ELOVLs Predict Distinct Prognosis Value and Immunotherapy Efficacy In Patients With Hepatocellular Carcinoma.

Background: Hepatocellular carcinoma (HCC) is a primary malignancy of the liver with high prevalence worldwide and poor prognosis. It has been verified that elongation of very-long-chain fatty acids gene family (ELOVLs), a group of genes that responsible for elongation of saturated and polyunsaturated fatty acids, participate in the pathogenesis and development of multiplex disease including cancers. However, the functions and prognosis of ELOVLs in HCC are still indistinguishable. Methods: First, we searched the mRNA expression and survival data of ELOVLs in patients with HCC via the data of The Cancer Genome Atlas (TCGA). The prognosis value of ELOVLs on HCC was assessed by Kaplan-Meier plotter and Cox regression analysis. reverse transcription quantitative- polymerase chain reaction (RT-qPCR), Western blot (WB), and immunohistochemistry were applied to assess the specific mRNA and protein expression of ELOVLs in HCC clinical specimens of our cohort. Then, the functional enrichment of ELOVL1 especially the pathways relating to the immune was conducted utilizing the Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and gene set enrichment analysis (GSEA) analysis. Additionally, TIMER, CIBERSOR, and tumor immune dysfunction and exclusion (TIDE) were employed to evaluate the relationship between ELOVL1 and immune responses. Last, the correlation of ELOVL1 with genome heterogeneity [microsatellite instability (MSI), tumor mutational burden (TMB), mutant-allele tumor heterogeneity (MATH), homologous recombination deficiency (HRD), purity, ploidy, loss of heterozygosity (LOH), and neoantigens] and mutational landscape were also evaluated basing on the date in TCGA. Results: Significant expression alteration was observed in ELOVLs family at the pan-cancer level. In liver cancer, ELOVL1 and ELOVL3 were strongly associated with poor prognosis of HCC by survival analysis and differential expression analysis. Immunohistochemistry microarray, WB, and RT-qPCR confirmed that ELOVL1 but not ELOVL3 played an important role in HCC. Mechanistically, functional network analysis revealed that ELOVL1 might be involved in the immune response. ELOVL1 could affect immune cell infiltration and immune checkpoint markers such as PD-1 and CTLA4 in HCC. Meanwhile, high expression of ELOVL1 would be insensitive to immunotherapy. Correlation analysis of immunotherapy markers showed that ELOVL1 has been associated with MSI, TMB, and oncogene mutations such as TP53. Conclusion: ELOVLs play distinct prognostic value in HCC. ELOVL1 could predict the poor prognosis and might be a potential indicator of immunotherapy efficacy in HCC patients.

Identification and validation of immune related core transcription factors GTF2I in NAFLD.

Background: Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide that endangers human health. Transcription factors (TFs) have gradually become hot spots for drug development in NAFLD for their impacts on metabolism. However, the specific TFs that regulate immune response in the development of NAFLD is not clear. This study aimed to investigate the TFs involved in the immune response of NAFLD and provide novel targets for drug development. Methods: Microarray data were obtained from liver samples from 26 normal volunteers and 109 NAFLD patients using the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were analyzed by limma package. Differentially expressed transcription factors (DETFs) were obtained on DEGs combined with Cistrome Cancer database. Immune signatures and pathways hallmark were identified by ssGSSEA and GSVA. The co-regulation network was constructed by the above results. Further, quantitative Real-time Polymerase Chain Reaction (qRT-PCR), Western blot (WB) and Immunohistochemistry (IHC) were used to validate the relationship between GTF2I and NAFLD. CIBERSORT analysis was performed to identify cell types to explore the relationship between differential expression of GTF2I and immune cell surface markers. Results: A total of 617 DEGs and six DETFs (ESR1, CHD2, GTF2I, EGR1, HCFC1, SP2) were obtained by differential analysis. Immune signatures and pathway hallmarks were identified by ssGSSEA and GSVA. GTF2I and CHD2 were screened through the co-regulatory networks of DEGs, DETFs, immune signatures and pathway hallmarks. Furthermore, qRT-PCR, WB and IHC indicated that GTF2I but not CHD2 was significantly upregulated in NAFLD. Finally, in silico, our data confirmed that GTF2I has a wide impact on the immune profile by negatively regulating the expression of the chemokine receptor family (227/261, count of significance). Conclusion: GTF2I plays a role in NAFLD by negatively regulating the chemokine receptor family, which affects the immune profile. This study may provide a potential target for the diagnosis or therapy of NAFLD.

