Precise Control of Metal Active Sites of Metal-Organic Framework Nanozymes for Achieving Excellent Enzyme-Like Activity and Efficient Pancreatitis Therapy.

Acute pancreatitis (AP) is a potentially life-threatening inflammatory disease that can lead to the development of systemic inflammatory response syndrome and its progression to severe acute pancreatitis. Hence, there is an urgent need for the rational design of highly efficient antioxidants to treat AP. Herein, an optimized Cu-based metal-organic framework (MOF) nanozyme with exceptional antioxidant activity is introduced, designed to effectively alleviate AP, by engineering the metal coordination centers in MN2Cl2 (M = Co, Ni, Cu). Specifically, the Cu MOF, which benefits from a Cu active center similar to that of natural superoxide dismutase (SOD), exhibited at least four times higher SOD-like activity than the Ni/Co MOF. Theoretical analyses further demonstrate that the CuN2Cl2 site not only has a moderate adsorption effect on the substrate molecule •OOH but also reduces the dissociation energy of the product H2O2. Additionally, the Cu MOF nanozyme possesses the excellent catalase-like activity and •OH removal ability. Consequently, the Cu MOF with broad-spectrum antioxidant activity can efficiently scavenge reactive oxygen species to alleviate arginine-induced AP. More importantly, it can also mitigate apoptosis and necrosis of acinar cells by activating the PINK1/PARK2-mediated mitophagy pathway. This study highlights the distinctive functions of tunable MOF nanozymes and their potential bio-applications.

Machine learning radiomics to predict the early recurrence of intrahepatic cholangiocarcinoma after curative resection: A multicentre cohort study.

PURPOSE: Postoperative early recurrence (ER) leads to a poor prognosis for intrahepatic cholangiocarcinoma (ICC). We aimed to develop machine learning (ML) radiomics models to predict ER in ICC after curative resection. METHODS: Patients with ICC undergoing curative surgery from three institutions were retrospectively recruited and assigned to training and external validation cohorts. Preoperative arterial and venous phase contrast-enhanced computed tomography (CECT) images were acquired and segmented. Radiomics features were extracted and ranked through their importance. Univariate and multivariate logistic regression analysis was used to identify clinical characteristics. Various ML algorithms were used to construct radiomics-based models, and the predictive performance was evaluated by receiver operating characteristic curves, calibration curves, and decision curve analysis. RESULTS: 127 patients were included for analysis: 90 patients in the training set and 37 patients in the validation set. Ninety-two patients (72.4%) experienced recurrence, including 71 patients exhibiting ER. Male sex, microvascular invasion, TNM stage, and serum CA19-9 were identified as independent risk factors for ER, with the corresponding clinical model having a poor predictive performance (AUC of 0.685). Fifty-seven differential radiomics features were identified, and the 10 most important features were utilized for modelling. Seven ML radiomics models were developed with a mean AUC of 0.87 ± 0.02, higher than the clinical model. Furthermore, the clinical-radiomics models showed similar predictive performance to the radiomics models (AUC of 0.87 ± 0.03). CONCLUSION: ML radiomics models based on CECT are valuable in predicting ER in ICC.

Noncoding RNA-mediated molecular bases of chemotherapy resistance in hepatocellular carcinoma.

