the absence of TRIM24, MRN mediated DSBs repair is remarkably diminished. Mechanistically, TRIM24 is phosphorylated by ataxia-telangiectasia mutated (ATM) and then recruited to DSBs sites, facilitating the accumulation of the MRN components to chromatin. Depletion of TRIM24 sensitizes human hepatocellular carcinoma cells to cancer therapy agent-induced apoptosis and retards the tumor growth in a subcutaneous xenograft tumor mouse model. Together, our data reveal a novel function of TRIM24 in response to DSBs through regulating the MRN complex, which suggests that TRIM24 may be a potential therapeutic molecular target for tumor treatment.

Clinical features, natural history and outcomes of pseudolymphoma of liver: A case-series and systematic review.

BACKGROUND: Pseudolymphoma is a rare, benign, nonspecific condition that forms a mass-like lesion characterized by the proliferation of non-neoplastic lymphocytes. Lacking of specific clinical symptoms, serological markers, and imaging features, the diagnosis is difficult. We reporte five cases of hepatic pseudolymphoma and provide a systematic review of existing literatures to improve our understanding of this rare liver disease. METHODS: We followed-up five cases of hepatic pseudolymphoma in West China Hospital from January 2002 to January 2022. We also summarized the cases of hepatic pseudolymphoma from January 1981 to December 2021 through the PubMed database and comprehensively analyzed the characteristics of the cases. RESULTS: The pathologic features of the five cases were characterized by benign lymphoid tissue hyperplasia, lymphoid follicle formation, and a polarized germinal center. Immunohistochemistry, in situ hybridization, and gene rearrangement revealed non-malignant lymphoma. Besides, a total of 116 cases have been reported in the PubMed database from 1981 to 2021. The incidence of hepatic pseudolymphoma is higher in middle-aged and elderly women and has been reported more frequently in Asia. All cases were pathologically diagnosed, among which 85.95% of the patients were treated by surgery. CONCLUSIONS: Hepatic pseudolymphoma is an extremely rare benign disease, mainly in middle-aged and elderly women. Without distinctive clinical and imaging characteristics, pathological diagnosis is the highly reliable method at present. Thus, in the absence of risk factors for a primary liver tumor or metastatic tumor in middle-aged and elderly women, the possibility of pseudolymphoma should be considered to avoid extensive treatments.

Preoperative evaluation of liver regeneration following hepatectomy in hepatocellular carcinoma using magnetic resonance elastography.

Background: For patients with hepatocellular carcinoma (HCC) undergoing hepatectomy, insufficient remnant liver regenerative capacity can lead to liver failure. The aim of this study was to evaluate the potential role of magnetic resonance elastography (MRE) for the preoperative prediction of liver regeneration in patients with HCC after partial hepatectomy (PH). Methods: A total of 54 patients with HCC undergoing MRE prior to PH were retrospectively included. The total functional liver, volume of preoperative future liver remnant (LVpre), and volume of postoperative liver remnant (LVpost), respectively, were measured, and the regeneration index (RI) and parenchymal hepatic resection rate (PHRR) were manually calculated. Univariate and multivariate logistic regression analyses were conducted to identify factors associated with a high RI, and receiver operating characteristic (ROC) curves were employed to evaluate the diagnostic performance of the liver stiffness (LS) values. Patients were classified into three subgroups based on the value of PHRR: low PHRR (<30%), intermediate PHRR (30-50%), and high PHRR (>50%). Subsequently, Spearman correlation analysis was used to investigate the relationship between LS values and RI in the subgroups. Results: Multivariable analysis revealed a low LS value was associated with greater odds of a high RI [odds ratio (OR), 0.049; 95% confidence interval (CI): 0.002 to 0.980]. An optimal cutoff value of 3.30 kPa was used to divide all patients into a low RI group and a high RI group with an area under the curve (AUC) value of 0.882 (95% CI: 0.767 to 0.996). A significant negative relationship between RI and LS values (r=-0.799; P<0.001) was observed in the intermediate PHRR subgroup. Conclusions: The LS values based on MRE may serve as a potential preoperative predictor of liver regeneration for patients with HCC undergoing PH.