A clinical and laboratory-based nomogram for predicting nonalcoholic fatty liver disease in non-diabetic adults: a cross-sectional study.

BACKGROUND: Although the close relationship between nonalcoholic fatty liver disease (NAFLD) and insulin resistance has been clarified and there is a five-fold higher prevalence of NAFLD in patients with diabetes compared to that in patients without diabetes, this is not a reason to focus only on the incidence of NAFLD in people with diabetes because people who are insulin resistant are not necessarily diagnosed with diabetes, which leads to the overlook of NAFLD in non-diabetic population. Actually, we are obligated to pay more attention to the non-diabetic population for early detection and intervention of NAFLD. There is a lack of a convenient tool for predicting NAFLD in non-diabetic adults, and thus we aim to develop and validate a novel clinical nomogram to predict NAFLD among non-diabetic population to save more medical resources and make less missed diagnosis. METHODS: Researchers initially enrolled 20,944 patients and excluded those with history of drinking, known medication usage, viral hepatitis, known liver disease, missing covariant data, age <18 years, and impaired fasting blood glucose, leaving 14,251 adults participating in the baseline analysis, who were randomly divided in a ratio of 3:1 into a training dataset with 10,689 participants and a validation dataset with 3,562 participants, using the classification and regression training (caret) package in R software v. 4.0.3. Variables for prediction were selected by multivariable logistic regression analysis, the LASSO method, and clinical experience. Based on these, we constructed a prediction model. Performance of this model was validated by the area under the receiver operator characteristic curve, calibration curve, and decision curve analysis. RESULTS: We used 6 variables to construct the prediction model: body mass index (BMI), aspartate aminotransferase (AST), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), hemoglobin A1c (HbA1c), and diastolic blood pressure (DBP). In the training and validation datasets, the AUROC value of this prediction was 0.891 [95% confidence interval (CI): 0.884 to 0.899] and 0.902 (95% CI: 0.890 to 0.914), respectively. The calibration plots and the decision curve analysis (DCA) demonstrated that the accuracy of this model was good, with high clinical practicability. CONCLUSIONS: The nomogram could screen non-diabetic adults for NAFLD and may aid clinical decision-making.

The adiposity indicators in relation to diabetes among adults in China: a cross-sectional study from China Health and Nutrition Survey.

