Experimental study on the monotonic mechanical behavior of completely decomposed granite soil reinforced by disposable face-mask chips.

In response to the global outbreak of the coronavirus pandemic (COVID-19), a staggering amount of personal protective equipment, such as disposable face masks, has been used, leading to the urgent environmental issue. This study evaluates the feasibility of mask chips for the soil reinforcement, through triaxial tests on samples mixed with complete decomposed granite (CDG) and mask chips (0%, 0.3%, 0.5%, 1%, 5% by volume). The experimental results show that adding a moderate volumetric amount of mask chips (0.3%-1%) improves the soil strength, especially under high confining pressure. The optimum volumetric content of mask chips obtained by this study is 0.5%, raising the peak shear strength up to 22.3% under the confining stress of 120 kPa. When the volumetric content of mask chips exceeds the optimum value, the peak shear strength decreases accordingly. A limited amount of mask chips also increases the elastic modulus and makes the volumetric response more dilative. By contrast, excessive mask chips create additional voids and shift the strong soil-mask contacts to weak mask-mask contacts. The laser scanning microscope (LSM) and scanning electron microscope (SEM) images on the typical samples demonstrate the microstructure of mask fibers interlocking with soil particles, highly supporting the macro-scale mechanical behavior.

Association of liver abnormalities with in-hospital mortality in patients with COVID-19.

BACKGROUND & AIMS: The evolution and clinical significance of abnormal liver chemistries and the impact of hepatitis B infection on outcome in patients with COVID-19 is not well characterized. This study aimed to explore these issues. METHODS: This large retrospective cohort study included 2,073 patients with coronavirus disease 2019 (COVID-19) and definite outcomes in Wuhan, China. Longitudinal liver function tests were conducted, with associated factors and risk of death determined by multivariate regression analyses. A prognostic nomogram was formulated to predict the survival of patients with COVID-19. The characteristics of liver abnormalities and outcomes of patients with COVID-19, with and without hepatitis B, were compared after 1:3 propensity score matching. RESULTS: Of the 2,073 patients, 1,282 (61.8%) had abnormal liver chemistries during hospitalization, and 297 (14.3%) had a liver injury. The mean levels of aspartate aminotransferase (AST) and direct bilirubin (D-Bil) increased early after symptom onset in deceased patients and showed disparity compared to levels in discharged patients throughout the clinical course of the disease. Abnormal AST (adjusted hazard ratio [HR] 1.39; 95% CI 1.04-1.86, p = 0.027) and D-Bil (adjusted HR 1.66; 95% CI 1.22-2.26; p = 0.001) levels at admission were independent risk factors for mortality due to COVID-19. A nomogram was established based on the results of multivariate analysis and showed sufficient discriminatory power and good consistency between the prediction and the observation. HBV infection in patients did not increase the risk of poor COVID-19-associated outcomes. CONCLUSIONS: Abnormal AST and D-Bil levels at admission were independent predictors of COVID-19-related mortality. Therefore, monitoring liver chemistries, especially AST and D-Bil levels, is necessary in hospitalized patients with COVID-19. LAY SUMMARY: Liver test abnormalities (in particular elevations in the levels of aspartate aminotransferase [AST] and direct bilirubin [D-Bil]) were observed after symptom onset in patients who went on to die of coronavirus disease 2019 (COVID-19). Abnormal levels of AST and D-Bil at admission were independent predictors of COVID-19-related mortality. HBV infection in patients did not increase the risk of poor COVID-19-associated outcomes.

The tumor suppressor DLC1 inhibits cancer progression and oncogenic autophagy in hepatocellular carcinoma.

Downregulation of deleted in liver cancer 1 (DLC1) is associated with poor prognosis of various cancers, but its functional mechanisms in hepatocellular carcinoma (HCC) remains unclear. In the present study, we investigated the roles of DLC1 in tumor progression and autophagy of HCC. We found that DLC1 was frequently downregulated in HCC tissues. Underexpression of DLC1 correlated with AFP level, vascular invasion, poor differentiation, and poor prognosis. In vitro assays revealed that DLC1 not only suppressed the proliferation, migration, and invasion of HCC cells, but also inhibited autophagy of HCC cells. Mechanistic investigation revealed that DLC1 decreased TCF4 expression and the interaction between ß-catenin and TCF4, then inactivated Wnt/ß-catenin signaling. Additionally, DLC1 suppressed the ROCK1 activity and the dissociation of the Beclin1-Bcl2 complex, thereby inhibiting autophagy of HCC cells. In conclusion, our findings imply that loss of DLC1 contributes to the progression and oncogenic autophagy of HCC.