Despite the significant progress in decreasing the occurrence and mortality of hepatocellular carcinoma (HCC), it remains a public health issue worldwide on the basis of its late presentation and tumor recurrence. To date, apart from surgical interventions, such as surgical resection, liver transplantation and locoregional ablation, current standard antitumor protocols include conventional cytotoxic chemotherapy. However, due to the high chemoresistance nature, most current therapeutic agents show dismal outcomes for this refractory malignancy, leading to disease relapse. Nevertheless, the molecular mechanisms involved in chemotherapy resistance remain systematically ambiguous. Herein, HCC is hierarchically characterized by the formation of primitive cancer stem cells (CSCs), progression of epithelial-mesenchymal transition (EMT), unbalanced autophagy, delivery of extracellular vesicles (EVs), escape of immune surveillance, disruption of ferroptosis, alteration of the tumor microenvironment and multidrug resistance-related signaling pathways that mediate the multiplicity and complexity of chemoresistance. Of note, anecdotal evidence has corroborated that noncoding RNAs (ncRNAs) extensively participate in the critical physiological processes mentioned above. Therefore, understanding the detailed regulatory bases that underlie ncRNA-mediated chemoresistance is expected to yield novel insights into HCC treatment. In the present review, a comprehensive summary of the latest progress in the investigation of chemotherapy resistance concerning ncRNAs will be elucidated to promote tailored individual treatment for HCC patients.

LINC00922 promotes the proliferation, migration, invasion and EMT process of liver cancer cells by regulating miR-424-5p/ARK5.

AMPK-related protein kinase 5 (ARK5) promotes the deterioration of hepatocellular carcinoma (HCC). From the perspective of lncRNA-miRNA-mRNA, this study explored in-depth the intervention mechanism of ARK5. The binding relationship between miR-424-5p and two genes (LINC00922 and ARK5) were analyzed by Bioinformatics and dual-luciferase experiments. After clinical sample collection, the expressions of miR-424-5p, LINC00922 and ARK5 in HCC tissues were analyzed by quantitative real-time polymerase chain reaction (qRT-PCR). The correlation between LINC00922, miR-424-5p, and ARK5 in HCC tissues was analyzed by Pearson correlation. The influences of miR-424-5p, LINC00922 and ARK5 on the basic functions (viability, migration and invasion) of cancer cells were detected by cell counting kit-8, wound healing, and Transwell experiments, and their regulatory effects on related genes, as well as their relationship, were tested by qRT-PCR and Western blot. MiR-424-5p was low expressed, whereas LINC00922 and ARK5 were high expressed in HCC tissues. MiR-424-5p was negatively associated with LINC00922 and ARK5 that was positively associated with LINC00922. Interestingly, LINC00922 partially shared an identical binding site of miR-424-5p with ARK5. LINC00922 its overexpression partially offset the inhibitory effect of miR-424-5p on cancer cell functions. ARK5 silencing repressed the malignant phenotype of cancer cells and inhibited the expressions of epithelial-to-mesenchymal transition (EMT)-related molecules (Vimentin, Snail and N-Cadherin). However, these effects were partially neutralized by miR-424-5p inhibitors. LINC00922 increases the cell viability, migration, invasion and EMT process of HCC cells by regulating the miR-424-5p/ARK5 axis, and thus may serve as a potential target for targeted therapy.

Retrospective Study to Compare Selective Decongestive Devascularization and Gastrosplenic Shunt versus Splenectomy with Pericardial Devascularization for the Treatment of Patients with Esophagogastric Varices Due to Cirrhotic Portal Hypertension.

BACKGROUND For patients with esophagogastric varices secondary to portal hypertension due to liver cirrhosis, portosystemic shunts and devascularization have become the most commonly used treatment methods. We have developed a novel surgical approach for the treatment of patients with cirrhotic portal hypertension, selective decongestive devascularization, and shunt of the gastrosplenic region (SDDS-GSR). This aim of this study was to compare the efficacy and safety of SDDS-GSR with splenectomy with pericardial devascularization (SPD). MATERIAL AND METHODS A retrospective study was undertaken between 2006 and 2013 and included 110 patients with cirrhotic portal hypertension, 34 of whom underwent SDDS-GSR; 76 patients underwent SPD. Kaplan-Meier analysis was used to evaluate clinical outcomes, mortality, the incidence of re-bleeding, encephalopathy, and portal venous system thrombosis (PVST). RESULTS Postoperatively portal venous pressure decreased by 20% in both groups. The long-term incidence of re-bleeding and PVST was significantly lower in the SDDS-GSR group compared with the SPD group (P=0.018 and P=0.039, respectively). CONCLUSIONS This preliminary retrospective study has shown that SDDS-GSR was an effective treatment for patients with esophagogastric varices secondary to portal hypertension that may be used as a first-line treatment to prevent variceal bleeding and lower the incidence of PVST.