BACKGROUND: Diabetes is a metabolic disease which has been confirmed to be involved with abnormal or excessive body fat accumulation. There is still a lack of nationwide research in China to discuss the relationship between adiposity indicators included body mass index (BMI), waist circumference (WC), visceral adiposity index, waist-height ratio, waist-to-hip ratio (WHR) and diabetes. The question of which one is the best indicator of obesity to predict diabetes in China remains to be unclear. METHODS: Data were collected from the China Health and Nutrition Survey (CHNS) in 2009, including 7,930 participants aged over 18 years old for cross-sectional analysis. Information about height, weight, WC, hip circumference, smoking status, alcohol consumption, physical activity, energy intake and blood samples were analyzed. Binary logistic regression models were used to explore the association of WC, BMI, WHR, waist-to-height ration (WHtR) and visceral adipose index (VAI) with the prevalence of diabetes in the 2009 CHNS respectively. Predictive potential of five adiposity indicators was validated by the area under the receiver operator characteristic curve (AUROC). The optimal cut-off points were determined by Youden's index, which was used to estimate the performance of adiposity indicators. RESULTS: The study shows patients in the highest quartile were more likely to have diabetes than those in the lowest quartile of WC (OR: 4.237, 95% CI: 3.265-5.499), BMI (OR: 3.312, 95% CI: 2.601-4.218), WHR (OR: 3.199, 95% CI: 2.493-4.104), WHtR (OR: 3.760, 95% CI: 2.891-4.890), VAI (OR: 4.347, 95% CI: 3.411-5.541). The area under the receiver operator characteristic curve of WC, BMI, WHR, WHtR and VAI for diabetes was 0.700, 0.663, 0.668, and 0.697 and 0.694, respectively. The optimal cut-offs regarding diabetes in Chinese are WHtR ≥0.520 for men and VAI ≥1.878 for women. CONCLUSIONS: Our findings indicate that WC, WHtR, BMI, WHR and VAI are all independent risk factors for diabetes among Chinese adults. WHtR is the most accurate indicator for diabetes in men, while VAI for women.

Effects of tumor origins and therapeutic options on the prognosis of hepatic neuroendocrine tumors: A retrospective study.

ABSTRACT: Hepatic neuroendocrine tumors (HNETs) are uncommon neoplasms that can be subdivided into 2 types: primary and metastatic HNETs. Due to its rarity, heterogeneity and complexity, the diagnosis, treatment modalities and prognosis are still controversial.This retrospective study reviewed the effects of tumor origins and therapeutic options on the prognosis of gastroenteropancreatic neuroendocrine tumors with liver metastasis (GEP-NETLM) and primary hepatic neuroendocrine tumors (PHNETs), providing additional evidence for clinicians evaluating patients.HNETs consisted of PHNETs and GEP-NETLM. GEP-NETLM (76.2%, 112/147) was more common, which was mainly manifested as multiple lesions in both lobes of the liver. PHNETs were relatively rare (23.8%, 35/147) and were mainly single lesion located in the right lobe of the liver. In patients with GEP-NETLM, primary tumor resection could prolong survival (P = .044). As the most widely used treatment method, systematic therapy alone could not achieve a satisfactory survival. However, the combination with hepatectomy or liver-directed therapy improved the prognosis (P = .023). As the main treatment, patients with PHNETs treated with local therapy could achieve a better prognosis (P = .049). Compared with PHNETs patients, GEP-NETLM patients with higher ki-67 index showed higher mortality and poorer prognosis (P = .006).Therefore, patients with PHNETs can be distinguished from GEP-NETLM by comprehensive imaging examinations and long-term follow-ups. The choice of appropriate treatment strategies can improve the prognosis of HNETs patients.

Effects of tumor types on treatment strategy formulation and prognostic evaluation of gastric neuroendocrine tumors.

Aim: The effects of different types of gastric neuroendocrine tumors (G-NETs) on treatment strategy formulation and prognostic evaluation still remain controversial due to their rarity. Methods: 187 patients diagnosed with G-NETs were subdivided into four types based on the pathophysiology, etiology and presentation. Results: Type I, II G-NETs >1.0 cm and type III, IV G-NETs >2.0 cm are proved with aggressive behavior (p < 0.05). Type III G-NETs with higher Ki-67 index and tumor stage showed more invasive potential than type I and II G-NETs (p < 0.05). Endoscopic resection is the primary treatment for type I, II G-NETs, while surgical combined with chemotherapy is associated with favorable outcomes for type IV G-NETs. Conclusion: The clinical classifications of G-NETs are of great significance for the choice of treatment and the evaluation of prognosis.

MicroRNA-628-5p inhibits invasion and migration of human pancreatic ductal adenocarcinoma via suppression of the AKT/NF-kappa B pathway.

