Molecular subtypes based on cuproptosis-related genes and tumor microenvironment infiltration characteristics in pancreatic adenocarcinoma.

BACKGROUND: Multiple molecular subtypes with distinct clinical outcomes in pancreatic adenocarcinoma (PAAD) have been identified in recent years. Cuproptosis is a new form of cell death that likely involved in tumor progression. However, the cuproptosis-related molecular subtypes as well as its mediated tumor microenvironment (TME) cell infiltration characteristics largely remain unclear. METHODS: Expression profiles of 10 cuproptosis-related genes (CRGs) and their association with patient survival, TME, cancer stemness and drug resistance were studied in 33 cancer types using the TCGA pan-cancer data. Using 437 PAAD samples from five cohorts (TCGA-PAAD cohort and four GEO cohorts), we explored the molecular subtypes mediated by CRGs, along with the associated TME cell infiltration. Unsupervised methods were utilized to perform cuproptosis subtype clustering. The cuproptosis score was constructed using the COX regression model with least absolute shrinkage and selection operator regression (LASSO) algorithm to quantify the cuproptosis characteristics of a single tumor. RESULTS: The expression of 10 CRGs varies in different cancer types with striking inter- and intra- cancer heterogeneity. We integrated the genomic profiling of the CRGs and identified three distinct cuproptosis subtypes, and found that multi-layer CRG alterations were correlated with patient prognosis and TME cell infiltration characteristics. In addition, a cuproptosis score signature was constructed to predict prognosis, and its clinical impacts were characterized in the TCGA-PAAD cohort. The cuproptosis signature was significantly associated with prognosis, tumor subtypes, CD8 T-cell infiltration, response to immune checkpoint inhibitors (ICIs) and chemotherapeutic drug sensitivity. Furthermore, the expression patterns of CRGs in pancreatic cancer cells and normal controls were validated, which was almost consistent with the results from the public database. The expression level and prognostic predictive capability of DLAT were verified in 97 PAAD patients from our patient cohort. CONCLUSIONS: These findings may help understand the roles of CRGs in PAAD and the molecular characterization of cuproptosis subtypes. In addition, the cuproptosis score could serve as a promising biomarker for predicting prognosis and response to immunotherapy in PAAD patients.

Increased expression of miR-194-5p through the circPVRL3/miR-194-5p/SOCS2 axis promotes proliferation and metastasis in pancreatic ductal adenocarcinoma by activating the PI3K/AKT signaling pathway.

BACKGROUND: MicroRNAs (miRNAs), as an indispensable type of non-coding RNA (ncRNA), participate in diverse biological processes. However, the specific regulatory mechanism of certain miRNAs in pancreatic ductal adenocarcinoma (PDAC) remains unclear. METHODS: The expression of miR-194-5p in PDAC tissue microarray and cell lines were detected by RNA-scope and real-time quantitative PCR (RT-qPCR). The function of proliferation and migration carried by miR-194-5p in vitro and vivo was observed by several functional experiments. Informatics methods and RNA sequencing data were applied to explore the target of miR-194-5p and the upstream circular RNA (circRNA) of miR-194-5p. RNA-binding protein immunoprecipitation (RIP) assay and dual-luciferase reporter assay confirmed the relationships between miR-194-5p and SOCS2 or miR-194-5p and circPVRL3. The proliferation and migration abilities of SOCS2 and circPVRL3 were accessed by rescue experiments. RESULTS: In this study, we aimed to clarify the molecular mechanisms of miR-194-5p, which has critical roles during PDAC progression. We found that the expression of miR-194-5p was significantly upregulated in PDAC tissue compared to tumor-adjacent tissue and was highly related to age and nerve invasion according to RNAscope and RT‒qPCR. Overexpression of miR-194-5p accelerated the cell cycle and enhanced the proliferation and migration processes according to several functional experiments in vitro and in vivo. Specifically, circPVRL3, miR-194-5p, and SOCS2 were confirmed to work as competing endogenous RNAs (ceRNAs) according to informatics methods, RIP, and dual-luciferase reporter assays. Additionally, the rescue experiments confirmed the relationship among miR-194-5p, circPVRL3, and SOCS2 mRNA. Finally, the circPVRL3/miR-194-5p/SOCS2 axis activates the PI3K/AKT signaling pathway to regulate the proliferation and metastasis of PDAC. CONCLUSION: Our findings indicated that an increase of miR-194-5p caused by circPVRL3 downregulation stimulates the PI3K/AKT signaling pathway to promote PDAC progression via the circPVRL3/miR-194-5p/SOCS2 axis, which suggests that the circPVRL3/miR-194-5p/SOCS2 axis may be a potential therapeutic target for PDAC patients.

Identifying potential biomarkers in hepatitis B virus infection and its response to the antiviral therapy by integrated bioinformatic analysis.