Menin promotes hepatocellular carcinogenesis and epigenetically up-regulates Yap1 transcription.

Menin is a scaffold protein encoded by the multiple endocrine neoplasia type 1 (MEN1) gene in humans, and it interacts with a variety of transcriptional proteins to control active or repressive cellular processes. Here, we show that heterozygous ablation of Men1 in female mice reduces chemical carcinogen-induced liver carcinogenesis and represses the activation of the inflammation pathway. Using ChIP-on-chip screens and ChIP assays, we find that menin occupancy frequently coincides with H3K4me3 at the promoter of many liver cancer-related genes, such as Yes-associated protein (Yap1). Increased menin and Yap1 expression in human hepatocellular carcinoma specimens was associated with poor prognosis. Our findings reveal that menin plays an important epigenetic role in promoting liver tumorigenesis, and support the notion that H3K4me3, which is regulated by the menin-mixed-lineage leukemia complex, is a potential therapeutic target in hepatocellular carcinoma.

The functional and mechanistic relatedness of EZH2 and menin in hepatocellular carcinoma.

BACKGROUND & AIMS: The alterations of histone modification may serve as a promising diagnostic biomarker of hepatocellular carcinoma (HCC), but the clinical and mechanistic relatedness of the histone H3 lysine 27 and 4 trimethylation (H3K27me3 and H3K4me3) in HCC remains poorly understood. Here we propose that the combination of H3K27me3 and H3K4me3 is a more precise predictive/prognostic value for outcome of HCC patients. METHODS: We used chromatin immunoprecipitation (ChIP) assays and a ChIP-on-chip screen to analyse HCC. RESULTS: We found that the EZH2 occupancy coincides with the H3K27me3 at promoters and directly silences the transcription of target genes in HCC. The H3K27me3-related gene network of EZH2 contains well-established genes, such as CDKN2A, as well as previously unappreciated genes, including FOXO3, E2F1, and NOTCH2, among others. We further observed independently increasing profiles of H3K27me3 and H3K4me3 at the promoters of certain target genes in HCC specimens. Importantly, Kaplan-Meier analysis reveals that 3-year overall and tumour-free survival rates are dramatically reduced in patients that simultaneously express EZH2 and menin, compared to rates in the EZH2 or menin under expressing patients. Furthermore, an inhibitor of H3K27me3 alone, or in combination with an H3K4me3 inhibitor, effectively blocked the aggressive phenotype of HCC cells. CONCLUSIONS: Our results indicate that a combined analysis of both H3K27me3 and H3K4me3 may serve as powerful diagnostic biomarkers of HCC, and targeting both might benefit anti-HCC therapy.

Risk assessment of e-waste - Liquid Crystal Monomers re-suspension caused by coastal dredging operations.

The Pearl River Estuary (PRE), one of the primary e-waste recycling centers in the world, has been suffering from the pollution of Liquid Crystal Monomers (LCMs), critical materials with persistent, bio-accumulative, and toxic substances used in electronic devices. It has been detected in seabed sediment with both high frequency and concentration near PRE - Hong Kong (HK) waters. In the same area, dredging operations with in-situ sediment have been frequently used in the last decades for coastal land reclamation projects. Dredging is known to cause a huge amount of sediment re-suspension into water columns, with potential damage to marine ecosystems and biodiversity. In this study, we proposed a new risk assessment strategy to estimate the secondary pollution due to the re-suspension sediment highly contaminated by LCMs. We formulate a robust and reliable probabilistic approach based on unsupervised machine learning and hydrodynamic and sediment transport numerical simulation. New risk indexes were also proposed to better quantify the impact of contaminated sediments. We applied the methodology to assess the potential impact of dredging operations in the PRE and Hong Kong waters on the local marine ecosystem. The results of the analysis showed how the potentially contaminated areas depended on the dredging locations.

