Prognosis after splenectomy plus pericardial devascularization vs transjugular intrahepatic portosystemic shunt for esophagogastric variceal bleeding.

BACKGROUND: Portal hypertension combined with esophagogastric variceal bleeding (EGVB) is a serious complication in patients with hepatitis B virus (HBV)-related cirrhosis in China. Splenectomy plus pericardial devascularization (SPD) and transjugular intrahepatic portosystemic shunt (TIPS) are effective treatments for EGVB. However, a comparison of the effectiveness and safety of those methods is lacking. AIM: To compare the prognosis after SPD vs TIPS for acute EGVB after failure of endoscopic therapy or secondary prophylaxis of variceal rebleeding (VRB) in patients with HBV-related cirrhosis combined with portal hypertension. METHODS: This retrospective cohort study included 318 patients with HBV-related cirrhosis and EGVB who underwent SPD or TIPS at West China Hospital of Sichuan University during 2009-2013. Propensity score-matched analysis (PSM), the Kaplan-Meier method, and multivariate Cox regression analysis were used to compare overall survival, VRB rate, liver function abnormality rate, and hepatocellular carcinoma (HCC) incidence between the two patient groups. RESULTS: The median age was 45.0 years (n = 318; 226 (71.1%) males). During a median follow-up duration of 43.0 mo, 18 (11.1%) and 33 (21.2%) patients died in the SPD and TIPS groups, respectively. After PSM, SPD was significantly associated with better overall survival (OS) (P = 0.01), lower rates of abnormal liver function (P < 0.001), and a lower incidence of HCC (P = 0.02) than TIPS. The VRB rate did not differ significantly between the two groups (P = 0.09). CONCLUSION: Compared with TIPS, SPD is associated with higher postoperative OS rates, lower rates of abnormal liver function and HCC, and better quality of survival as acute EGVB treatment after failed endoscopic therapy or as secondary prophylaxis of VRB in patients with HBV-related cirrhosis combined with portal hypertension. There is no significant between-group difference in VRB rates.

circYap inhibits oral squamous cell carcinoma by arresting cell cycle.

OBJECTIVE: Circular RNAs (circRNAs) involve in the development and progression of tumour. The mechanism of circRNAs in oral squamous cell carcinoma (OSCC) has remained unclear. This study aimed to investigate the role of circular Yes-associated protein (circYap) in OSCC. METHODS: Quantification reverse transcription-polymerase chain reaction (qRT-PCR) was applied to measure circYap expression in patients with OSCC tissues and cells. Flow cytometry was performed to evaluate cell cycle. circYap interaction with CDK4 was detected by RNA immunoprecipitation (RIP) and RNA pull-down. The interaction of Cyclin D1 and CDK4 was determined using co-immunoprecipitation (co-IP). RESULTS: We showed that circYap expression was downregulated in OSCC tissues. Using small interfering circular (Si-circYap) and overexpression plasmid, we found that circYap overexpression inhibited proliferation and arrested cell cycle in OSCC cells, while, circYap knockdown yielded the opposite result. Cyclin D1/CDK4 complexes and nuclear translocation is essential for cell cycle progression. We found that CDK4 interacted with circYap was increased when circYap overexpression, meanwhile, Cyclin D1/CDK4 complexes and of nuclear distribution were decreased. CONCLUSIONS: Our findings suggest that circYap impedes progression of OSCC. Overexpression of circYap suppresses proliferation and cell cycle through binding to CDK4 to block formation and nuclear translocation of Cyclin D1/CDK4 complexes. Thus, circYap may serves as a valuable therapeutic target for OSCC.

Gujiansan Ameliorates Avascular Necrosis of the Femoral Head by Regulating Autophagy via the HIF-1α/BNIP3 Pathway.