The antiviral treatment efficacy varies among chronic hepatitis B (CHB) patients and the underlying mechanism is unclear. An integrated bioinformatics analysis was performed to investigate the host factors that affect the therapeutic responsiveness in CHB patients. Four GEO data sets (GSE54747, GSE27555, GSE66698 and GSE66699) were downloaded from the Gene Expression Omnibus (GEO) database and analysed to identify differentially expressed genes(DEGs). Enrichment analyses of the DEGs were conducted using the DAVID database. Immune cell infiltration characteristics were analysed by CIBERSORT. Upstream miRNAs and lncRNAs of hub DEGs were identified by miRWalk 3.0 and miRNet in combination with the MNDR platform. As a result, seventy-seven overlapping DEGs and 15 hub genes were identified including CCL5, CXCL9, MYH2, CXCR4, CD74, CCL4, HLA-DRB1, ACTA1, CD69, CXCL10, HLA-DRB5, HLA-DQB1, CXCL13, STAT1 and CKM. The enrichment analyses revealed that the DEGs were mainly enriched in immune response and chemokine signalling pathways. Investigation of immune cell infiltration in liver samples suggested significantly different infiltration between responders and non-responders, mainly characterized by higher proportions of CD8+ T cells and activated NK cells in non-responders. The prediction of upstream miRNAs and lncRNAs led to the identification of a potential mRNA-miRNA-lncRNA regulatory network composed of 2 lncRNAs (H19 and GAS5) and 5 miRNAs (hsa-mir-106b-5p, hsa-mir-17-5p, hsa-mir-20a-5p, hsa-mir-6720-5p and hsa-mir-93-5p) targeting CCL5 mRNA. In conclusion, our study suggested that host genetic factors could affect therapeutic responsiveness in CHB patients. The antiviral process might be associated with the chemokine-mediated immune response and immune cell infiltration in the liver microenvironment.

Increased PRIM2 expression associated with poor-prognosis in patients with pancreatic ductal adenocarcinoma.

OBJECTIVES: To explore the association between PRIM2 expression and prognosis of patients with pancreatic ductal adenocarcinoma (PDAC) from multi clinic centers. METHODS: Samples from PDAC patients were collected and processed to tissue microarray (TMA). PRIM2 expression was detected by immunohistochemistry (IHC) of in 127 enrolled PDAC patients, which underwent surgical resection from January 2012 to December 2018, with complete follow-up, were enrolled and grouped by PRIM2 stain level into two groups. The expression differences, the association to clinicopathologic features and the survival were evaluated by the groups. Data of RNA/protein expression and clinical features from public databases were used for validation. RESULTS: PRIM2 was highly expressed in PDAC patients and associated with poor-prognosis in patients with PDAC. Association was found between increased PRIM2 levels and pathology grade (p = 0.050). Moreover, in multivariate analysis of survival, the highly expression of PRIM2 was identified as an independent risk factor for poor survival (HR1.78, p = 0.031). Analysis on public databases validated above results. CONCLUSIONS: High expression of PRIM2 associated with poor prognosis in PDAC patients, PRIM2 could be used as an independent risk indicator.

Corrigendum: The m6A methyltransferase METTL16 inhibits the proliferation of pancreatic adenocarcinoma cancer cells via the p21 signaling pathway.

[This corrects the article DOI: 10.3389/fonc.2023.1138238.].

The m6A methyltransferase METTL16 inhibits the proliferation of pancreatic adenocarcinoma cancer cells via the p21 signaling pathway.

Background: Many studies have reported that N6-methyladenosine (m6A) modification plays a critical role in the epigenetic regulation of organisms and especially in the pathogenesis of malignant diseases. However, m6A research has mainly focused on methyltransferase activity mediated by METTL3, and few studies have focused on METTL16. The aim of this study was to investigate the mechanism of METTL16, which mediates m6A modification, and its role in pancreatic adenocarcinoma (PDAC) cell proliferation. Methods: Clinicopathologic and survival data were retrospectively collected from 175 PDAC patients from multiple clinical centers to detect the expression of METTL16. CCK-8, cell cycle, EdU and xenograft mouse model experiments were used to evaluate the proliferation effect of METTL16. Potential downstream pathways and mechanisms were explored via RNA sequencing, m6A sequencing, and bioinformatic analyses. Regulatory mechanisms were studied through methyltransferase inhibition, RIP, MeRIP‒qPCR assays. Results: We found that METTL16 expression was markedly downregulated in PDAC, and multivariate Cox regression analyses revealed that METTL16 was a protective factor for PDAC patients. We also demonstrated that METTL16 overexpression inhibited PDAC cell proliferation. Furthermore, we identified a METTL16-p21 signaling axis, with downregulation of METTL16 resulting in inhibition of CDKN1A (p21). Additionally, METTL16 silencing and overexpression experiments highlighted m6A modification alterations in PDAC. Conclusions: METTL16 plays a tumor-suppressive role and suppresses PDAC cell proliferation through the p21 pathway by mediating m6A modification. METTL16 may be a novel marker of PDAC carcinogenesis and target for the treatment of PDAC.