Black liver in a patient with Wilson's disease.

Wilson's disease is an autosomal recessive inherited disease with congenital copper metabolism disorder, characterized by decreased ceruloplasmin and increased urine copper, which can involve multiple organs. This case was complicated by iron overload, which is of great value in differentiating hereditary hemochromatism.

Upregulation of microRNA-125b-5p alleviates acute liver failure by regulating the Keap1/Nrf2/HO-1 pathway.

Background: Acute liver failure (ALF) and acute-on-chronic liver failure (ACLF) are the two most common subtypes of liver failure. They are both life-threatening clinical problems with high short-term mortality. Although liver transplantation is an effective therapeutic, its application is limited due to the shortage of donor organs. Given that both ACLF and ALF are driven by excessive inflammation in the initial stage, molecules targeting inflammation may benefit the two conditions. MicroRNAs (miRNAs) are a group of small endogenous noncoding interfering RNA molecules. Regulation of miRNAs related to inflammation may serve as promising interventions for the treatment of liver failure. Aims: To explore the role and mechanism of miR-125b-5p in the development of liver failure. Methods: Six human liver tissues were categorized into HBV-non-ACLF and HBV-ACLF groups. Differentially expressed miRNAs (DE-miRNAs) were screened and identified through high-throughput sequencing analysis. Among these DE-miRNAs, miR-125b-5p was selected for further study of its role and mechanism in lipopolysaccharide (LPS)/D-galactosamine (D-GalN) -challenged Huh7 cells and mice in vitro and in vivo. Results: A total of 75 DE-miRNAs were obtained. Of these DE-miRNAs, miR-125b-5p was the focus of further investigation based on our previous findings and preliminary results. We preliminarily observed that the levels of miR-125b-5p were lower in the HBV-ACLF group than in the HBV-non-ACLF group. Meanwhile, LPS/D-GalN-challenged mice and Huh7 cells both showed decreased miR-125b-5p levels when compared to their untreated control group, suggesting that miR-125b-5p may have a protective role against liver injury, regardless of ACLF or ALF. Subsequent results revealed that miR-125b-5p not only inhibited Huh7 cell apoptosis in vitro but also relieved mouse ALF in vivo with evidence of improved liver histology, decreased alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, and reduced tumor necrosis factor-α (TNF-α) and IL-1ß levels. Based on the results of a biological prediction website, microRNA.org, Kelch-like ECH-associated protein 1 (Keap1) was predicted to be one of the target genes of miR-125b-5p, which was verified by a dual-luciferase reporter gene assay. Western blot results in vitro and in vivo showed that miR-125b-5p could decrease the expression of Keap1 and cleaved caspase-3 while upregulating the expression of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and heme oxygenase-1(HO-1). Conclusion: Upregulation of miR-125b-5p can alleviate acute liver failure by regulating the Keap1/Nrf2/HO-1 pathway, and regulation of miR-125b-5p may serve as an alternative intervention for liver failure.

Dopamine receptor D2 antagonism normalizes profibrotic macrophage-endothelial crosstalk in non-alcoholic steatohepatitis.