Application of artificial intelligence radiomics in the diagnosis, treatment, and prognosis of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer, with an increasing incidence and poor prognosis. In the past decade, artificial intelligence (AI) technology has undergone rapid development in the field of clinical medicine, bringing the advantages of efficient data processing and accurate model construction. Promisingly, AI-based radiomics has played an increasingly important role in the clinical decision-making of HCC patients, providing new technical guarantees for prediction, diagnosis, and prognostication. In this review, we evaluated the current landscape of AI radiomics in the management of HCC, including its diagnosis, individual treatment, and survival prognosis. Furthermore, we discussed remaining challenges and future perspectives regarding the application of AI radiomics in HCC.

Impact of sarcopenia on the short-term and long-term outcomes of intrahepatic cholangiocarcinoma undergoing hepatectomy: A multi-center study.

BACKGROUND: Sarcopenia is associated with adverse prognosis of intrahepatic cholangiocarcinoma (iCCA) after surgery. METHODS: 321 patients with iCCA undergoing surgery were retrospectively recruited and assigned to training and validation cohort. Skeletal muscle index (SMI) was assessed to define sarcopenia. Logistic regression and cox regression analysis were used to identify risk factors. A novel sarcopenia-based nomogram was constructed and validated by ROC curves, calibration curves, and DCA curves. RESULTS: 260 patients were included for analysis. The median age was 63.0 years and 161 patients (61.9%) were diagnosed with sarcopenia. Patients with sarcopenia exhibited a higher rate of postoperative complications, a worse OS and RFS than patients without sarcopenia. Sarcopenia, low albumin and intraoperative blood transfusion were independent risk factors of postoperative complications, while sarcopenia and low albumin were risk factors of high CCI≥26.2. Sarcopenia, high PS score, low-undifferentiated differentiation, perineural invasion, TNM stage III-IV were risk factors of OS, and a novel nomogram based on these five factors was built to predict the 12-, 24-, and 36-months OS, with the mean AUC > 0.6. CONCLUSION: Sarcopenia is negatively associated with both postoperative complications and survival prognosis of iCCA undergoing hepatectomy.

Synergistic activity of Enterococcus Faecium-induced ferroptosis via expansion of IFN-γ+CD8+ T cell population in advanced hepatocellular carcinoma treated with sorafenib.

The gut microbiota plays an important role in the development and treatment of hepatocellular carcinoma (HCC). However, the implication of specific gut microbiota in targeted sorafenib therapy for advanced HCC and the microbiota mode of action, remain to be elucidated. Here, we confirmed that four bacterial genera, Lachnoclostridium, Lachnospira, Enterobacter and Enterococcus, are associated with the therapeutic efficacy of Sorafenib, and that Enterobacter faecium (Efm) plays a crucial role in modulating the sorafenib activity. The effective colonization by Emf induced the IL-12 and IFN-γ production and an increased proportion of IFN-γ+CD8+ T cells in the tumor microenvironment. Finally, exopolysaccharides (EPS) from Efm were the primary inducer to prompt IFN-γ+CD8+ T cells to secrete IFN-γ, which together with sorafenib instigated ferroptosis in HCC cells. Collectively, these results indicate that Efm is a promising probiotics that enhances the efficacy of sorafenib treatment in advanced HCC.

Development of sarcopenia-based nomograms predicting postoperative complications of benign liver diseases undergoing hepatectomy: A multicenter cohort study.