BACKGROUND: Clinically, the traditional Chinese medicine compound Gujiansan has been widely used in the treatment of steroid-induced avascular necrosis of the femoral head (SANFH). The present study aimed to investigate the mechanisms underlying the therapeutic effect of Gujiansan. METHODS: A rat model of SANFH was established by the injection of dexamethasone (DEX) at a high dosage of 25 mg/kg/d. Then, Gujiansan was intragastrically administered for 2 weeks, 4 weeks, and 8 weeks, and histological examination of the femoral head was performed. The expression levels of related mRNAs and proteins were analyzed by qRT-PCR, Western blotting, and immunohistochemistry, and the levels of bone biochemical markers and cytokines were detected with ELISA kits. RESULTS: Gujiansan administration ameliorated SANFH and induced the expression of hypoxia-inducible factor-1α (HIF-1α), Bcl-2/adenovirus E1B 19 kDa interacting protein 3 (BNIP3), LC3, and Beclin-1 in the rat model in a dose- and time-dependent manner, and Gujiansan promoted osteocalcin secretion at the femoral head. In addition, Gujiansan increased the levels of bone formation- and bone resorption-specific markers (osteocalcin (OC), bone-specific alkaline phosphatase (BAP), tartrate resistant acid phosphatase-5b (TRACP-5b), N-terminal telopeptides of type I collagen (NTX-1), and C-terminal telopeptide of type I collagen (CTX-1)) and decreased the levels of proinflammatory cytokines (TNF-α, IL-6, and CRP) in a dose- and time-dependent manner. CONCLUSIONS: Gujiansan accelerates the formation of a new bone, promotes the absorption of the damaged bone, inhibits the inflammatory response, induces autophagy of the femoral head via the HIF-1α/BNIP3 pathway, and ultimately ameliorates SANFH.

Prognostic significance of postoperative change of PALBI grade for patients with hepatocellular carcinoma after hepatectomy.

ABSTRACT: The platelet-albumin-bilirubin (PALBI) grade plays critical role in evaluating liver function. However, the change of PALBI grade from the preoperative to postoperative period in predicting patient outcomes after hepatectomy remains unclear.A total of 489 HCC patients who underwent hepatectomy in West China Hospital between January, 2010 and June, 2016 were analyzed retrospectively.ΔPALBI grade was calculated by PALBI grade at the first postoperative month - preoperative PALBI grade.ΔPALBI >0 was considered as stable; otherwise, worse PALBI grade was considered. Kaplan- Meier method and Cox proportional hazard regression analyses were performed for survival analysis. Prognostic model was constructed by nomogram method.Three hundred forty two patients and 147 patients were classified into training group and validation group, respectively. In the training group, results from Cox model suggested that worse PALBI grade (HR 1.328, 95% CI 1.010-1.746, P = .042), tumor size (HR 1.460, 95% CI 1.058-2.015, P = .021), microvascular invasion (MVI, HR 1.802, 95% CI 1.205-2.695, P < .001), and high alpha-fetoprotein level (AFP, HR 1.364, 95% CI 1.044-1.781, P = .023) negatively influenced postoperative recurrence. Similarly, worse PALBI grade (HR 1.403, 95% CI 1.020-1.930, P = .038), tumor size (HR 1.708, 95% CI 1.157-2.520, P = .007), MVI (HR 1.914, 95% CI 1.375-2.663, P < .001), and presence of cirrhosis (HR 1.773, 95% CI 1.226-2.564, P = .002) had negatively impacts on overall survival. Patients with worse PALBI grade had worse recurrence free (RFS) and overall survival (OS). The prognostic model incorporating the change of PALBI grade constructed in training group and tested in the validation group could perform well in predicting the outcomes.Postoperative change of PALBI grade was independently risk factor related with prognosis. Prognostic model incorporating the change of PALBI grade might be a useful index to predict the prognosis of HCC patients following hepatectomy.

The transcriptional landscape of Shh medulloblastoma.