BACKGROUND & AIMS: Currently there is no effective treatment for liver fibrosis, which is one of the main histological determinants of non-alcoholic steatohepatitis (NASH). While Hippo/YAP (Yes-associated protein) signaling is essential for liver regeneration, its aberrant activation frequently leads to fibrosis and tumorigenesis. Unravelling "context-specific" contributions of YAP in liver repair might help selectively bypass fibrosis and preserve the pro-regenerative YAP function in hepatic diseases. METHODS: We used murine liver fibrosis and minipig NASH models, and liver biopsies from patients with cirrhosis. Single-cell RNA-sequencing (scRNA-Seq) was performed, and a G-protein-coupled receptor (GPCR) ligand screening system was used to identify cell-selective YAP inhibitors. RESULTS: YAP levels in macrophages are increased in the livers of humans and mice with liver fibrosis. The increase in type I interferon and attenuation of hepatic fibrosis observed in mice specifically lacking Yap1 in myeloid cells provided further evidence for the fibrogenic role of macrophage YAP. ScRNA-Seq further showed that defective YAP pathway signaling in macrophages diminished a fibrogenic vascular endothelial cell subset that exhibited profibrotic molecular signatures such as angiocrine CTGF and VCAM1 expression. To specifically target fibrogenic YAP in macrophages, we utilized a GPCR ligand screening system and identified a dopamine receptor D2 (DRD2) antagonist that selectively blocked YAP in macrophages but not hepatocytes. Genetic and pharmacological targeting of macrophage DRD2 attenuated liver fibrosis. In a large animal (minipig) NASH model recapitulating human pathology, the DRD2 antagonist blocked fibrosis and restored hepatic architecture. CONCLUSIONS: DRD2 antagonism selectively targets YAP-dependent fibrogenic crosstalk between macrophages and CTGF+VCAM1+ vascular niche, promoting liver regeneration over fibrosis in both rodent and large animal models. LAY SUMMARY: Fibrosis in the liver is one of the main histological determinants of non-alcoholic steatohepatitis (NASH), a disease paralleling a worldwide surge in metabolic syndromes. Our study demonstrates that a macrophage-specific deficiency in Yes-associated protein (YAP) attenuates liver fibrosis. Dopamine receptor D2 (DRD2) antagonism selectively blocks YAP in macrophages and thwarts liver fibrosis in both rodent and large animal models, and thus holds potential for the treatment of NASH.

Case Report: A Novel Homozygous Variant Identified in a Chinese Patient With Benign Recurrent Intrahepatic Cholestasis-Type 1.

Benign recurrent intrahepatic cholestasis (BRIC) is a rare hereditary cholestatic liver disorder. Accurate diagnosis and timely interventions are important in determining outcomes. Besides clinical and pathologic diagnosis, genetic study of BRIC remains limited. Here, we report a young man enduring recurrent jaundice and severe pruritus for 15 years. The increased level of direct bilirubin was the main biochemical abnormality, and the work-up for common causes of jaundice were unremarkable. Liver biopsy showed extensive cholestasis of hepatocytes in zone 3. The novel homozygous variant including c.1817T > C and p.I606T was detected on his ATP8B1gene. The patient was finally diagnosed with BRIC-1. His symptoms were relieved, and liver function tests returned to normal after taking ursodeoxycholic acid. This case provides a different perspective to the methodology employed when dealing with cases of jaundice and helping diagnose rare diseases.

Antiviral Therapy for Chronic HBV Infection With Persistently Normal Alanine Aminotransferase: Controversy and Consensus.

ALT is one of the most sensitive biochemical indexes to reflect liver injury. It is generally believed that hepatitis B virus (HBV) infected patients with normal ALT levels are in either immune tolerance or low replication stage of the natural history of hepatitis B, and there is no or only mild inflammation in liver tissue, so antiviral therapy is not recommended. However, chronic HBV-infected patients with normal ALT levels are not always in a stable state. A considerable number of patients will develop active hepatitis or occult progress to liver fibrosis, cirrhosis, and hepatocellular carcinoma. Therefore, whether antiviral therapy should be recommended for chronic HBV infection with normal ALT level has been a hot topic in clinical practice. In this paper, the definition of immune tolerance, the relationship between ALT and liver inflammation, and the benefits of antiviral therapy were reviewed, and we hope it will be helpful for clinicians to have a deeper understanding of whether antiviral therapy should be considered for chronic HBV infection with normal ALT.

Cell heterogeneity, rather than the cell storage solution, affects the behavior of mesenchymal stem cells in vitro and in vivo.