Background: Sarcopenia has a remarkable negative impact on patients with liver diseases. We aimed to evaluate the impact of preoperative sarcopenia on the short-term outcomes after hepatectomy in patients with benign liver diseases. Methods: A total of 558 patients with benign liver diseases undergoing hepatectomy were prospectively reviewed. Both the muscle mass and strength were measured to define sarcopenia. Postoperative outcomes including complications, major complications and comprehensive complication index (CCI) were compared among four subgroups classified by muscle mass and strength. Predictors of complications, major complications and high CCI were identified by univariate and multivariate logistic regression analysis. Nomograms based on predictors were constructed and calibration cures were performed to verify the performance. Results: 120 patients were involved for analysis after exclusion. 33 patients were men (27.5%) and the median age was 54.0 years. The median grip strength was 26.5 kg and the median skeletal muscle index (SMI) was 44.4 cm2/m2. Forty-six patients (38.3%) had complications, 19 patients (15.8%) had major complications and 27 patients (22.5%) had a CCI ≥ 26.2. Age (p = 0.005), SMI (p = 0.005), grip strength (p = 0.018), surgical approach (p = 0.036), and operation time (p = 0.049) were predictors of overall complications. Child-Pugh score (p = 0.037), grip strength (p = 0.004) and surgical approach (p = 0.006) were predictors of major complications. SMI (p = 0.047), grip strength (p < 0.001) and surgical approach (p = 0.014) were predictors of high CCI. Among the four subgroups, patients with reduced muscle mass and strength showed the worst short-term outcomes. The nomograms for complications and major complications were validated by calibration curves and showed satisfactory performance. Conclusion: Sarcopenia has an adverse impact on the short-term outcomes after hepatectomy in patients with benign liver diseases and valuable sarcopenia-based nomograms were constructed to predict postoperative complications and major complications.

A distinct microbiota signature precedes the clinical diagnosis of hepatocellular carcinoma.

Oral, gut, and tumor microbiota have been implicated as important regulators in the carcinogenesis and progression of gastrointestinal malignancies. However, few studies focused on the existence and association of resident microbes within different body regions. Herein, we aim to reveal the durability of the oral-gut-tumor microbiome and its diagnostic performance in hepatocellular carcinoma (HCC). Our study included two cohorts: a retrospective discovery cohort of 364 HBV-HCC patients and 160 controls with oral or fecal samples, a prospective validation cohort of 91 cases, and 124 controls for matching samples, as well as 48 HBV, and 39 HBV-cirrhosis patients for gut microbial patterns examined by 16S rRNA gene sequencing. With the random forest analysis, 10 oral and 9 gut genera that could distinguish HCC from controls in the retrospective cohort were validated among the prospective matching participants, with area under the curve (AUC) values of 0.7971 and 0.8084, respectively. When influential taxa were merged, the AUC of the consistent classifier increased to 0.9405. The performance continued to improve to 0.9811 when combined with serum levels of alpha-fetoprotein (AFP). Specifically, microbial biomarkers represented by Streptococcus displayed a constantly increasing trend during the disease transition. Furthermore, the presence of several dominant microbiota species was confirmed in hepatic tumor and non-tumor tissues with fluorescence in situ hybridization (FISH) and 5 R 16S rRNA gene sequencing. Overall, our findings based on the oral-gut-tumor microbiota provide a reliable approach for the early detection of HCC.

Prediction of Response to Lenvatinib Monotherapy for Unresectable Hepatocellular Carcinoma by Machine Learning Radiomics: A Multicenter Cohort Study.