Sonic hedgehog medulloblastoma encompasses a clinically and molecularly diverse group of cancers of the developing central nervous system. Here, we use unbiased sequencing of the transcriptome across a large cohort of 250 tumors to reveal differences among molecular subtypes of the disease, and demonstrate the previously unappreciated importance of non-coding RNA transcripts. We identify alterations within the cAMP dependent pathway (GNAS, PRKAR1A) which converge on GLI2 activity and show that 18% of tumors have a genetic event that directly targets the abundance and/or stability of MYCN. Furthermore, we discover an extensive network of fusions in focally amplified regions encompassing GLI2, and several loss-of-function fusions in tumor suppressor genes PTCH1, SUFU and NCOR1. Molecular convergence on a subset of genes by nucleotide variants, copy number aberrations, and gene fusions highlight the key roles of specific pathways in the pathogenesis of Sonic hedgehog medulloblastoma and open up opportunities for therapeutic intervention.

Icariin Accelerates Fracture Healing via Activation of the WNT1/ß-catenin Osteogenic Signaling Pathway.

BACKGROUND: Icariin has been shown to enhance bone formation. OBJECTIVE: The present study aimed to investigate whether icariin also promotes bone fracture healing and its mechanisms. METHODS: First, we isolated and cultured rat bone marrow stromal cells (rBMSCs) with icariincontaining serum at various concentrations (0%, 2.5%, 5% and 10%) and then measured alkaline phosphatase (ALP) activity and the expression of Core-binding factor, alpha 1 (Cbfα1), bone morphogenetic protein-2 (BMP-2) and bone morphogenetic protein-4 (BMP-4) in the rBMSCs. Second, we established a model of fracture healing in rats and performed gavage treatment for 20 days. Then, we detected bone biochemical markers (ELISA kits) in the serum, fracture healing (digital radiography, DR), and osteocalcin expression (immunohistochemistry). RESULTS: Icariin treatment increased ALP activity and induced the expression of Cbfα1, BMP-2 and BMP-4 in rBMSCs in a dose-dependent manner. In addition, Icariin increased the serum levels of osteocalcin (OC), bone-specific alkaline phosphatase (BAP), N-terminal telopeptides of type I collagen (NTX-1), C-terminal telopeptide of type I collagen (CTX-1) and tartrate-resistant acid phosphatase 5b (TRACP-5b); promoted osteocalcin secretion at the fracture site; and accelerated fracture healing. CONCLUSION: Icariin can promote the levels of bone-formation markers, accelerate fracture healing, and activate the WNT1/ß-catenin osteogenic signaling pathway.

Profiles of immune cell infiltration and immune-related genes in the tumor microenvironment of osteosarcoma.

This work aimed to investigate tumor-infiltrating immune cells (TIICs) and immune-associated genes in the tumor microenvironment of osteosarcoma. An algorithm known as ESTIMATE was applied for immune score assessment, and osteosarcoma cases were assigned to the high and low immune score groups. Immune-associated genes between these groups were compared, and an optimal immune-related risk model was built by Cox regression analyses. The deconvolution algorithm (referred to as CIBERSORT) was applied to assess 22 TIICs for their amounts in the osteosarcoma microenvironment. Osteosarcoma cases with high immune score had significantly improved outcome (P<0.01). The proportions of naive B cells and M0 macrophages were significantly lower in high immune score tissues compared with the low immune score group (P<0.05), while the amounts of M1 macrophages, M2 macrophages, and resting dendritic cells were significantly higher (P<0.05). Important immune-associated genes were determined to generate a prognostic model by Cox regression analysis. Interestingly, cases with high risk score had poor outcome (P<0.01). The areas under the curve (AUC) for the risk model in predicting 1, 3 and 5-year survival were 0.634, 0.781, and 0.809, respectively. Gene set enrichment analysis suggested immunosuppression in high-risk osteosarcoma patients, in association with poor outcome.

Diosgenin Suppresses Cholangiocarcinoma Cells Via Inducing Cell Cycle Arrest And Mitochondria-Mediated Apoptosis.