Bear bile inhibits the immunosuppression activity of hepatic stellate cells in vivo.

BACKGROUND/AIMS: In the injured liver, hepatic stellate cells (HSCs) induce immunosuppression activity and thus participate in the pathogenesis of liver disease, including HCC. Therefore, finding new drugs to inhibit their immunosuppression activity is necessary. This study tests whether bear bile can affect the immunosuppression activities of HSCs. METHODOLOGY: The mice were gavaged with bear bile for 4 weeks. The expression of HSCs was detected through desmin and ±-smooth muscle antibody immunohistochemistry. HSCs were isolated from these mice liver and then cultured with T cells in a mixed leukocyte reaction for 3 days. Stellate cell surface makers, T-cell apoptosis, regulatory T cells and the ability of T cells to kill hepatocellular carcinoma were determined via flow cytometry. Cytokines were determined by a mouse cytokine array panel and T-cell proliferation was determined through a BrdU kit. RESULTS: Bear bile decreased HSCs and their surface molecules, and affected cytokine secretion. Interestingly, HSCs from the mice gavaged with bear bile promoted T-cell proliferation, inhibited T-cell apoptosis, decreased CD4+CD25+Foxp3+ regulatory T cells and enhanced the activation of T cells killing hepatocellular carcinoma. CONCLUSIONS: Bear bile can inhibit the immunosuppression activity of HSCs and enhance immune response especial anti-tumor immune response.

[Influence of bear bile on rat hepatocarcinoma induced by diethylnitrosamine].

To investigate the influence of bear bile on rat hepatocarcinoma induced by diethylnitrosamine (DEN), a total of 40 rats were randomly divided into 4 groups: normal control group, model group, and two bear bile treatment groups. The rat liver cancer model was induced by breeding with water containing 100 mg x L(-1) DEN for 14 weeks. The rats of the bear bile groups received bear bile powder (200 or 400 mg x kg(-1)) orally 5 times per week for 18 weeks. The general condition and the body weight of rats were examined every day. After 18 weeks the activities of serum alanine transaminase (ALT), aspartate transaminase (AST) and total bilirubin (TBIL) were detected. Meanwhile, the pathological changes of liver tissues were observed after H&E staining. The expression of proliferative cell nuclear antigen (PCNA) and a-smooth muscle actin (alpha-SMA) in liver tissue were detected by immunohistochemical method. After 4 weeks the body weights of rats in normal group were significantly more than that in other groups (P < 0.05); and that in the two bile groups was significantly more than that in the model group. Compared with normal group, the level of serum glutamic-pyruvic transaminase and total bilirubin increased significantly in other groups; compared with model group, these two indexes decreased significantly in two bile groups. Hepatocellular carcinoma occurred in all rats except for normal group; there were classic cirrhosis and cancer in model group while there were mild cirrhosis and high differentiation in two bile groups. There were almost no expressions of PCNA and alpha-SMA in normal group while there were high expressions in model group; the two bile groups had some expressions but were inferior to the model group, and alpha-SMA reduced markedly. It indicated that bear bile restrained the development of liver cancer during DEN inducing rat hepatocarcinoma, which may be related to its depressing hepatic stellate cell activation and relieving hepatic lesion and cirrhosis.

Lifespan dynamics of cluster conformations in stationary regimes in granular materials.

We examine stationary regimes in granular materials from a dynamical systems theory perspective. The aim is to enrich the classical view of the critical state regime in granular materials, and more broadly, to improve the fundamental understanding of the underlying mesoscale mechanisms responsible for macroscopic stationary states in complex systems. This study is based on a series of discrete element method simulations, in which two-dimensional assemblies of nonuniformly sized circular particles are subjected to biaxial compression under constant lateral confining pressure. The lifespan and life expectancy of specific cluster conformations, comprising particles in force chains and grain loops, are tracked and quantified. Results suggest that these conformational clusters reorganize at similar rates in the critical state regime, depending on strain magnitudes and confining pressure levels. We quantified this rate of reorganization and found that the material memory rapidly fades, with an entirely new generation of force chains and grain loops replacing the old within a few percent strain.