Efficacy and Safety of Pegylated Interferon for the Treatment of Chronic Hepatitis B in Children and Adolescents: A Systematic Review and Meta-analysis.

BACKGROUND: Pegylated interferon (PEG-IFN) has recently been approved for the treatment of chronic hepatitis B in children and adolescents. However, the exact efficacy and safety remains to be confirmed. OBJECTIVES: A systematic review and meta-analysis was performed to assess the efficacy and safety of PEG-IFN for the treatment of chronic hepatitis B in children and adolescents. METHODS: Databases including MEDLINE/PubMed, Ovid-EMbase, the Cochrane Library and China National Knowledge Internet were searched to collect clinical trials examining the efficacy and safety of PEG-IFN in children and adolescents with confirmed hepatitis B virus infection. Data for treatment response, relapse, treatment discontinuations and adverse events were extracted and summarized. RESULTS: A total of 10 clinical trials involving 658 patients were identified. Results indicate that 43% (95% confidence interval [CI]: 25%-61%) of the subjects treated with PEG-IFN achieved HBeAg serologic response, 18% (95% CI: 6%-35%) achieved HBsAg serologic response, 68% (95% CI: 55%-79%) achieved virologic response after the end of treatment and 60% (95% CI: 30%-87%) achieved sustained virologic response. CONCLUSION: Current evidence indicates that PEG-IFN is effective in children and adolescents with hepatitis B virus and that treatment discontinuation due to serious adverse events is infrequent.

Repetitive Transcranial Magnetic Stimulation on Motor Recovery for Patients With Stroke: A PRISMA Compliant Systematic Review and Meta-analysis.

OBJECTIVE: A systematic review and meta-analysis were conducted to determine the efficacy of repetitive transcranial magnetic stimulation in recovering motor function in patients with stroke. DESIGN: A comprehensive literature search was performed to identify studies published before September 20, 2018. Electronic databases were searched. Standard mean differences and 95% confidence intervals were used to evaluate the effects of repetitive transcranial magnetic stimulation. The stability and sensitivity of the results and sources of heterogeneity were also analyzed. The Cochrane Risk of Bias Tool was used to determine the quality of the studies. RESULT: Twenty randomized controlled trials (N = 841 patients) were included. The results showed that repetitive transcranial magnetic stimulation is beneficial to patients with poststroke hemiplegia, as demonstrated by the following four scales: the Fugl-Meyer Assessment (standard mean difference = 0.635, 95% confidence interval = 0.421 to 0.848); grip strength (standard mean difference = 1.147, 95% confidence interval = 0.761 to 1.534); Barthel Index (Standard mean difference = 0.580, 95% confidence interval = 0.377 to 0.783); and National Institutes of Health Stroke Scale (standard mean difference = -0.555, 95% confidence interval = -0.813 to -0.298). Few adverse events were observed. CONCLUSIONS: The analysis showed that low-frequency repetitive transcranial magnetic stimulation has a positive effect on grip strength and lower limb function as assessed by FMA.

Pleomorphic rhabdomyosarcoma of the liver with a hepatic cyst in an adult: Case report and literature review.

RATIONALE: Rhabdomyosarcoma (RMS), a malignant tumor with striated muscle differentiation, is the most common type of soft-tissue sarcoma in children and adolescents, but rarely occurs in adults, and especially in human livers. Moreover, this disease has a very poor prognosis. Here we report a case of primary RMS of the liver in a 66-year-old woman. This case is rare with respect to the location and clinical course of the tumor. The tumor had enlarged rapidly, ruptured, and eventually caused the patient's death after a long history of a stable abdominal mass that indicated a hepatic cyst. PATIENT CONCERNS: Before admission, a patient with a 5-year history of an abdominal mass was admitted to another hospital with symptoms of aggravated epigastric pain for the past 10 days. She was diagnosed with a hepatic cyst that had ruptured and hemorrhaged and was infected. This initial diagnosis was based on operative and pathologic findings. DIAGNOSES: Pleomorphic RMS of the liver with a hepatic cyst was diagnosed and confirmed by imaging, surgery, and histopathological evaluation. INTERVENTIONS: Following admission, an emergency laparotomy was performed to treat the intra-abdominal hemorrhaging while further examinations were performed. Post-surgical histopathological evaluation found pleomorphic RMS tissue in the large mass that occupied the right lobe of the liver. No adjuvant chemotherapy was administered. OUTCOMES: The patient died from malnutrition and multiple organ failure 141 days after her initial admission. LESSONS: Rhabdomyosarcomas in the liver are highly malignant tumors; therefore, early diagnosis and timely surgical resection are necessary to improve a patient's prognosis. We recommend that greater attention should be paid to a differential diagnosis of RMS for patients with hepatic masses that have ruptured. Moreover, preoperative imaging studies and percutaneous biopsy would be helpful for making a more specific diagnosis, and adjuvant chemotherapy should be administered for further treatment and for the purposes of future research.