BACKGROUND: Mesenchymal stem cells (MSCs) have to be expanded in vitro to reach a sufficient cell dose for the treatment of various diseases. During the process of expansion, some obstacles remain to be overcome. The purpose of this study was to investigate the effects of storage solutions and heterogeneity on the behavior of MSCs in vitro and in vivo. METHODS: Umbilical cord MSCs (UC-MSCs) of similar sizes within normal ranges were suspended in three different storage solutions, phosphate buffer solution, normal saline, and Dulbecco's modified Eagle medium. Then, the ultrastructure, viability, and safety of these cells were compared. Other two UC-MSC populations of different sizes were categorized based on their mean diameters. The ultrastructure, proliferation, immunosuppression, hepatic differentiation potential, and number of senescent cells were investigated and compared. The survival rates of mice after the infusion of UC-MSCs of different sizes were compared. RESULTS: For UC-MSCs suspended in different storage solutions, the cell apoptosis rates, ultrastructure, and survival rates of mice were similar, and no differences were observed. Cells with a diameter of 19.14 ± 4.89 µm were categorized as the larger UC-MSC population, and cells with a diameter of 15.58 ± 3.81 µm were categorized as the smaller population. The mean diameter of the larger UC-MSC population was significantly larger than that of the smaller UC-MSC population (p < 0.01). Smaller UC-MSCs had more powerful proliferation and immunosuppressive potential and a higher nucleus-cytoplasm ratio than those of large UC-MSCs. The number of cells positive for ß-galactosidase staining was higher in the larger UC-MSC population than in the smaller UC-MSC population. The survival rates of mice receiving 1 × 106 or 2 × 106 smaller UC-MSCs were 100%, both of which were higher than those of mice receiving the same amounts of larger UC-MSCs (p < 0.01). The cause of mouse death was explored and it was found that some larger UC-MSCs accumulated in the pulmonary capillary in dead mice. CONCLUSION: Different storage solutions showed no significant effects on cell behavior, whereas heterogeneity was quite prevalent in MSC populations and might limit cells application. Hence, it is necessary to establish a more precise standardization for culture-expanded MSCs.

Simple non-invasive scoring systems and histological scores in predicting mortality in patients with non-alcoholic fatty liver disease: A systematic review and meta-analysis.

BACKGROUND AND AIM: There is debate among the hepatology community regarding the simple non-invasive scoring systems and histological scores (even it was developed for histological classification) in predicting clinical outcomes in patients with non-alcoholic fatty liver disease (NAFLD). This study aimed to determine whether the presence of simple non-invasive scoring systems and histological scores could predict all-cause mortality, liver-related mortality, and liver disease decompensation (liver failure, cirrhosis, hepatocellular carcinoma, or decompensated liver disease). METHODS: The pooled hazard ratio of prognostic factors and incidence rate per 1000 person-years in patients with NAFLD was calculated and further adjusted by two different models of handling the duplicated data. RESULTS: A total of 19 longitudinal studies were included. Most simple non-invasive scoring systems (Fibrosis-4 Score, BARD, and aspartate aminotransferase-to-platelet ratio index ) and histological scores (NAFLD activity score, Brunt, and "steatosis, activity, and fibrosis" ) failed in predicting mortality, and only the NAFLD fibrosis score > 0.676 showed prognostic ability to all-cause mortality (four studies, 7564 patients, 118 352 person-years followed up, pooled hazard ratio 1.44, 95% confidence interval [CI] 1.05-1.96). The incidence rate per 1000 person-years of all-cause mortality, liver-related mortality, cardiovascular-related mortality, and liver disease decompensation resulted in a pooled incidence rate per 1000 person-years of 22.65 (14 studies, 95% CI 9.62-53.31), 3.19 (7 studies, 95% CI 1.14-8.93), 6.02 (6 studies, 95% CI 4.69-7.74), and 11.46 (4 studies, 95% CI 5.33-24.63), respectively. CONCLUSION: Non-alcoholic fatty liver disease fibrosis score showed promising prognostic value to all-cause mortality. Most present simple non-invasive scoring systems and histological scores failed to predict clinical outcomes.

EZH2 promotes the expression of LPA1 by mediating microRNA-139 promoter methylation to accelerate the development of ovarian cancer.