Lenvatinib combined with anti-PD-1 antibodies plus transcatheter arterial chemoembolization for neoadjuvant treatment of resectable hepatocellular carcinoma with high risk of recurrence: A multicenter retrospective study.

Background: Early recurrence is common after surgical resection (SR) for hepatocellular carcinoma (HCC) with high risk of recurrence and is associated with poor prognosis. The combinations of lenvatinib (LEN), anti-PD-1 antibodies (PD-1) and transcatheter arterial chemoembolization (TACE) (triple therapy) has shown better trend in tumor response and survival outcomes on unresectable HCC. It is unknown whether triple therapy for neoadjuvant treatment of resectable HCC with high risk of recurrence is effective. This article aimed to compare the outcomes of surgery alone and neoadjuvant combination treatment with triple therapy before SR in patients with HCC with high risk of recurrence. Methods: A retrospective study was conducted on patients diagnosed with HCC with high risk of recurrence who received treatment with or without triple therapy. The records of 24 patients in the triple therapy group and 76 patients in the surgery-alone group were analyzed. Propensity score matching (PSM) was performed to minimize the influence of potential confounders. Results: One hundred patients were enrolled. In the triple therapy group, 8 (33.3%) and 12 (50.0%) patients had complete and partial responses, respectively, as assessed by an investigator. Before PSM, the overall survival (OS) rates for the triple therapy group at 6, 12, 18, and 24 months were 100.0%, 100.0%, 100.0%, and 85.7%, respectively, compared with corresponding 92.1%, 73.7%, 53.9%, and 48.7% for the surgery-alone group (P<0.001). The disease-free survival (DFS) rates were 82.2%, 66.95%, 48.8%, and 48.8% for the triple therapy and 41.92%, 28.34%, 27.05%, and 22.99% for the surgery-alone group (P=0.003). After PSM, DFS and OS were significantly longer in the triple therapy group than in the surgery-alone group (DFS, p=0.019; OS, p=0.003). Conclusions: Neoadjuvant combination treatment before SR had a high rate of tumor response and provided significantly better postoperative survival outcomes than surgery alone in patients with HCC with high risk of recurrence.

Lenvatinib Combined with Anti-PD-1 Antibodies Plus Transcatheter Arterial Chemoembolization for Unresectable Hepatocellular Carcinoma: A Multicenter Retrospective Study.

BACKGROUND: Lenvatinib (LEN) combined with anti-PD-1 antibodies (PD-1) exerted promising effects on unresectable hepatocellular carcinoma (uHCC). We assessed the safety and clinical efficacy of triple therapy [LEN+PD-1+transcatheter arterial chemoembolization (TACE)] in uHCC. METHODS: uHCC patients with an ECOG PS score of 0-1 and Child-Pugh class A who underwent triple therapy were included. The primary endpoint was objective response rate (ORR) based on mRECIST. Secondary endpoints were conversion rate to liver resection and treatment-related adverse events. RESULTS: Between November 2018 and December 2020, 62 uHCC patients who underwent triple therapy at four major cancer centers in China were analyzed, including 35 in BCLC-C, 21 in BCLC-B, and 6 in BCLC-A. With a median follow-up of 12.2 months (range, 7.6-33.3 months), the investigator and blinded independent central review-assessed ORR were 80.6% and 77.4%, respectively. A total of 33 patients (53.2%) reached the standard of conversion to resectable HCC and 29 patients underwent resection. The median interval between start of triple therapy and resection was 123 days (range, 55-372 days). Pathological complete response and major pathological response were observed in 16 and 24 patients, respectively. Median overall survival and progression-free survival were not reached. Treatment-related adverse events occurred in 74.2% of the patients (grade ≥3, 14.5%; grade ≥4, 4.8%). CONCLUSION: Combination of LEN, PD-1 and TACE showed a high rate of tumor response and convert resection in uHCC patients, with manageable toxicity.

Data in intelligent approach for estimation of disc cutter life using hybrid metaheuristic algorithm.