PURPOSE: We aimed to construct machine learning (ML) radiomics models to predict response to lenvatinib monotherapy for unresectable hepatocellular carcinoma (HCC). EXPERIMENTAL DESIGN: Patients with HCC receiving lenvatinib monotherapy at three institutions were retrospectively identified and assigned to training and external validation cohorts. Tumor response after initiation of lenvatinib was evaluated. Radiomics features were extracted from contrast-enhanced CT images. The K-means clustering algorithm was used to distinguish radiomics-based subtypes. Ten ML radiomics models were constructed and internally validated by 10-fold cross-validation. These models were subsequently verified in an external validation cohort. RESULTS: A total of 109 patients were identified for analysis, namely, 74 in the training cohort and 35 in the external validation cohort. Thirty-two patients showed partial response, 33 showed stable disease, and 44 showed progressive disease. The overall response rate (ORR) was 29.4%, and the disease control rate was 59.6%. A total of 224 radiomics features were extracted, and 25 significant features were identified for further analysis. Two distant radiomics-based subtypes were identified by K-means clustering, and subtype 1 was associated with a higher ORR and longer progression-free survival (PFS). Among the 10 ML algorithms, AutoGluon displayed the highest predictive performance (AUC = 0.97), which was relatively stable in the validation cohort (AUC = 0.93). Kaplan-Meier analysis showed that responders had a better overall survival [HR = 0.21; 95% confidence interval (CI): 0.12-0.36; P < 0.001] and PFS (HR = 0.14; 95% CI: 0.09-0.22; P < 0.001) than nonresponders. CONCLUSIONS: Valuable ML radiomics models were constructed, with favorable performance in predicting the response to lenvatinib monotherapy for unresectable HCC.

Impact of sarcopenia on outcomes of patients undergoing liver resection for hepatocellular carcinoma.

BACKGROUND: Previous studies have indicated that sarcopenia is associated with poor post-operative outcomes in liver cancer patients, but the studies are limited by confounding from mixed diseases, retrospective data, and non-standardized measurement methods. At present, there is no research with both muscle mass and strength as predictors for hepatocellular carcinoma (HCC) outcomes. We studied the impact of sarcopenia on post-operative outcomes in HCC patients in a cohort study designed according to the European Working Group on Sarcopenia in Older People standards. METHODS: A total of 781 consecutive patients admitted to our centre were registered from May 2020 to August 2021. All participants submitted questionnaires and underwent handgrip strength, chair stand test, physical performance, and computed tomographic evaluation. Then, they were divided into three groups according to muscle mass and strength: Group A (reduced muscle mass and strength), Group B (reduced muscle strength or reduced muscle mass), and Group C (normal muscle mass and strength). The baseline data and post-operative outcomes were compared and analysed. The primary outcome variable in this study was the presence of a major post-operative complication, and the secondary outcome was the 90-day re-admission rate. RESULTS: A total of 155 patients [median age, 60.00 (IQR, 51.00-66.00) years; 20 females (12.90%)] were included after strict exclusion. The mean (SD) BMI was 23.37 ± 0.23 kg/m2 . The mean (SD) SMI of all participants was 47.05 ± 0.79 cm2 /m2 , and the mean (SD) handgrip strength was 32.84 ± 0.69 kg. Among them, 77 (49.68%) patients underwent laparoscopic hepatectomy, and 73 (47.10%) patients received major hepatectomy. Regarding the post-operative results, Group A had a higher rate of major complications [40.91% (9 of 22) vs. 11.94% (8 of 67) in Group B and 6.06 (4 of 66) in Group C; P = 0.001], higher rate of blood transfusion (77.27% vs. 46.27% in Group B and 42.42% in Group C; P = 0.015), higher hospitalization expenses (P = 0.001), and longer hospital stay (P < 0.001). There was no difference in 90-day re-admission rates among the three groups. Sarcopenia (hazard ratio, 10.735; 95% CI, 2.547-45.244; P = 0.001) and open surgery (hazard ratio, 4.528; 95% CI, 1.425-14.387; P = 0.010) were independent risk factors associated with major complications. CONCLUSIONS: Sarcopenia is associated with adverse outcomes after liver resection for HCC. It should be evaluated upon admission to classify high-risk patients and reduce the risk of major complications.

Expression pattern and prognostic value of circadian clock genes in pancreatic adenocarcinoma.

