Construction and validation of a prognostic model based on autophagy-related genes for hepatocellular carcinoma in the Asian population.

BACKGROUND AND OBJECTIVE: Hepatocellular carcinoma (HCC), which has a complex pathogenesis and poor prognosis, is one of the most common malignancies worldwide. Hepatitis virus B infection is the most common cause of HCC in Asian patients. Autophagy is the process of digestion and degradation, and studies have shown that autophagy-associated effects are closely related to the development of HCC. In this study, we aimed to construct a prognostic model based on autophagy-related genes (ARGs) for the Asian HCC population to provide new ideas for the clinical management of HCC in the Asian population. METHODS: The clinical information and transcriptome data of Asian patients with HCC were downloaded from The Cancer Genome Atlas (TCGA) database, and 206 ARGs were downloaded from the human autophagy database (HADB). We performed differential and Cox regression analyses to construct a risk score model. The accuracy of the model was validated by using the Kaplan-Meier (K-M) survival curve, receiver operating characteristic (ROC) curve, and univariate and multivariate Cox independent prognostic analyses. The results Thirteen ARGs that were significantly associated with prognosis were finally identified by univariate and multivariate Cox regression analyses. The K-M survival curves showed that the survival rate of the low-risk group was significantly higher than that of the high-risk group (p < 0.001), and the multi-indicator ROC curves further demonstrated the predictive ability of the model (AUC = 0.877). CONCLUSION: The risk score model based on ARGs was effective in predicting the prognosis of Asian patients with HCC.

[Immune-Related Pancreatitis Caused by Immune Checkpoint Inhibitor Nivolumab:Report of One Case].

In recent years,great progress has been achieved in the application of immune checkpoint inhibitors (ICI) in tumor immunotherapy.However,a variety of adverse reactions induced by ICI have been reported.Despite the high overall incidence of adverse reactions caused by ICI,some adverse reactions,such as immune-related pancreatitis,are rare in clinical practice.In this paper,a case of immune-related pancreatitis after treatment of advanced gastric cancer with nivolumab was identified.We analyzed the cause,treatment,incidence,and risk factors of the adverse reaction,aiming to improve the clinical diagnosis,treatment,and safe medication of rare adverse reactions associated with ICI.

Biomarker exploration of microRNA-203 as a promising substrate for predicting poor survival outcome in colorectal cancer.

BACKGROUND: Increasing studies indicated that microRNA-203 (miR-203) may play an important part in the prognosis of CRC. Nevertheless, the prognostic and influential mechanism of miR-203 expression in CRC remains to be inconclusive. Accordingly, we conducted the current study to investigate the biomarker performance of miR-203 in CRC. METHODS: In the present study, we conducted an evidence synthesis of the published literatures to identify the prognostic roles of miR-203 in patients with CRC. Moreover, several bioinformatics methods were applied for exploring the biomarker roles of miR-203. RESULTS: It was demonstrated that elevated miR-203 expression was clearly related to worse overall survival (HR: 1.55, 95% CI: 1.07-2.24, P = 0.021) for CRC. The gene Ontology (GO) analysis indicated that miR-203 targets were primarily involved in a series of GO items closely associated with the molecular pathogenesis of CRC. The pathway analysis exhibited the potential signal pathways of miR-203 involved in CRC including pathways in cancer, wnt pathway, prolactin signaling pathway, proteoglycans in cancer, FoxO pathway, focal adhesion and Ras pathway. By constructing a protein-protein interaction (PPI) network of the targets of miR-203, ten crucial proteins and a significant network module were retrieved and found to serve important roles in the molecular pathogenesis of CRC. CONCLUSIONS: Our results indicated that miR-203 may function as a promising biomarker to monitor CRC survival outcomes and progression. Notably, large-scale prospective cohort studies and biological experiments are required to confirm our conclusions.

Integrated analyses of microRNA-29 family and the related combination biomarkers demonstrate their widespread influence on risk, recurrence, metastasis and survival outcome in colorectal cancer.

BACKGROUND: Emerging evidence has revealed miR-29 family as promising biomarkers for colorectal cancer (CRC), but their biomarker potential and molecular mechanisms remain poorly understood. METHODS: We performed a comprehensive meta-analysis to evaluate the biomarker performance of individual miR-29 and the related miRNA combination biomarkers. Meanwhile, we conducted an integrative bioinformatics analysis to unfold the underlying biological function of miR-29 and their relationship with CRC. RESULTS: Using miR-29 expression to diagnose CRC produced 0.82 area under the curve, 70% sensitivity and 81% specificity while the combination biomarkers based on miR-29 enhanced the diagnostic power with an AUC of 0.86, a sensitivity of 78% and a specificity of 91%. For the prognosis evaluation, patients with higher expression of miR-29 had better survival outcome (pooled HR 0.78; 95% CI 0.56-1.07). In addition, miR-29 has also been identified as potential biomarker for predicting recurrence and metastasis in CRC. Then the genes regulated by the miR-29 family were retrieved and found closely associated with the molecular pathogenesis of CRC according to the gene ontology and pathway analysis. Furthermore, hub nodes and significant modules were identified from the protein-protein interaction network constructed with miR-29 family targets, which were also confirmed highly involved in the establishment and development of CRC. CONCLUSIONS: Current evidences suggest miR-29 family may become promising biomarkers for risk, recurrence, metastasis and survival outcome of CRC. Meanwhile our data highlight the potential clinical use of miRNA combination biomarkers. Nevertheless, further prospective studies are warranted before the application of the useful biomarkers in the clinical.