This data in brief presents the monitoring data measured during shield tunnelling of Guangzhou-Shenzhen intercity railway project. The monitoring data includes shield operational parameters, geological conditions, and geometry at the site. The presented data were arbitrarily split into two subsets including the training and testing datasets. The field observations are compared to the forecasting values of the disc cutter life assessed using a hybrid metaheuristic algorithm proposed for "Prediction of disc cutter life during shield tunnelling with artificial intelligent via incorporation of genetic algorithm into GMDH-type neural network" [1]. The presented data can provide a guidance for cutter exchange in shield tunnelling.

Data on evolutionary hybrid neural network approach to predict shield tunneling-induced ground settlements.

The dataset presented in this article pertains to records of shield tunneling-induced ground settlements in Guangzhou Metro Line No. 9. Field monitoring results obtained from both the two tunnel lines are put on display. In total, 17 principal variables affecting ground settlements are tabulated, which can be divided into two categories: geological condition parameters and shield operation parameters. Shield operation parameters are specifically provided in time series. Another value of the dataset is the consideration of karst encountered in the shield tunnel area including the karst cave height, the distance between karst cave and tunnel invert, and the karst cave treatment scheme. The dataset can be used to enrich the database of settlement caused by shield tunneling as well as to train artificial intelligence-based ground settlement prediction models. The dataset presented herein were used for the article titled "Evolutionary hybrid neural network approach to predict shield tunneling-induced ground settlements" (Zhang et al., 2020).

Durable response to pulsatile icotinib for central nervous system metastases from EGFR-mutated non-small cell lung cancer: A case report.

BACKGROUND: Central nervous system (CNS) metastases are a catastrophic complication of non-small cell lung cancer (NSCLC), including brain and leptomeningeal carcinomatosis, and are always accompanied by a poor prognosis. Despite the continuous development of existing treatments, the therapy of CNS metastases remains challenging. CASE SUMMARY: We report a patient who was definitively diagnosed with brain and leptomeningeal metastases from NSCLC with a targeted mutation in epidermal growth factor receptor (EGFR). A standard dosage of icotinib (125 mg three times daily) was implemented but ineffective. CNS lesions developed despite stable systemic control, so pulsatile icotinib (1125 mg every 3 d) was administered. This new strategy for administration has lasted 25 mo so far, and resulted in complete remission of neurological symptoms, almost vanished lesions, and longer survival with no notable side effects. CONCLUSION: This is the first successful example of pulsatile icotinib for treating isolated CNS progression from EGFR mutation-positive NSCLC, providing a new alternative for the local treatment of CNS metastases.

Long non-coding RNA RP11-284P20.2 promotes cell proliferation and invasion in hepatocellular carcinoma by recruiting EIF3b to induce c-met protein synthesis.

A newly identified lncRNA designated as RP11-284P20.2 has been identified to be up-regulated in hepatocellular carcinoma (HCC), but its role in HCC remain poorly understood. Quantitative PCR and immunocytochemical analysis were performed using the HCC tissues to identify the potential interaction partners of RP11-284P20.2. Moreover, RP11-284P20.2 was knocked down in HCC cell lines, HepG2 and SMMC7721, to investigate the influence of this lncRNA on cell growth properties. Additionally, RNA fluorescence in situ hybridization and immunofluorescence, RNA immunoprecipitation, and RNA pull-down assays were performed to determine the interaction of RP11-284P20.2 with c-met mRNA and eukaryotic translation initiation factor 3b (EIF3b). Silencing RP11-284P20.2 inhibited cell viability, migration, invasion, and colony formation, and increased apoptosis. Overexpression of c-met abolished these effects of RP11-284P20.2 in HCC cells. Histopathological examination showed that HCC tissues with high RP11-284P20.2 expression had higher c-met protein level than that in HCC tissues with low RP11-284P20.2 expression. However, there was no positive correlation between the expression levels of RP11-284P20.2 and c-met mRNA. RP11-284P20.2 knockdown led to a decease in c-met protein expression level, but did not affect the c-met mRNA expression level. These data suggest that RP11-284P20.2 regulates c-met protein expression level, which is independent of c-Met mRNA expression level. It was also confirmed that RP11-284P20.2 has high affinity toward both c-met mRNA and EIF3b protein, and hence RP11-284P20.2 probably recruits EIF3b protein to c-met mRNA and further facilitates its translation. RP11-284P20.2 promotes cell proliferation and invasion in hepatocellular carcinoma by recruiting EIF3b to induce c-met protein synthesis.