BACKGROUND: It has been known that ovarian cancer (OC) is a leading cause for women mortality globally. We aimed to analyze the underlying mechanism supporting that enhancer of zeste homolog 2 (EZH2) affected the development of OC via the involvement of microRNA-139 (miR-139)/transforming growth factor beta (TGF-ß)/lysophosphatidic acid-1 (LPA1) axis. METHODS: High expression patterns of EZH2 and miR-139 and low LPA1 expression pattern in OC were evaluated using RT-qPCR and immunoblotting, while their correlation was assessed by the Spearman's rank and Pearson's correlation coefficient. Subsequently, dual-luciferase reporter gene assay was applied to validate the binding relationship between miR-139 and LPA1, while H3K27me enrichment was assessed by ChIP assay. After that, the effects of altered expression of EZH2, miR-194, or LPA1 on the cell biological functions and the expression pattern of TGF-related factors were evaluated. RESULTS: We found that EZH2 repressed the miR-139 expression pattern by recruiting H3K27me3 to promote miR-139 promoter methylation, while silencing of EZH2 suppressed in vitro cancer progression by increasing miR-139. LPA1 was a target of miR-139, and could activate the TGF-ß signaling pathway, which hastened the OC progression. miR-139-targeted inhibition of LPA1 and LPA1-activated TGF-ß signaling pathway were evidenced to be critical mechanisms underlying the effects of EZH2 on OC cells. Lastly, silencing of EZH2 inhibited the xenograft growth in vivo. CONCLUSIONS: EZH2 could down-regulate miR-139 expression pattern by recruiting H3K27me3 to promote the miR-139 promoter methylation and activate the TGF-ß pathway by up-regulating LPA1, which contributed to the progression of OC. The current study may possess potentials for OC treatment.

TRAIL inhibits HBV replication and expression by down-regulating liver-enriched transcription factors.

BACKGROUND AND STUDY AIMS: To investigate the role of low-concentration TRAIL on HBV replication and expression. MATERIAL AND METHODS: MTT assay was performed to determine the minimum concentrations of TRAIL protein in HepG2 cell apoptosis. HepG2 cells were transfected by HBV replication plasmid pHBV4.1. After the treatment with low concentration of TRAIL, the culture supernatant was collected to detect HBsAg and HBeAg by ELISA. Proteins were extracted from the resulted cells, followed by total RNA and HBV DNA intermediate replication. Southern Blot and Northern Blot were carried out to detect HBV RNA and HBV DNA replication intermediates, respectively. RT-PCR and Western Blot were carried out to detect gene and protein expressions for HNF4α, PPARα, and RXRα, respectively. RESULTS: 50 ng/ml of TRAIL protein led to significant decline on the secretions of HBsAg and HBeAg. Expression levels of HBV RNA and HBV DNA replication intermediates were significantly decreased too. In addition, gene and protein expressions of HNF4α, PPARα and RXRα also dropped, especially for PPARα whose expressions significantly decreased. CONCLUSION: TRAIL could inhibit HBV replication and expression by downregulating the expressions of liver-enriched transcription factors HNF4α, PPARα, and RXRα.

Present and Future Therapies for Chronic Hepatitis B.

Chronic hepatitis B (CHB) remains the leading cause of liver-related morbidity and mortality across the world. If left untreated, approximately one-third of these patients will progress to severe end-stage liver diseases including liver failure, cirrhosis, and hepatocellular carcinoma (HCC). High level of serum HBV DNA is strongly associated with the development of liver failure, cirrhosis, and HCC. Therefore, antiviral therapy is crucial for the clinical management of CHB. Current antiviral drugs including nucleoside/nucleotide analogues (NAs) and interferon-α (IFN-α) can suppress HBV replication and reduce the progression of liver disease, thus improving the long-term outcomes of CHB patients. This chapter will discuss the standard and optimization antiviral therapies in treatment-naïve and treatment-experienced patients, as well as in the special populations. The up-to-date advances in the development of new anti-HBV agents will be also discussed. With the combination of the current antiviral drugs and the newly developed antiviral agents targeting the different steps of the viral life cycle or the newly developed agents modulating the host immune responses, the ultimate eradication of HBV will be achieved in the future.

