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Abstract Background Collagen type XII alpha 1 chain (COL12A1) is associated with human cancer progression. Nevertheless, the expression pattern and the function of COL12A1 in intrahepatic cholangiocarcinoma (iCCA) remain unknown. The present study was performed to assess the role of COL12A1 in iCCA. Results A total of 1669 genes, differentially expressed between iCCA and nontumor liver tissue samples, were identified as potential tumor-specific biomarkers for iCCA patients. Of these, COL12A1 was significantly upregulated in clinical iCCA tissue samples and correlated with epithelial–mesenchymal transition gene set enrichment score and advanced tumor stage in clinical iCCA. COL12A1-high expression was associated with the poor prognoses of iCCA patients (n = 421) from four independent cohorts. Promoter hypermethylation-induced downregulation of miR-424-5p resulted in COL12A1 upregulation in clinical iCCA. Experimental knockout of COL12A1 inhibited the proliferation, invasiveness and growth of iCCA cells. MiR-424-5p had a therapeutic potential in iCCA via directly targeting COL12A1. Conclusions Promoter hypermethylation-induced miR-424-5p downregulation contributes to COL12A1 upregulation in iCCA. COL12A1 is a promising druggable target for epigenetic therapy of iCCA. Graphical Abstract

Abstract Background Identification of novel biomarker is important for development of molecular-targeted therapy agents for patients with hepatocellular carcinoma (HCC). This study aims to identify potential prognostic biomarkers and investigate epigenetic mechanism of HCC development. Methods Public bulk-RNA seq datasets and proteomic dataset were screened for identification of potential prognostic biomarkers for HCC patients. Public methylomic datasets were analyzed for deciphering the epigenetic mechanism regulating HCC-associated gene expression. Immunoblotting, immunohistochemistry, real-time PCR, and pyrosequencing were used to validate the findings from bioinformatic analyses. Results Minichromosome maintenance complex component 2 (MCM2) and nucleoporin 37 (NUP37) were overexpressed in human HCC tissues and hepatoma cell lines. MCM2 significantly positively correlated with NUP37 expression. Higher expression of MCM2 or NUP37 was significantly associated with advanced tumor stage and worse overall survival in 3 large independent HCC cohorts (n = 820). MCM2 and NUP37 overexpression are independent prognostic risk factors for HCC patients. Demethylation at an enhancer of MCM2 gene was a common event in patients with HCC, which significantly negatively correlated with MCM2 and NUP37 mRNA expression. Conclusions Demethylation at enhancer regulates MCM2 and NUP37 expression in HCC. MCM2 and NUP37 are promising prognostic biomarkers and potential targets for epigenetic therapy in HCC patients.

Accurate mapping of crop distribution on Earth's surface aids in predicting grain production. Pattern classification along with remote sensing imagery can facilitate traditional manual field measurement techniques using machine learning. With the rapid increase in satellite sensor resolution, the object-based classification paradigm has increasingly been applied. However, scale parameter selection is always a difficult part of the object-based classification. Based on ensemble learning, this study proposes a classification method using the multiscale object-based weighted method which includes manual digitizing of crop distribution in the southern region of Jishan County, Shanxi Province, China, applying Gaofen-2 (GF-2) images. This method initially uses estimations of the scale parameter (ESP) tool to select “good” scales, defined here as “preferred” scales, after which feature subsets are screened by each preferred scale as the input of multiple classifiers and classifies. Finally, all classification results are then fused. Our research results indicate that: 1) Feature importance values are sorted differently at different preferred scales; 2) accuracy differences become clear when different preferred scales are combined with different classifiers, and determining the “best” single appropriate scale is generally difficult; 3) accuracy of the multiscale weighted classification method is higher compared to the single preferred scale approach. Furthermore, ensemble learning can be achieved using this method on multiple scales and on multiple classifiers. With this method, procedures that necessitate the selection of segmentation scales and the selection and optimization of classifiers can be skipped altogether.