Immunological protection of small bowel by simultaneously transplanted liver graft in pigs.

BACKGROUND: A simultaneously transplanted liver shields a bowel graft from immunologic attack in small animals, while the possible immuno-tolerance induced by the liver in liver and small bowel transplantation (LSBT) is uncertain in large animal models. To investigate the clinically suspected beneficial effect of the liver on small bowel allograft, we developed a new model of composite LSBT in the pig. METHODS: Seventy outbred long-white pigs were randomized into four groups. LSBT without immunosuppressive treatment (n=10, group A); LSBT with routine immunosuppressive treatment (n=10, group B); LSBT with a lower dose of immunosuppressive treatment (n=10, group C); and small bowel segment allotransplantation without immunosuppressive treatment (n=10, group D). RESULTS: There was no remarkable difference in survival time between groups A and D (10.33 vs. 12.89 days, P>0.05), but the initial time of acute rejection of the intestinal graft in group A was clearly delayed when compared to group D (8.22 vs. 4.33 days, P<0.05), and the rejection scores in group A were remarkably lower than those in group D at each postoperative time point (0 vs. 0.44 on day 3, P<0.05; 0.22 vs. 1.78 on day 5, P<0.05; 1.11 vs. 2.56 on day 7, P<0.05). There were evident differences in postoperative survival time, initial time of acute rejection and postoperative rejection scores between groups A, B and C. Postoperative survival time (30.00 vs. 28.13 days, P>0.05), initial acute rejection time (25.40 vs. 22.13 days, P>0.05) or rejection score did not differ between groups B and C within one postoperative month. CONCLUSIONS: Compared to isolated segment small bowel allotransplantation, the intestinal graft in LSBT (group A) had a delayed initial time of acute rejection and a lower postoperative acute rejection score, and a lower dose of immunosuppressive treatment led to persistent graft immuno-tolerance in LSBT. Thus the simultaneously transplanted liver graft may reduce the risk of intestinal rejection and protect the bowel graft from severe acute rejection.

[Immunocharacteristics of bone marrow mesenchymal stem cell].

OBJECTIVE: To study the immunocharacteristics of bone marrow mesenchymal stem cell (MSC) and provide experimental evidence for the potential therapeutic application. METHODS: MSCs were isolated from rat bone marrow and confirmed by immunophenotype, and the growth dynamic and cell cycle were analyzed. MSCs were cultured with or without 200 U/ml interferon gamma (IFNg) , the expression of PDL-1, CD54, CD40, CD80, CD86, MHC-I, and MHC-II was detected by flow cytometry. MSCs were used as regulatory cells in mixed lymphocyte reaction (MLR), the PDL-1 and CD54 molecules on MSCs were blocked to explore their roles in MLR. The IFN, IL-2, IL-4 and IL-10 molecules in culture supernatant were quantified by ELISA. The homing of MSCs to liver and induction of microchimerism were analyzed after MSCs transplantation. RESULTS: The purity of MSCs was high. The growth curve showed that the first two days were the lag phase; the third, fourth, fifth days were the log phase; the sixth and seventh days were the stationary phase. Flow cytometry indicated that 76.0%+/-2.0% of the MSCs were in G1/G0 phase, 13.0%+/-2.0% in S phase, 10.0%+/-1.7% in G2 and M phase. IFNg treatment led to up-regulation of CD54, PDL-1, MHC-I and MHC-II, however, CD40, CD80 and CD86 were not expressed on MSCs even after IFNg treatment. MSCs inhibited MLR, IFNg treatment enhanced the inhibitory effect of MSCs on MLR. Blocking of PDL-1 or CD54 on MSCs partially alleviated the inhibition effect. There were high levels of IFNg and IL-10, and low level of IL-4 in the culture supernatant of MLR, however, IL-2 was not detected. MSCs can home to the liver and induce formation of microchimerism after transplantation. CONCLUSION: IFNg treatment enhances the inhibitory effect of MSCs on MLR, PDL-1 and CD54 are key molecules mediating this inhibitory effect. MSC can home to the liver and induce formation of microchimerism after transplantation.