TIPS Is Not Associated with a Higher Risk of Developing HCC in Cirrhotic Patients: A Systematic Review and Meta-analysis.

Background and Aims: The association between portal-systemic shunt and hepatocellular carcinoma (HCC) development in patients who have cirrhosis is still controversial. This systematic review with meta-analysis was performed to systematically clarify the potential role of portal-systemic shunt in the development of HCC. Methods: The PubMed, Embase, and Cochrane Library databases were searched for potentially eligible literature. Meta-analysis with random-effects model was performed to combine the incidence rates of HCC after portal-systemic shunt. Finally, seven studies were included. In the present review, we mainly focused on 859 patients (365 in the transjugular intrahepatic portal-systemic shunt (TIPS) group and 494 in the non-TIPS group) from five studies to analyze incidence rates after TIPS. Results: At the end of follow-up, there were 66 (18%, 66/365) patients who developed HCC after TIPS intervention and 63 (13%, 63/494) patients who developed HCC after non-TIPS treatments. Pooled estimates with random-effects model did not demonstrate a significant increase of incidence of HCC after TIPS (risk ratio: 1.37 [confidence interval (CI): 0.96 to 1.97]; p = 0.08) compared with non-TIPS treatments. Subgroup analyses for those patients with transplanted liver also did not detect a significant difference between the TIPS group and non-TIPS group (risk ratio: 1.10 [CI: 0.59 to 2.07]; p = 0.75). Conclusions: Current evidence suggests that portal-systemic shunt is not associated with a higher risk of HCC development in cirrhotic patients.

Autologous stem cell transplantation for patients with viral hepatitis-induced liver cirrhosis: a systematic review and meta-analysis.

BACKGROUND: Recently, stem cells have been used in the treatment of viral hepatitis-induced liver cirrhosis (LC), and stem cell therapy is showing potential therapeutic effects on liver function improvement. The consensus on effects and safety of stem cell therapy has not been reached, thus it is essential for us to conduct a systematic review and meat-analysis to investigate the efficacy and safety of stem cell therapy for viral hepatitis-induced LC. MATERIALS AND METHODS: Medline, Embase, SinoMed and Cochrane Library databases were searched with appropriate keywords through 5 August 2018. We included eight trials involving 467 patients. The pooled weight mean difference (WMD) and 95% confidence interval (CI) were calculated using a fixed or random effects model. Quality assessment and publication bias were also performed. The selected studies were considered for meta-analysis using RevMan V5.3. RESULTS: Compared with traditional therapy group, autologous stem cell transplantation increased the level of albumin (WMD: 2.47, 95% CI: 1.05-3.90, P < 0.001), but decreased the level of total bilirubin (WMD: -2.26, 95% CI: -3.61 to -0.90, P = 0.001), alanine aminotransferase (WMD: -9.16, 95% CI: -16.47 to -1.85, P = 0.01) and prothrombin time (WMD: -3.02, 95% CI: -4.83 to -1.22, P = 0.001). Clinical symptoms such as edema, fatigue, anorexia and abdominal distention were alleviated. Model for End-Stage Liver Disease and Child-Pugh scores were decreased after stem cell therapy. Whereas, there was no statistically significant difference between two groups regarding aspartate aminotransferase, prothrombin time activity, ascites and pleural fluid. No procedure-related complications were found. CONCLUSION: Autologous stem cell transplantation might have beneficial effects on patients with viral hepatitis-induced LC and is relatively safe for these patients. Further high-quality randomized controlled trials are needed.

Apolipoprotein A5 alleviates LPS/D-GalN-induced fulminant liver failure in mice by inhibiting TLR4-mediated NF-κB pathway.