PURPOSE: Diosgenin (DSG) is the precursor of steroid hormones and plays a crucial part in the proliferation of various carcinomas including human colorectal cancer and gastric carcinoma. Nevertheless, its specific features and mechanisms in human cholangiocarcinoma (CCA) remain unknown. METHODS: MTS assay, colony-forming assay, and EdU assay were performed to determine the role of DSG on the progression of human CCA cells. The distributions of cell cycle, the ratio of apoptosis, and the mitochondrial membrane potential (ΔΨm) were studied by flow cytometry (FCM). AO/EB and Hoechst 33258 staining were performed to observe the morphological features of cell apoptosis. TEM was performed to observe the ultrastructures of QBC939 and HuCCT1 cells. The mRNA and protein expression of mitochondrial apoptotic pathway and GSK3ß/ß-catenin pathway were further confirmed by qPCR and Western blotting. The xenograft tumor model of HuCCT1 cells was built. Immunohistochemistry of tumor tissues was performed. RESULTS: Our results indicated that DSG inhibited the progression of six CCA cell lines. In vivo tumor studies also indicated that DSG significantly inhibited tumor growth in xenografts in nude mice. The expression of mitosis-promoting factor cyclinB1 was decreased along with the elevating level of cell cycle inhibitor p21, resulting in arresting CCA cell cycles at G2/M phase. Furthermore, DSG induced apoptosis with the increased expressions of cytosol cytochrome C, cleaved-caspase-3, cleaved-PARP1 and the Bax/Bcl-2 ratio. Mechanistically, our study showed that GSK3ß/ß-catenin pathway was involved in the apoptosis of CCA cells. Thus, DSG might provide a new clue for the drug therapy of CCA. CONCLUSION: In our data, DSG was found to have efficient antitumor potential of human CCA cells in vitro and in vivo.

The preoperative platelet to albumin ratio predicts the prognosis of hepatocellular carcinoma patients without portal hypertension after liver resection.

There is little information concerning the predictive ability of the preoperative platelet to albumin ratio (PAR) in hepatocellular carcinoma (HCC) patients after liver resection. In the current study, we aimed to assess the prognostic power of the PAR in HCC patients without portal hypertension (PH) following liver resection.Approximately 628 patients were included in this study. A receiver operating characteristic (ROC) curve analysis was performed to evaluate the predictive value of the PAR for both recurrence-free survival (RFS) and overall survival (OS). Univariate and multivariate analyses were used to identify the independent risk factors for both RFS and OS.During the follow-up period, 361 patients experienced recurrence, and 217 patients died. ROC curve analysis suggested that the best cut-off value of the PAR for RFS was greater than 4.8. The multivariate analysis revealed that microvascular invasion (MVI), tumor size >5 cm, high aspartate aminotransferase-to-platelet count ratio index (APRI) and high PAR were four independent risk factors for both RFS and OS. Patients with a low PAR had significantly better RFS and OS than those with a high PAR.The PAR may be a useful marker to predict the prognosis of HCC patients after liver resection. HCC patients with a high preoperative PAR had a higher recurrent risk and lower long-term survival rate than those with a low preoperative PAR.

In silico toxicity evaluation of dioxins using structure-activity relationship (SAR) and two-dimensional quantitative structure-activity relationship (2D-QSAR).

Prediction of pEC50 values of dioxins binding with the aryl hydrocarbon receptor (AhR) is of great significance for exploring how dioxins induce toxicity in human body and evaluating their environmental behaviors and risks. To reveal the factors that influence the toxicity of dioxins, provide more accurate mathematical models for predicting the pEC50 values of dioxins, and supplement the toxicity database of persistent organic pollutants, qualitative structure-activity relationship (SAR) and two-dimensional quantitative structure-activity relationship (2D-QSAR) were used in this study. The research objects in this study were 60 organic compounds with pEC50 values and 162 compounds without pEC50 values, which included polychlorinated dibenzofurans (PCDFs), polychlorinated dibenzo-p-dioxins (PCDDs), and polybrominated dibenzo-p-dioxins (PBDDs). The qualitative structure-activity relationship (SAR) was performed first and concluded that halogen substitutions at any of the 2, 3, 7, and 8 sites increased the pEC50 value of the compound. Moreover, two-dimensional quantitative structure-activity relationship (2D-QSAR) models were established by employing multiple linear regression (MLR) method and artificial neural network (ANN) algorithm to investigate the factors affecting the pEC50 values of dioxins molecules. MLR was used to establish the well-understood linear model and ANN was used to establish a more accurate non-linear model. Both models have good fitting, robustness, and predictive ability. Importantly, the ability of dioxins binding to AhR is mainly determined by molecular descriptors including E1m, SM09_AEA (dm), RDF065u, F05 [Cl-Cl], and Neoplastic-80. In addition, the pEC50 values of the 162 dioxins without toxicity data were predicted by MLR and ANN models, respectively.