Accumulating studies indicate that circadian clock genes are pivotal regulators of tumorigenesis and development of various cancers. Nevertheless, their implications in pancreatic adenocarcinoma (PAAD) remain poorly characterized. We investigated the expression pattern of circadian clock genes and evaluated their prognostic values in PAAD. Firstly, we systematically analyzed data from The Cancer Genome Atlas (TCGA) database pertaining to patient clinical information and gene expression data. We found that 19 of 20 circadian clock genes showed significantly different expression levels in comparisons between PAAD and normal tissues. In addition, 10 circadian clock genes with regression coefficients were selected to construct a new risk signature, which was then identified as an independent prognostic factor for PAAD. Mechanistically, circadian clock genes in PAAD may impact the basic state of cells and the composition of tumor-infiltrating immune cells, thus affecting disease prognosis. Finally, we construct a novel prognostic nomogram on the basis of histological nodes and risk score to precisely predict prognosis of patients with PAAD. In conclusion, our study uncovered the important role of circadian clock genes in PAAD and developed a risk signature as a promising prognostic biomarker for patients with PAAD.

PINK1/PARK2 dependent mitophagy effectively suppresses NLRP3 inflammasome to alleviate acute pancreatitis.

BACKGROUND: Acute pancreatitis (AP) is a clinically common acute inflammatory disease in digestive system, leading to systemic inflammatory response syndrome (SIRS) and severe acute pancreatitis (SAP). It was reported that PINK1/PARK2 dependent mitophagy played an important role in various inflammatory diseases. However, its role in AP has not been elucidated. Herein, we explore the effect of mitophagy in the pathogenesis of AP. METHODS: Firstly, we established cerulein-induced AP group and arginine-induced SAP group based on wild, PINK1-/- and PARK2-/- mice. Pancreatic samples were harvested for further investing the mitochondrial dynamics, mitophagy alterations, NLRP3 inflammatory pathway etc. Furthermore, peripheral blood mononuclear cells from SAP patients were collected to examine the expression of mitophagy-related indicators. Additionally, the interrelationship between mitophagy and NLRP3 inflammasome was also explored in AP. RESULTS: It was confirmed that mitochondria were damaged in both AP and SAP models. The expressions of PINK1, PARK2 and mitochondrial autophagosomes were elevated in wild AP group, which were decreased in SAP group over time. Similarly, the expressions of PINK1 and PAKR2 in peripheral blood mononuclear cells were significantly lower in SAP patients. Besides, in PINK1-/- and PARK2-/- mice AP groups, more pronounced inflammatory infiltration, increased apoptotic and necrotic levels and upregulated NLRP3 inflammasome pathway were detected. After injection with MCC950, NLRP3 inflammasome production was notably reduced in PINK1-/-and PARK2-/-mice, which effectively alleviated the pancreatic damage and inflammatory cell infiltration. CONCLUSION: Our study suggested that mitochondrial dysfunction activated PINK1/PARK2-mediated mitophagy in AP, while mitophagy was impaired in SAP. PINK1-/- and PARK2-/- mice were more sensitive to onset of SAP and the deficiency of mitophagy could lead to the formation of NLRP3 inflammasome.

Associations of sirtuins with clinicopathological variables and prognosis in human ovarian cancer.