BACKGROUND: Fulminant liver failure (FHF) is a serious clinical problem and liver transplantation is the major intervention. But the overall survival rate of FHF is low owing to the donated organ shortage. Apolipoprotein A-V (ApoA5) is a regulator of triglyceride metabolism and has been reported to act as a predictor for remnant liver growth after preoperative portal vein embolization and liver surgery. This study aimed to investigate the therapeutic effect of ApoA5 on lipopolysaccharide/D-galactosamine (LPS/D-GalN)-induced fulminant liver failure in mice. METHODS: FHF mouse model was established using LPS/D-GalN and ApoA5 plasmid was injected by tail vein prior to LPS/D-GalN treatment. The expressions of ApoA5, toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88), and nuclear factor kappa B p65 (NF-κBp65) were assessed by real-time PCR and western blotting. Serum alanine aminotransferase (ALT) and tumor necrosis factor-α (TNF-α) levels were measured using automatic biochemical analyzer. Histological assessment and immunohistochemical (IHC) staining were conducted. Survival rate after LPS/D-GalN administration was also determined with Kaplan-Meier curve. Meanwhile, the expression of ApoA5 in injured huh7 cells was tested. Cell apoptosis analysis was performed after huh7 cells were transfected with ApoA5 plasmid and stimulated with LPS. RESULTS: The expressions of ApoA5 decreased both in injured huh7 cells and FHF mice. ApoA5 overexpression reduced cell death rate using flow cytometry. ApoA5 not only decreased the serum ALT and TNF-α levels but also attenuated hepatic damage in hematoxylin-eosin (HE)-stained liver section. The protein expressions of TLR4, MyD88 and NF-κBp65 were inhibited when ApoA5 overexpressed. But the inhibitory effect would weaken with the increasing concentration of LPS in spite of ApoA5 overexpression. Besides, ApoA5 improved liver injury in a dose-dependent manner and the survival rate in FHF mice increased with increasing concentration of ApoA5. CONCLUSION: ApoA5 had a protective effect against LPS/D-GalN-induced fulminant liver failure in mice within a certain range by inhibiting TLR4-mediated NF-κB pathway.

IVIM improves preoperative assessment of microvascular invasion in HCC.

PURPOSE: To prospectively evaluate the potential role of intravoxel incoherent motion (IVIM) and conventional radiologic features for preoperative prediction of microvascular invasion (MVI) in patients with hepatocellular carcinoma (HCC). METHODS: Institutional review board approval and written informed consent were obtained for this study. A cohort comprising 115 patients with 135 newly diagnosed HCCs between January 2016 and April 2017 were evaluated. Two radiologists independently reviewed the radiologic features and the apparent diffusion coefficient (ADC), true diffusion coefficient (D), pseudodiffusion coefficient (D*), and pseudodiffusion component fraction (f) were also measured. Interobserver agreement was checked and univariate and multivariate logistic regressions were used for screening the risk factors. Receiver operating characteristics (ROC) curve analyses were performed to evaluate the diagnostic performance. RESULTS: Features significantly related to MVI of HCC at univariate analysis were reduced ADC (odds ratio, 0.341; 95% CI, 0.211-0.552; p < 0.001), D (odds ratio, 0.141; 95% CI, 0.067-0.299; p < 0.001), and irregular circumferential enhancement (odds ratio, 9.908; 95% CI, 3.776-25.996; p < 0.001). At multivariate analysis, only D value (odds ratio, 0.096; 95% CI, 0.025-0.364; p < 0.001) was the independent risk factor for MVI of HCC. The mean D value for MVI of HCC showed an area under ROC curves of 0.815 (95% CI, 0.740-0.877). CONCLUSION: IVIM model-derived D value is superior to ADC measured with mono-exponential model for evaluating the MVI of HCC. Among MR imaging features, tumor margin, enhancement pattern, tumor capsule, and peritumoral enhancement were not predictive for MVI. KEY POINTS: • Diffusion MRI is useful for non-invasively evaluating the microvascular invasion of hepatocellular carcinoma. • IVIM model is advantageous over mono-exponential model for assessing the microvascular invasion of hepatocellular carcinoma. • Decreased D value was the independent risk factor for predicting MVI of HCC.