A novel model for predicting posthepatectomy liver failure in patients with hepatocellular carcinoma.

Posthepatectomy liver failure (PHLF) is the most leading cause of mortality following hepatectomy in patients with hepatocellular carcinoma (HCC). Platelet count was reported to be a simple but useful indicator of liver cirrhosis and function of spleen. Spleen stiffness (SS) was used to evaluate the morphological change of spleen and was reported to be related to liver cirrhosis and portal hypertension. However, the predictive value of platelet to spleen stiffness ratio (PSR) on PHLF remains unknown. A retrospective study was performed to analyze 158 patients with HCC following hepatectomy from August 2015 to February 2016. Univariate and multivariate analyses were performed to evaluate the value of each risk factor for predicting PHLF. The predictive efficiency of the risk factors was evaluated by receiver operating characteristic (ROC) curve. PHLF occured in 23 (14.6%) patients. PSR (P<0.001, odds ratio (OR) = 0.622, 95% confidence interval (CI) 0.493~0.784), hepatic inflow occlusion (HIO) (P = 0.003, OR = 1.044, 95% CI 1.015~1.075) and major hepatectomy (P = 0.019, OR = 5.967, 95% CI 1.346~26.443) were demonstrated to be the independent predictive factors for development of PHLF in a multivariate analysis. Results of the present study suggested PSR is a novel and non-invasive model for predicting PHLF in patients with HCC.

Biocompatiable silk fibroin/carboxymethyl chitosan/strontium substituted hydroxyapatite/cellulose nanocrystal composite scaffolds for bone tissue engineering.

Bone defects arise from trauma, skeletal diseases or tumor resections have become a critical clinical challenge. Biocomposite materials as artificial bone repair materials provide a promising approach for bone regeneration. In this study, we used silk fibroin (SF), carboxymethyl chitosan (CMCS), cellulose nanocrystals (CNCs) and strontium substituted hydroxyapatite (Sr-HAp) to prepare the biocomposite scaffolds of SF/CMCS, SF/CMCS/CNCs, SF/CMCS/CNCs/Sr-HAp. The characterization results showed that all the SF-based scaffolds have a porous sponge-like structure with porosities over 80%. In addition, there was a significant increase in compressive strength of SF/CMCS/Sr-HAp/CNCs scaffold when compared to that of SF/CMCS scaffolds, while maintaining high porosity with lower swelling ratio. All the SF-based scaffolds were non-toxic and had a good hemocompatibility. Comparing to the SF/CMCS scaffold, the scaffolds with addition of Sr-HAp and/or CNCs showed enhanced protein adsorption and ALP activity. In addition, higher expression of osteogenic gene markers such as RUNX2, ALP, OCN, OPN, BSP and COL-1 further substantiated the applicability of SF/CMCS/Sr-HAp/CNCs scaffolds for bone related applications. Hence, this study suggests that SF/CMCS/Sr-HAp/CNCs scaffolds have a potential in non-loading bone repair application.

Spleen stiffness and volume help to predict posthepatectomy liver failure in patients with hepatocellular carcinoma.