Detection of a novel panel of somatic mutations in plasma cell-free DNA and its diagnostic value in hepatocellular carcinoma.

Background/aims: Circulating cell-free DNA (cfDNA) contains tumor-specific alterations and could potentially serve as "liquid biopsy". The study was to identify a novel panel of hepatocellular carcinoma (HCC)-specific mutations in plasma cfDNA and to assess its value in the diagnosis of HCC. Materials and methods: 33 HCC tissue, 37 blood, and 37 swab specimens were collected from HCC patients and control individuals. Genomic DNA was subjected to next-generation sequencing. The selected mutations in the plasma cfDNA in the HCC versus control groups were compared, and the diagnostic performance of cfDNA mutations was evaluated. Results: A majority of selected mutations in the HCC tissue DNA, ranging from 52% to 84%, was detected in the matched plasma cfDNA. For the selected mutations, receiver operating characteristic (ROC) analysis revealed an area under the ROC curve (AUC) of 0.92, sensitivity of 65%, and specificity of 100% for the diagnosis of HCC regardless of alpha-fetoprotein (AFP) status. Detection of the selected mutations in cfDNA in combination with AFP exhibited better diagnosis performance, with AUC of 0.96, sensitivity of 73%, and specificity of 100% for AFP-negative patients, whereas the AUC was 0.86 with sensitivity of 53% and specificity of 100% for AFP-positive patients. Furthermore, the rates of the selected mutations were significantly greater in recurrent HCC than in non-recurrent HCC (P<0.05). Conclusions: This study has identified a novel panel of somatic mutations, and detection of the mutations in plasma cfDNA shows good diagnostic performance. Therefore, this approach holds promise as a novel tool for diagnosing HCC.

FGF15 Activates Hippo Signaling to Suppress Bile Acid Metabolism and Liver Tumorigenesis.

The external factors that modulate Hippo signaling remain elusive. Here, we report that FGF15 activates Hippo signaling to suppress bile acid metabolism, liver overgrowth, and tumorigenesis. FGF15 is induced by FXR in ileal enterocytes in response to increased amounts of intestinal bile. We found that circulating enterohepatic FGF15 stimulates hepatic receptor FGFR4 to recruit and phosphorylate NF2, which relieves the inhibitory effect of Raf on the Hippo kinases Mst1/2, thereby switching FGFR4's role from pro-oncogenic to anti-tumor signaling. The activated Mst1/2 subsequently phosphorylates and stabilizes SHP to downregulate the key bile acid-synthesis enzyme Cyp7a1 expression, thereby limiting bile acid synthesis. In contrast, Mst1/2 deficiency impairs bile acid metabolism and remarkably increases Cyp7a1 expression and bile acid production. Importantly, pharmacological depletion of intestinal bile abrogates Mst1/2-mutant-driven liver overgrowth and oncogenesis. Therefore, FGF15-Hippo signaling along the gut-liver axis acts as a sensor of bile acid availability to restrain liver size and tumorigenesis.

Preventive effect of regional radiotherapy with phosphorus-32 glass microspheres in hepatocellular carcinoma recurrence after hepatectomy.

AIM: To evaluate the preventive effects of phosphorus-32 glass microspheres (P32-GMS) in the recurrence of massive hepatocellular carcinomas (HCCs) after tumor resection. METHODS: Twenty-nine patients with massive HCCs received local P32-GMS implantation after liver tumors were removed, while the other 38 patients with massive HCCs were not treated with P32-GMS after hepatectomies. The radioactivity of the blood, urine and liver were examined. The complications, HCC recurrence and overall survival rates in the patients were analyzed. RESULTS: P32-GMS implanted in the liver did not cause systemic absorption of P32. There were no significant differences of postoperative complications between the patients with and without P32-GMS treatment. The short-term (six months and 1 year) and long-term (2, 3 and over 3 years) recurrence rates in patients who received P32-GMS radiotherapy were significantly decreased, and the overall survival rates in this group were significantly improved. CONCLUSION: P32-GMS implantation in the liver can significantly decrease the postoperative recurrence and improve the overall survival in HCCs patients after hepatectomy. This therapy may provide an innovative method in prevention of HCC recurrence after operation.