AimThe effect of recombinant human thrombopoietin (rhTPO) is largely unknown in lower-risk myelodysplastic syndrome (LR-MDS). This study aimed at investigating the safety and efficacy of rhTPO in patients with LR-MDS.MethodsLR-MDS patients receiving stanozolol (2 mg, t.i.d.) and supportive care alone (non-rhTPO) or additional rhTPO were enrolled in this study prospectively. rhTPO was given at 15,000 U (q.d.) for 7 days/month for at least 3 months. Patients stopped rhTPO if the platelet count was higher than 50 × 109/L or had no effects after 3 months of treatment. The overall response (OR), complete response (CR), platelet response, side effects, clone evolution, and clinical outcome were evaluated.ResultThirty-five patients were enrolled: 20 (57.1%) patients in the rhTPO group and 15 (42.9%) patients in the non-rhTPO group. The demographic and baseline characteristics were balanced between the two groups. Platelet response was higher at 1 and 2 months as compared with that in the non-rhTPO group (p = 0.006 and p = 0.001, respectively). Meanwhile, the rhTPO group had a shorter time to achieve a platelet transfusion-free state compared with the non-rhTPO group (p = 0.034). Hematologic response was higher at 1 and 2 months compared with that in the non-rhTPO group (p = 0.006 and p = 0.001, respectively). There was no significant difference in the overall response or complete response at 1, 2, 3, 6, and 12 months between the two groups. One patient in the rhTPO group evolved into higher-risk MDS at 9 months. No significant difference in disease progression, infection, gastrointestinal disorders, or drug-related liver/renal injuries was found between the two groups (p > 0.05).ConclusionAdding short-term rhTPO can accelerate the early platelet response and decrease platelet transfusion, with no obvious side effects.Clinical Trial Registrationhttps://clinicaltrials.gov/ct2/show/NCT04324060?cond=NCT04324060&draw=2, identifier NCT04324060

Background and Aims: This study aimed at comparing the efficacy and safety of eltrombopag (EPAG) plus immunosuppressive therapies (ISTs) and haploidentical hematopoietic stem cell transplantation (haplo-HSCT) in the frontline treatment for severe aplastic anemia (SAA) patients.Methods: Four electronic databases and Clinicaltrials.gov were comprehensively searched from January 2010 to August 2020. Studies that aimed at evaluating the efficacy and safety of EPAG+IST or haplo-HSCT in SAA patients were included. One-/2-year overall survival (OS), complete response (CR), and overall response rates (ORRs) were indirectly compared between EPAG+IST and haplo-HSCT.Results: A total of 447 patients involved in 10 cohort studies were found to be eligible for this study. A narrative synthesis was performed due to lack of data directly comparing the outcome of EPAG+IST and haplo-HSCT. Consistent with the analysis results in the whole population, subgroup analyses in the age-matched population showed that there was no significant difference in ORR between EPAG+IST and haplo-HSCT groups. However, the CR rate was lower in the EPAG+IST group when compared with the haplo-HSCT group. The incidence rate of clonal evolution/SAA relapse ranged at 8–14 and 19–31% in the EPAG+IST group but not reported in the haplo-HSCT group. The incidence rate for acute graft vs. host disease (aGVHD) and chronic graft vs. host disease (cGVHD) ranged at 52–57 and 12–67%, respectively, for the haplo-HSCT group. The main causes of deaths were infections in the EPAG+IST group, and GVHD and infections in the haplo-HSCT group.Conclusion: EPAG+IST has a comparable ORR and 1-/2-year OS but lower CR rate when indirectly compared with haplo-HSCT in the frontline treatment of patients with SAA. Patients treated with haplo-HSCT may exhibit a high incidence of GVHD, whereas patients treated with EPAG+IST may experience more relapses or clone evolution.

Among hundreds of thousands of signal receptors contributing to oncogenic activation, tumorigenesis, and metastasis, the hepatocyte growth factor (HGF) receptor – also called tyrosine kinase MET – is a promising target in cancer therapy as its axis is involved in several different cancer types. It is also associated with poor outcomes and is involved in the development of therapeutic resistance. Several HGF/MET-neutralizing antibodies and MET kinase-specific small molecule inhibitors have been developed, resulting in some context-dependent progress in multiple cancer treatments. Nevertheless, the concomitant therapeutic resistance largely inhibits the translation of such targeted drug candidates into clinical application. Until now, numerous studies have been performed to understand the molecular, cellular, and upstream mechanisms that regulate HGF/MET-targeted drug resistance, further explore novel strategies to reduce the occurrence of resistance, and improve therapeutic efficacy after resistance. Intriguingly, emerging evidence has revealed that, in addition to its conventional function as an oncogene, the HGF/MET axis stands at the crossroads of tumor autophagy, immunity, and microenvironment. Based on current progress, this review summarizes the current challenges and simultaneously proposes future opportunities for HGF/MET targeting for therapeutic cancer interventions.