Efficacy and safety of gemcitabine plus raltitrexed or S-1 versus standard third-line therapies in metastatic colorectal cancer: a retrospective cohort study.

Background: After the failure of standard first- and second-line treatments, including oxaliplatin, irinotecan, and 5-fluorouracil (5-FU) combined with targeted drugs, the currently recommended third-line regimens for metastatic colorectal cancer (mCRC) include TAS-102, regorafenib, and fruquintinib. However, these regimens have the drawbacks of mediocre efficacy, substantive side effects, and high cost. Therefore, more effective, economical regimens with fewer side effects are needed in clinical practice. In this study, we assessed the efficacy and safety of gemcitabine plus raltitrexed or S-1 as a third- or later-line treatment in comparison to those of standard third-line therapies for patients with mCRC. Methods: Patients with previous failures of at least two lines of standard therapy with oxaliplatin, 5-FU, irinotecan, or capecitabine combined with targeted drugs were included. The participants received standard third-line therapies (including TAS-102, regorafenib, and fruquintinib) or gemcitabine plus raltitrexed or S-1 until disease progression, death, or intolerable toxicity arose. Imaging follow-up was performed every 3 months during their treatment. Progression-free survival (PFS) and overall survival (OS) were recorded. Cox regression analysis was used to investigate the potential predictors of survival. Results: From April 2018 to October 2022, 60 patients with mCRC were enrolled in our study. The numbers of patients in the chemotherapy, fruquintinib, regorafenib, and TAS-102 groups were 13, 15, 17, and 15, respectively; the median OS of the four groups was 7.4, 6.1, 8.3, and 6.7 months (P=0.384), respectively; the median PFS was 4.1, 3.4, 4.4, and 2.3 months (P=0.656), respectively; the overall response rate was 7.69%, 6.67%, 0.00%, and 13.33%, respectively; and the disease control rate was 61.54%, 60.00%, 70.59%, and 60.00%, respectively. Additionally, multivariate analysis revealed that primary lesion located in the rectum was adverse independent prognostic factors for OS. A typical case is presented in this article. Conclusions: The gemcitabine plus raltitrexed or S-1 regimen is a potential regimen with tolerable adverse reactions and low cost for patients with mCRC.

Molecular, biological characterization and drug sensitivity of chidamide-resistant MCF7 cells.

Background: Chidamide (CHI) is a subtype-selective histone deacetylase inhibitor (HDACI) developed in China and approved as a second-line treatment combined with the aromatase inhibitor for hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer. However, drug resistance is commonly occurred after a long period of medication. This study aimed to investigate the characterization of induced resistance to CHI and explore the potential cross-resistance to chemotherapeutic agents. Methods: CHI with gradually increasing concentrations was added to breast cancer MCF7 cells to establish a CHI-resistant MCF7 (MCF7-CHI-R) cell line. Cell counting kit-8 (CCK-8) assays were performed to detect half-maximal inhibitory concentration (IC50) of CHI. Colony formation was used to determine the proliferation inhibition rate. Western blot analysis was conducted to detect expressions of protein related with cell cycle, apoptosis, ferroptosis, and histone deacetylase (HDAC). Flow cytometry was used to analyze apoptosis and cell cycle. Results: The IC50 value of CHI of MCF7-CHI-R cells was increased in comparison with MCF7 cells. And CHI led to cell cycle arrest and ferroptosis, which were not exhibited in MCF7-CHI-R cells. Moreover, HDAC activity decreased in MCF7-CHI-R cells in comparison with MCF7 cells, and HDAC1 and HDAC10 might be involved in the resistance to CHI. In addition, MCF7-CHI-R cells were resistant to gemcitabine (GEM), doxorubicin (ADM), docetaxel (DXT), albumin-bound paclitaxel (nab-PTX) and paclitaxel (PTX). Conclusions: The MCF7-CHI-R was established and the anti-ferroptosis pathway activation was involved in the resistance of MCF-CHI-R cells. Also, MCF7-CHI-R cells were resistant to GEM, ADM, DXT, nab-PTX and PTX.