Ovarian cancer (OC) is the fifth most frequent cause of cancer-associated mortality worldwide, and is accompanied by asymptomatic progression. Sirtuins (SIRTs) are a family of nicotinamide adenine dinucleotide-dependent protein deacetylases, comprising seven members (SIRT1, SIRT2, SIRT3, SIRT4, SIRT5, SIRT6 and SIRT7). Accumulating evidence has demonstrated that SIRTs act as prognostic estimators in certain types of cancer such as lung cancer, prostate cancer, gastric cancer, breast cancer and colorectal cancer. However, it remains unknown whether individual SIRTs can serve as independent prognostic factors in OC. In the present study, the Kaplan-Meier plotter online database was utilized to examine the prognostic values of SIRT mRNA expression in patients with OC. The results demonstrated that the overexpression of SIRT3, SIRT5, SIRT6 and SIRT7 mRNAs was associated with a good prognosis in patients, whereas elevated mRNA levels of SIRT1 and SIRT4 indicated poor survival in patients with OC. In addition, among the favorable predictors, SIRT3, SIRT5, SIRT6 and SIRT7 overexpression were associated with overall survival (OS), according to clinical characteristics, such as histological classification, clinical stage, pathology grade, drug therapy and tumor protein p53 mutation status in patients with OC. Similarly, SIRT4 mRNA overexpression was associated with poor OS in pathological grade III cancer. High SIRT1 and SIRT4 expression were associated with unfavorable OS at all clinical stages. Furthermore, SIRT1 and SIRT4 were negatively associated with OS in drug-treated patients. In summary, the present study demonstrated that the SIRT family is associated with the prognosis of human OC, suggesting that individual SIRTs may also act as prognostic predictors in patients.

Identification of key genes and pathways by bioinformatics analysis with TCGA RNA sequencing data in hepatocellular carcinoma.

Improved insight into the molecular characteristics of hepatocellular carcinoma (HCC) is required to predict prognosis and to develop a new rationale for targeted therapeutic strategy. Bioinformatics methods, including functional enrichment and network analysis combined with survival analysis, are required to process a large volume of data to obtain further information on differentially expressed genes (DEGs). The RNA sequencing data related to HCC in The Cancer Genome Atlas (TCGA) database were analyzed to screen DEGs, which were separately submitted to perform gene enrichment analysis to identify gene sets and signaling pathways, and to construct a protein-protein interaction (PPI) network. Subsequently, hub genes were selected by the core level in the network, and the top hub genes were focused on gene expression analysis and survival analysis. A total of 610 DEGs were identified, including 444 upregulated and 166 downregulated genes. The upregulated DEGs were significantly enriched in the Gene Ontology analysis (GO): Cell division and in the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway: Cell cycle, whereas the downregulated DEGs were enriched in GO: Negative regulation of growth and in the KEGG pathway: Retinol metabolism, with significant differences. Cyclin-dependent kinase (CDK)1 was selected as the top hub gene by the PPI network, which exhibited a similar expression trend with the data from the Gene Expression Omnibus (GEO) database. Survival analysis revealed a significantly negative correlation between CDK1 expression level and overall survival in the TCGA group (P<0.01) and the GEO group (P<0.01). Therefore, high-throughput TCGA data analysis appears to be an effective method for screening tumor molecular markers, and high expression of CDK1 is a prognostic factor for HCC.

Capsaicin and sorafenib combination treatment exerts synergistic anti­hepatocellular carcinoma activity by suppressing EGFR and PI3K/Akt/mTOR signaling.

Capsaicin (8­methyl N­vanillyl­6 nonenamide) is a natural plant extract that has antitumor properties and induces apoptosis and autophagy in various types of malignancies, including hepatocellular carcinoma (HCC). Sorafenib is a multi­kinase inhibitor that improves the survival of patients with advanced HCC. In the present study, capsaicin and sorafenib were found to inhibit the growth of LM3, Hep3B and HuH7 cells. In addition, the combination of capsaicin and sorafenib exerted a synergistic inhibitory effect on HCC cell growth. In LM3 cells, capsaicin and sorafenib combination treatment achieved a markedly stronger induction of apoptosis by increasing caspase­3, Bax and poly(ADP­ribose) polymerase activity and inhibiting Bcl­2, and induction of autophagy by upregulating the levels of beclin­1 and LC3A/B II, enhancing P62 degradation. The combination of capsaicin and sorafenib also inhibited cell invasion and metastasis via upregulation of E­cadherin and downregulation of N­cadherin, vimentin, matrix metalloproteinase (MMP)2 and MMP9. Additional studies suggested an association between the abovementioned anticancer activities and inhibition of the epidermal growth factor receptor/phosphoinositide 3 kinase/Akt/mammalian target of rapamycin pathway. Taken together, these data confirm that capsaicin and sorafenib combination treatment inhibits the growth, invasion and metastasis of HCC cells and induces autophagy in a synergistic manner, supporting its potential as a therapeutic option for HCC.