Posthepatectomy liver failure (PHLF) is the main cause of perioperative death, and liver cirrhosis is one of the most important risk factors for PHLF. Spleen stiffness (SS) is a novel ultrasonic indicator for liver cirrhosis and portal hypertension, however, it is not clear that whether it has a significant influence on PHLF. Future remnant liver volume (FRLV) is a significant factor for liver regeneration after hepatectomy, spleen volume (SV) could also predict the degree of liver cirrhosis, and recent literatures reported that SV to FRLV ratio (SV/FRLV) could predict small for size syndrome (SFSS) in liver transplantation, however, the relationship between SV/FRLV and PHLF in patients receiving hepatectomy is not known. Systemic inflammatory response (SIR) plays a significant role in the pathogenesis and progression of liver cirrhosis, however, it is not very clear about the exact relationship between SIR and PHLF.We prospectively collected the medical data of consecutive patients diagnosed with hepatocellular carcinoma (HCC) who underwent hepatectomy from August 2015 to February 2016. Preoperative measurements of SS, liver stiffness (LS), SV, FRLV, and SIR were performed on all patients. A univariate analysis was performed to find the risk factors of PHLF and a multivariate analysis was used to identify independent risk factors. The predictive efficiency of the risk factors was evaluated by receiver operating characteristic (ROC) curve.Twenty three (23) (14.6%) patients developed PHLF. Univariate analysis found several variables significantly related to PHLF, they were as follows: tumor diameter (P = .01), cirrhosis (P = .001), neutrophil to lymphocyte ratio (NLR) (P = .018), LS (P = .001), SS (P = .001), SV/FRLV (P < .001), operation duration (P = .003), transfusion (P = .009), hepatic inflow occlusion (HIO) (P = .001). Finally, SV/FRLV (P < .001, hazard ratio (HR) = 26.356, 95% confidence interval (CI) 1.627-425.21), SS (P = .009, HR = 1.077, 95%CI 1.017-1.141), and HIO time (P = .002, HR = 1.043, 95%CI 1.014-1.072) were determined as the independent risk factors of PHLF by multivariate analysis.SS and SV/FRLV help to predict the development of PHLF in patients with hepatocellular carcinoma.

Molecular inhibitory mechanism study on the potent inhibitor brigatinib against four crizotinib-resistant ALK mutations.

As a potent and selective drug, brigatinib exhibits high efficacy against wild-type and mutant anaplastic lymphoma kinase (ALK) proteins to treat non-small cell lung cancer. In this work, the mechanisms of brigatinib binding to wild type and four mutant ALKs were investigated to gain insight into the dynamic energetic and structural information with respect to the design of novel inhibitors. Comparison between ALK-brigatinib and ALK-crizotinib suggests that the scaffold of brigatinib is well anchored to the residue Met1199 of hinge region by two hydrogen bonds, and the residue Lys1150 has the strong electrostatic interaction with the dimethylphosphine oxide moiety in brigatinib. These ALK mutations have significant influences on the flexibility of P-loop region and DFG sequences, but do not impair the hydrogen bonds between brigatinib and the residue Met1199 of hinge region. And mutations (L1196M, G1269A, F1174L, and R1275Q) induce diverse conformational changes of brigatinib and the obvious energy variation of residues Glu1167, Arg1209, Asp1270, and Asp1203. Together, the detailed explanation of mechanisms of those mutations with brigatinib further provide several guidelines for the development of more effective ALK inhibitors.

Correlation Between Tumor Vasculogenic Mimicry and Poor Prognosis of Human Digestive Cancer Patients: A Systematic Review and Meta-Analysis.

Vasculogenic mimicry (VM) is a new pattern of blood supplement independent of endothelial vessels, which is related with tumor invasion, metastasis and prognosis. However, the role of VM in the prognosis of cancer patients is controversial. This study aimed to perform a meta-analysis of the published data to attempt to clarify the prognostic value of VM in the digestive cancer. Relevant studies were retrieved from the PubMed, Web of Science, Cochrane Library, Chinese National Knowledge Infrastructure and VIP databases published before March 29, 2018. Studies were included if they detected VM in the digestive cancer and analyzed the overall survival (OS) or disease-free survival (DFS) according to VM status. Two independent reviewers screened the studies, extracted data, and evaluated the quality of included studies with the Newcastle-Ottawa scale. Meta-analysis was performed using STATA 12.0 software. A total of 22 studies with 2411 patients were included in this meta-analysis. Meta-analysis showed that VM was related with the poor OS (HR = 2.30, 95% CI: 2.06-2.56, P < 0.001) and DFS (HR = 2.60, 95% CI: 2.07-3.27, P < 0.001) of patients with digestive cancer. Subgroup analysis showed VM was related with tumor differentiation, lymph node metastasis and TNM stage. Moreover, the present meta-analysis was reliable, and there was no obvious publication bias. This meta-analysis suggested that VM was a poor prognosis of digestive cancer patients. Further large and well-designed studies are required.