Establishment and verification of a prognostic risk score model based on immune genes for hepatocellular carcinoma in an Asian population.

Background: Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide, with the highest incidence in East Asia, and hepatitis B virus (HBV) infection is the most common cause of HCC in Asian population. The immune system is closely related to the development of HCC and plays an important role in the treatment of this disease. In this study, we analyzed the data of HCC from The Cancer Genome Atlas (TCGA) database and constructed a risk-score prognostic model based on immune genes of an Asian HCC population, aiming to provide new perspectives for clinical treatment and management of HCC in Asian population. Methods: Data concerning clinical attributes and transcriptomic profiles of individuals in the Asian population diagnosed with HCC were retrieved from the TCGA database. Concurrently, immune-related genes were sourced from the Immport database for incorporation into our analysis. A total of 265 immune-related genes displaying differential expression were identified through wilcoxTest analysis in R. Further refinement using univariate and multivariate Cox regression analysis led to the identification of 15 genes that exhibited strong associations with prognosis. MICB/PSMD14/TRAF3/SP1/NDRG1/HDAC1/HRAS/NRAS/SEMA5B/GMFB/ACVR2B/BRD8/MMP12/KITLG/DCK, and a prognostic risk score model was constructed based on the above genes. Results: The findings demonstrated notable differences in survival rates between the low-risk and high-risk groups, as depicted by the Kaplan-Meier (K-M) survival curves (P<0.001). Furthermore, the model's predictive capability was evidenced by receiver operating characteristic (ROC) curves, with area under the curve (AUC) =0.901. Finally, the relationship of the model with each clinical trait and immune cells was assessed by correlation analysis. Conclusions: The prognostic risk score model constructed by immune genes based on the Asian HCC population has certain predictive capacity.

Multifaceted Roles of Retromer in EGFR Trafficking and Signaling Activation.

Mammalian retromer complex contributes to multiple early endosome-associated trafficking pathways whose origins are dependent on which sorting nexin (SNX) they are complexed with. In an attempt to dissect out the contribution of individual retromer-SNX complexes, we examined the trafficking of EGFR in detail within a series of KO cell line models. We demonstrated that the depletion of retromer subunit Vps35 leads to decreased EGFR protein levels in resting cells with enhanced association of EGFR with lysosomal compartments. Compared to control cells, the addition of EGF to Vps35 KO cells resulted in a reduced rate of EGFR degradation; AKT activation and cell prolferation rates were elevated, while ERK activation remained relatively unchanged. These observations are consistent with a prolonged temporal association of EGFR within early endosomes due to the inefficiency of early endosome-associated protein trafficking pathways or organelle maturation due to retromer absence. We did not fully delineate the discrete contributions from retromer-associated SNXs to the phenotypes observed from retromer Vps35 depletion. While each of the knock-outs of SNX1/2, SNX3, or SNX27 promotes the enhanced association of EGFR with early endosomal compartments, only the decreased EGF-mediated EGFR degradation was observed in SNX1/2 dKO cells, while the enhanced AKT activation was only increased in SNX3 KO or SNX27 KO cells. Despite this, each of the knock-outs showed increased EGF-stimulated cell proliferation rates.

The clinical implications of circulating microRNAs as potential biomarkers in screening oral squamous cell carcinoma.

Background: Recent studies have highlighted the biomarker role of circulating miRNAs in oral squamous cell carcinoma (OSCC), indicating their potential application as early diagnostic markers for OSCC. However, the diagnostic results have proven inconclusive. This study was conducted to evaluate the diagnostic value of circulating miRNAs for OSCC diagnosis. Methods: Eligible published studies were identified by a literature search carried out in several databases by using combinations of keywords associated with OSCC, circulating miRNAs, and diagnosis. The bivariate meta-analysis model was adopted to summarize the pooled parameters. Afterwards, we thoroughly explored the sources of heterogeneity after evaluating the risk of bias. Results: A total of 60 studies focusing on 41 circulating miRNAs were included. The pooled sensitivity, specificity, and AUC were 0.75 (95%CI: 0.69-0.80), 0.76 (0.70-0.81), 0.82 (0.79-0.85), respectively. Subgroup analyses showed that miRNA combinations were more accurate than single miRNAs. Additionally, plasma may be a better matrix for miRNAs assays in OSCC diagnosis as the plasma-based miRNA assay had a higher level of diagnostic accuracy than serum-based miRNA assay. Subgroup analyses also suggested that using circulating miRNAs for OSCC diagnosis is more effective in Caucasians than in Asian ethnic groups. Finally, circulating miRNA assays based on large sample sizes have superior diagnostic accuracy than small sample sizes. Conclusion: Circulating miRNAs might be applied as effective surrogate biomarkers for early diagnosis of OSCC. Nevertheless, future larger-scale prospective studies should be performed to enhance the diagnostic efficiency and investigate the miRNA combinations with more pronounced accuracy.