The rat pancreatic body tail as a source of a novel extracellular matrix scaffold for endocrine pancreas bioengineering.

BACKGROUND: Regenerative medicine and tissue engineering are promising approaches for organ transplantation. Extracellular matrix (ECM) based scaffolds obtained through the decellularization of natural organs have become the preferred platform for organ bioengineering. In the field of pancreas bioengineering, acellular scaffolds from different animals approximate the biochemical, spatial and vascular relationships of the native extracellular matrix and have been proven to be a good platform for recellularization and in vitro culture. However, artificial endocrine pancreases based on these whole pancreatic scaffolds have a critical flaw, specifically their difficult in vivo transplantation, and connecting their vessels to the recipient is a major limitation in the development of pancreatic tissue engineering. In this study, we focus on preparing a novel acellular extracellular matrix scaffold derived from the rat pancreatic body tail (pan-body-tail ECM scaffold). RESULTS: Several analyses confirmed that our protocol effectively removes cellular material while preserving ECM proteins and the native vascular tree. DNA quantification demonstrated an obvious reduction of DNA compared with that of the natural organ (from 931.9 ± 267.8 to 11.7 ± 3.6 ng/mg, P < 0.001); the retention of the sGAG in the decellularized pancreas (0.878 ± 0.37) showed no significant difference from the natural pancreas (0.819 ± 0.1) (P > 0.05). After transplanted with the recellularized pancreas, fasting glucose levels declined to 9.08 ± 2.4 mmol/l within 2 h of the operation, and 8 h later, they had decreased to 4.7 ± 1.8 mmol/l (P < 0.05). CONCLUSIONS: The current study describes a novel pancreatic ECM scaffold prepared from the rat pancreatic body tail via perfusion through the left gastric artery. We further showed the pioneering possibility of in vivo circulation-connected transplantation of a recellularized pancreas based on this novel scaffold. By providing such a promising pancreatic ECM scaffold, the present study might represent a key improvement and have a positive impact on endocrine pancreas bioengineering.

Comprehensive anti-tumor effect of Brusatol through inhibition of cell viability and promotion of apoptosis caused by autophagy via the PI3K/Akt/mTOR pathway in hepatocellular carcinoma.

Brusatol, a natural quassinoid isolated from a traditional Chinese herbal medicine known as Bruceae Fructus, has recently been reported to possess powerful cytotoxic effects against various cancer cell lines, highlighting its potential as an anti-cancer drug. However, the precise molecular mechanisms by which Brusatol exerts its anti-cancer effects remain poorly understood in hepatocellular carcinoma (HCC). In this study, we demonstrated that Brusatol inhibited cell viability, proliferation and induced apoptosis in liver cancer lines. Furthermore, Brusatol could activate autophagy in diverse liver cell lines, and the autophagy inhibitor chloroquine (CQ) reversed Brusatol-induced apoptosis in Bel7404 cells. In addition, we found that Brusatol inhibited PI3K/Akt/mTOR. Brusatol may also inhibit invasion, migration and the epithelial-mesenchymal transition (EMT). In a human liver xenograft tumor model in nude mice, immunohistochemistry showed that Brusatol significantly inhibited tumor invasion and proliferation. Taken together, these results revealed that Brusatol effectively inhibited proliferation and induced apoptosis in HCC through autophagy induction, probably via the PI3K/Akt/mTOR pathway, and inhibited tumor invasion and migration in vivo and in vitro. All above indicated that Brusatol is an encouraging anti-tumor drug candidate or a supplement to the current chemotherapeutic systematic plan.