Retinoic Acid Receptor α Knockdown Suppresses the Tumorigenicity of Esophageal Carcinoma via Wnt/ß-catenin Pathway.

BACKGROUND: Aberrant expression of retinoic acid receptor α (RARα) was correlated with diverse carcinomas such as acute promyelocytic leukemia and colorectal carcinoma. Nevertheless, the function and mechanism of RARα in esophageal carcinoma (EC) remain unclear. AIM: To investigate the expression of RARα in EC and its effect in the tumorigenesis of EC. METHODS AND RESULTS: In immunohistochemistry study, RARα was overexpressed in human EC tissues, and its overexpression was closely related to the pathological differentiation, lymph node metastasis, and clinical stages in EC patients. Functionally, RARα knockdown suppressed the proliferation and metastasis of EC cells through downregulating the expression of PCNA, Ki67, MMP7, and MMP9, as well as enhanced drug susceptibility of EC cells to 5-fluorouracil and cisplatin. Mechanistically, RARα knockdown inhibited the activity of Wnt/ß-catenin pathway through reducing the phosphorylation level of GSK3ß at Ser-9 and inducing phosphorylation level at Tyr-216, which resulted in downregulation of its downstream targets such as MMP7, MMP9, and P-gP. CONCLUSIONS: Our results demonstrated that RARα knockdown suppressed the tumorigenicity of EC via Wnt/ß-catenin pathway. RARα might be a potential molecular target for EC clinical therapy.

Selective mechanisms and molecular design of 2,4 Diarylaminopyrimidines as ALK inhibitors.

As an attractive therapeutic target for non-small-cell lung cancer (NSCLC), anaplastic lymphoma kinase (ALK) has got increased attention, and the selectivity of ALK inhibitors is an enormous challenge. Recently, 2,4-Diarylaminopyrimidines with high inhibitory activity over InsR/IGF1R were reported as ALK inhibitors, which harboring phosphine oxide moiety. In this work, it is the first time to reveal that the incorporation of dimethylphosphine oxide moiety and the smaller active pocket of ALK is key factor in the selectivity of inhibitor 11q toward ALK over IGF1R/InsR. The results of molecular simulation indicate that the subtle change in the binding pocket of ALK is mainly associated with the flexibility of P-loop and the own residues K1150 and D1270. The replacement of the dimethylphosphine oxide and methylpiperazine of inhibitor 11q would alter the major inhibitory effects of binding and activation. The results further combined 3D-QSAR can not only profile the binding mechanism between the 2,4-Diarylaminopyrimidines inhibitors and ALK, but also supply the useful information for the rational design of a more potential small molecule inhibitor bound to ALK receptor.

Preoperative albumin-bilirubin grade plus platelet-to-lymphocyte ratio predict the outcomes of patients with BCLC stage A hepatocellular carcinoma after liver resection.

There is little information regarding the predictive ability of albumin-bilirubin grades (ALBI) plus platelet-to-lymphocyte ratio (PLR) in patients with hepatocellular carcinoma (HCC) following liver resection. In this study, we aimed to evaluate the prognostic power of the ALBI-PLR score in patients with hepatitis B virus-related (HBV-related) HCC within Barcelona Clinic Liver Cancer (BCLC) stage A after liver resection.Around 475 patients were included in this study. Patients with preoperative ALBI grades 1, 2, or 3 were allocated a score of 0, 1, or 2, respectively. Patients with preoperative PLR >150 or ≤150 were allocated a score of 0 or 1, respectively. The ALBI-PLR score was the summary of the ALBI and PLR scores.During the follow-up period, 256 patients experienced recurrence, and 150 patients died. Multivariate analysis revealed tumor size, multiple tumors, positive HBV-DNA load, cirrhosis, and ALBI-PLR score as being independently associated with postoperative recurrence, whereas tumor size, high preoperative α-fetoprotein level, and ALBI-PLR score were independent risk factors for postoperative mortality. HCC patients with high ALBI-PLR score had poor recurrence-free and overall survival.The preoperative ALBI-PLR score is a surrogate marker for predicting HBV-related HCC patient's prognosis after liver resection. A high ALBI-PLR score is associated with a high incidence of postoperative recurrence and mortality.