Development of dynamical network biomarkers for regulation in Epstein-Barr virus positive peripheral T cell lymphoma unspecified type.

Background: This study was performed to identify key regulatory network biomarkers including transcription factors (TFs), miRNAs and lncRNAs that may affect the oncogenesis of EBV positive PTCL-U. Methods: GSE34143 dataset was downloaded and analyzed to identify differentially expressed genes (DEGs) between EBV positive PTCL-U and normal samples. Gene ontology and pathway enrichment analyses were performed to illustrate the potential function of the DEGs. Then, key regulators including TFs, miRNAs and lncRNAs involved in EBV positive PTCL-U were identified by constructing TF-mRNA, lncRNA-miRNA-mRNA, and EBV encoded miRNA-mRNA regulatory networks. Results: A total of 96 DEGs were identified between EBV positive PTCL-U and normal tissues, which were related to immune responses, B cell receptor signaling pathway, chemokine activity. Pathway analysis indicated that the DEGs were mainly enriched in cytokine-cytokine receptor interaction and chemokine signaling pathway. Based on the TF network, hub TFs were identified regulate the target DEGs. Afterwards, a ceRNA network was constructed, in which miR-181(a/b/c/d) and lncRNA LINC01744 were found. According to the EBV-related miRNA regulatory network, CXCL10 and CXCL11 were found to be regulated by EBV-miR-BART1-3p and EBV-miR-BHRF1-3, respectively. By integrating the three networks, some key regulators were found and may serve as potential network biomarkers in the regulation of EBV positive PTCL-U. Conclusion: The network-based approach of the present study identified potential biomarkers including transcription factors, miRNAs, lncRNAs and EBV-related miRNAs involved in EBV positive PTCL-U, assisting us in understanding the molecular mechanisms that underlie the carcinogenesis and progression of EBV positive PTCL-U.

Identification of microRNA-181 as a promising biomarker for predicting the poor survival in colorectal cancer.

BACKGROUND: A series of studies have investigated the vital role of microRNA-181 (miR-181) in the initiation and development of colorectal cancer (CRC), and demonstrated that it might be associated with the prognosis of CRC. However, inconsistent findings have hindered its clinical application. METHODS: A comprehensive meta-analysis and an integrative bioinformatics analysis were carried out for concluding current available evidence, clarifying the preliminary prognostic value and unfolding the underlying biological function of miR-181 in CRC patients. RESULTS: The findings revealed that elevated expression levels of miR-181 were associated with significantly poorer overall survival rates (HR = 1.75, 95% CI: 1.26-2.43, P < .05). Meanwhile, the target genes of miR-181 were identified and enriched into several important gene ontology (GO) categories and signaling pathways including miRNAs in cancer, pathways in cancer, proteoglycans in cancer, colorectal cancer, FoxO signaling pathway, PI3K-Akt signaling pathway, VEGF signaling pathway, HIF-1 signaling pathway, mTOR signaling pathway, and cAMP signaling pathway, which were confirmed highly involved in the initiation and progression of CRC. In addition, the protein-protein interaction (PPI) networks were set up by miR-181 targets to screen hub nodes and significant modules, which were also considerably associated with the molecular pathogenesis of CRC. CONCLUSIONS: The present study demonstrated that miR-181 could be a promising biomarker with predictive value for prognosis for CRC patients. However, future studies comprising large cohorts from multicenter are warranted to further investigate the biomarker value of miR-181.

Identification of biomarker microRNA-mRNA regulatory pairs for predicting the docetaxel resistance in prostate cancer.

Background: Docetaxel resistance is a cursing problem with adverse effects on the therapeutic efficacy of prostate cancer (PCa), involving interactions among multiple molecular components. Single or limited molecules are not strong enough as prediction biomarkers of drug resistance. Network biomarkers are considered to outperform individual markers in disease characterization. Methods: In this study, key microRNAs (miRNAs) as biomarkers were identified from the PubMed citations and miRNA expression profiles. Targets of miRNAs were predicted and enriched by biological function analysis. Key target mRNAs of the biomarker miRNAs were screened from protein-protein interaction network and gene expression profiles, respectively. The results were validated by the assessment of their predictive power and system biological analysis. Results: With this approach, we identified 13 miRNAs and 31 target mRNAs with 66 interactions in the constructed network. Integrative functional enrichment analysis and literature exploration further confirmed that the network biomarkers were highly associated with the development of docetaxel resistance. Conclusions: The findings from our results demonstrated that the identified network biomarkers provide a useful tool for predicting the docetaxel resistance and may be helpful for serving as prediction biomarkers and therapeutic targets. However, it is necessary to conduct biological experiments for further investigating their roles in the development of docetaxel resistance.