Curcumol is the major component extracted from root of Rhizoma Curcumae. Recent studies have shown that curcumol exerts therapeutic effects against multiple conditions, particularly cancers. However, the therapeutic role and mechanism of curcumol against cholangiocarcinoma cells are still unclear. In our current research, we tested the effect of curcumol in cholangiocarcinoma cells, and using two-dimensional electrophoresis, proteomics and bioinformatics, we identified cyclin-dependent kinase like 3 (CDKL3) as a potential target for curcumol. We have demonstrated that curcumol can evidently suppress growth and migration of cholangiocarcinoma cells. Furthermore, curcumol could significantly block the cell cycle progression of the cholangiocarcinoma cells. These effects could be largely attributed to the inhibition of CDKL3 by curcumol. Further studies have recapitulated the oncogenic role of CDKL3 in that knockdown of CDKL3 by lentiviral mediated transfection of shRNA against CDKL3 also led to a significant inhibition on cell proliferation, migration, invasion, and cell cycle progression. Given the high level of CDKL3 expression in human cholangiocarcinoma tissues and cell lines, we speculated that CDKL3 may constitute a potential biological target for curcumol in cholangiocarcinoma.

The gut microbiota and liver cancer have a complex interaction. However, the role of gut microbiome in liver tumor initiation remains unknown. Herein, liver cancer was induced using hydrodynamic transfection of oncogenes to explore liver tumorigenesis in mice. Gut microbiota depletion promoted liver tumorigenesis but not progression. Elevated sterol regulatory element-binding protein 2 (SREBP2) was observed in mice with gut flora disequilibrium. Pharmacological inhibition of SREBP2 or Srebf2 RNA interference attenuated mouse liver cancer initiation under gut flora disequilibrium. Furthermore, gut microbiota depletion impaired gut tryptophan metabolism to activate aryl hydrocarbon receptor (AhR). AhR agonist Ficz inhibited SREBP2 posttranslationally and reversed the tumorigenesis in mice. And, AhR knockout mice recapitulated the accelerated liver tumorigenesis. Supplementation with Lactobacillus reuteri, which produces tryptophan metabolites, inhibited SREBP2 expression and tumorigenesis in mice with gut flora disequilibrium. Thus, gut flora disequilibrium promotes liver cancer initiation by modulating tryptophan metabolism and up-regulating SREBP2. [ABSTRACT FROM AUTHOR]

Objective Serum carbohydrate antigen 19-9 (CA19-9) is a widely used tumour marker for cholangiocarcinoma (CCA). However, it is not a necessarily good CCA marker in terms of diagnostic accuracy. The purpose of this study is to evaluate the diagnostic value of Wisteria floribundaagglutinin-sialylated Mucin1 (WFA-MUC1) and the prognostic role of Mucin1 (MUC1) in human CCA. Design Meta-analysis. Data sources Studies published in PubMed, Web of Science, The Cochrane Library and the China National Knowledge Infrastructure up to 11 October 2017. Eligibility criteria We included reports assessing the diagnostic capacity of WFA-MUC1 and the prognostic role of MUC1 in CCA. The receiver operating characteristic curve (ROC) of WFA-MUC1 and/or CA19-9 was described, and the HRs including 95% CI and the corresponding p value for MUC1 can be extracted. Data extraction and synthesis Two independent researchers extracted data and assessed risk of bias. The diagnostic sensitivity and specificity data of WFA-MUC1 were extracted and analysed as bivariate data. Pooled HRs and its 95% CI for MUC1 were calculated with a random-effects meta-analysis model on overall survival of resectable CCA. Results Sixteen reports were included in this study. The pooled sensitivity and specificity of WFA-MUC1 were 0.76 (95% CI 0.71 to 0.81) and 0.72 (95% CI 0.59 to 0.83) in serum, 0.85 (95% CI 0.81 to 0.89) and 0.72 (95% CI 0.64 to 0.80) in bile and 0.72 (95% CI 0.50 to 0.87) and 0.85 (95% CI 0.70 to 0.93) in tissue, respectively. The summary ROC (SROC) were 0.77 (95% CI 0.73 to 0.81) in serum, 0.88 (95% CI 0.85 to 0.90) in bile and 0.86 (95% CI 0.83 to 0.89) in tissue, respectively. Furthermore, the pooled sensitivity and specificity and the SROC of CA19-9 in serum were 0.67 (95% CI 0.61 to 0.72), 0.86 (95% CI 0.75 to 0.93) and 0.75 (95% CI 0.71 to 0.79), respectively. The pooled HRs for MUC1 was 2.20 (95% CI 1.57 to 3.01) in CCA and 4.17 (95% CI 1.71 to 10.17) in mass-forming intrahepatic CCA. Conclusions Compared with CA19-9, WFA-MUC1 was shown to possess stronger diagnostic capability. MUC1 could serve as a prognosis factor for poor outcomes of CCA, particularly, mass-forming intrahepatic CCA. [ABSTRACT FROM AUTHOR]