Molecular modeling study on resistance of WT/D473H SMO to antagonists LDE-225 and LEQ-506.

The smoothened (SMO) receptor, an essential signal transducer in the Hedgehog pathway, was targeted with antagonists to suppress the tumor. It is interesting that SMO D473H mutation confers resistance on inhibitor LDE-225 rather than LEQ-506. In this paper, the binding modes of them against the wild type and mutant SMO receptors were identified to gain insights into the resistant and non-resistant factors, based on a comprehensive protocol involving molecular docking, molecular dynamic simulations, free energy calculation and decomposition. A comparison of resistant LDE-225 and non-resistant LEQ-506 indicates that the volume of the binding cavity decreases seriously in the mutant complex with resistant LDE-225. In addition, the D473H mutation disrupts the hydrogen bond network with residues R400 and Q477, which results in the TM6 conformation inward. Owing to the absence of the hydrogen bond, residues R400 and Q477 make weak contributions to LDE-225. However, the D473H mutation along with TM6 conformational change has no effect on non-resistant LEQ-506. Finally, the resistance ascribes to adverse interaction between the greater polarity of mutant residue H473 and the nonpolar phenmethyl of LDE-225. The elaborate insights into structural and energetic mechanism of drug resistance provide an effective strategy to design rationally non-resistant antagonists.

Postoperative Albumin-Bilirubin Grade Change Predicts the Prognosis of Patients with Hepatitis B-Related Hepatocellular Carcinoma Within the Milan Criteria.

OBJECTIVE: Albumin-bilirubin (ALBI) grade has been validated as a simple, evidence-based, and objective prognostic tool for patients with hepatocellular carcinoma (HCC). However, minimal information is available concerning postoperative ALBI grade changes in HCC. This study aimed to investigate the prognostic value of postoperative ALBI grade changes in patients with hepatitis B virus (HBV)-related HCC within the Milan criteria after liver resection. METHODS: Patients with HBV-related HCC within the Milan criteria who underwent liver resection between 2010 and 2016 at West China Hospital were reviewed (N = 258). A change in ALBI grade was defined as first postoperative month ALBI grade-preoperative ALBI grade. If the value was >0, postoperative worsening of ALBI grade was considered; otherwise, stable ALBI grade was considered. Cox proportional hazard regression analyses were used to determine the factors that influence recurrence and survival. RESULTS: During the follow-up, 130 patients experienced recurrence and 47 patients died. Multivariate analyses revealed that postoperative worsening of ALBI grade (HR 1.541, 95% CI 1.025-2.318, P = 0.038), microvascular invasion (MVI, HR 1.802, 95% CI 1.205-2.695, P = 0.004), and multiple tumors (HR 1.676, 95% CI 1.075-2.615, P = 0.023) were associated with postoperative recurrence, whereas MVI (HR 2.737, 95% CI 1.475-5.080, P = 0.001), postoperative worsening of ALBI grade (HR 2.268, 95% CI 1.227-4.189, P = 0.009), high alpha-fetoprotein level (HR 2.055, 95% CI 1.136-3.716, P = 0.017), and transfusion (HR 2.597, 95% CI 1.395-4.834, P = 0.003) negatively influenced long-term survival. Patients with postoperative worsening of ALBI grade exhibited increased incidence of recurrence and worse long-term survival. CONCLUSION: Postoperative worsening of ALBI grade was associated with increased recurrence and poorer overall survival for patients with HBV-related HCC within the Milan criteria. We should pay attention to liver function changes in HCC patients after liver resection.