The biological function and underlying mechanism of microRNA-628-5p (miR-628-5p) remains to be clarified in the growth and progression of pancreatic ductal adenocarcinoma (PDAC). Here, the expression levels of miR-628-5p in PDAC tissues and cells were detected by quantitative reverse transcriptase polymerase chain reaction and in situ hybridization. The relationship between miR-628-5p expression and clinicopathologic characteristics was examined in human PDAC tissue samples. Gain- and loss-of-function and the putative targets of miR-628-5p were evaluated in PDAC cell lines. The upstream and downstream signals of miR-628-5p in PDAC were also examined. MiR-628-5p was lowly expressed in PDAC tissues and cell lines, and low miR-628-5p expression in PDAC tissues was associated with poor clinicopathological characteristics and shorter overall survival. Functionally, restoration of miR-628-5p expression decreased PDAC cell proliferation, migration, invasion, and promoted cell apoptosis, whereas miR-628-5p silencing abolished these biological behaviors. MiR-628-5p was found to target and negatively regulate phospholipid scramblase 1 and insulin receptor substrate 1 expression, which resulted in the inhibition of the AKT/NF-κB signaling pathway. MYC knockdown led to miR-628-5p upregulation, whereas MYC overexpression repressed miR-628-5p expression. These findings indicate that miR-628-5p functions as a tumor-suppressive microRNA in PDAC and implicate miR-628-5p as a potential therapeutic target for PDAC patients.

Influence of non-jaundice stage at diagnosis on clinicopathological features and long-term survival of patients with periampullary carcinomas.

The effect of non-jaundice stage at diagnosis on clinicopathological features and prognosis of patients with periampullary carcinomas (PACs) remains uncertain.The 504 patients who were pathologically diagnosed with PACs between 2012 and 2017 were retrospective analyzed. Kaplan-Meier method was used to estimate survival and log-rank tests were used for comparisons between groups.Patients were divided into the non-jaundice group and the jaundice group according to serum total bilirubin (3 mg/dL) at diagnosis. By comparison with the jaundice group, more patients of the non-jaundice group manifested abdominal pain with longer duration. The degree of deterioration of complete blood count, liver function and CA19-9 in the non-jaundice group was significantly lower (P < .001). The non-jaundice group had larger tumor size (P = .001), more duodenal carcinoma and pancreatic carcinoma (P < .001), lower resection rate (P = .001) and less pancreatic and perineural invasion (P = .017, P = .002). The I stage was significantly more common in the non-jaundice group (P < .001). The cumulative 5-year survival of the non-jaundice group was significantly higher (P = .032). Multivariate analysis for all patients demonstrated that CEA level, cell differentiation, chemotherapy, and recurrence were independent prognostic factors.Patients with PACs in a non-jaundice stage at diagnosis showed more favorable clinicopathological features and long-term survival than such patients with jaundice.

Akt/mTOR-Mediated Autophagy Confers Resistance To BET Inhibitor JQ1 In Ovarian Cancer.

BACKGROUND: Bromodomain and extra-terminal domain inhibitors like JQ1 have proved to be promising epigenetic agents for the treatment of malignant ovarian carcinoma. However, the resistance of ovarian cancer cells to BET inhibitors has not been elucidated. In this study, we investigated the potential mechanisms underlying the resistance of ovarian cancer cell lines to the BET inhibitor JQ1. MATERIALS AND METHODS: We evaluated the apoptotic and proliferative response of four ovarian cancer cell lines to JQ1. The cell lines were designated as resistant (A2780 and HO-8910) and sensitive groups (SKOV-3 and HEY). Further experiments detected the different levels of JQ1-induced autophagy. Anti-tumour effect of the combination of JQ1 and autophagy inhibitors was tested both in vitro and in vivo. RESULTS: In the JQ1-sensitive group, JQ1 effectively inhibited proliferation and apoptosis in a concentration-dependent manner. Conversely, JQ1 showed modest inhibition of proliferation and negligible apoptosis in the resistant group. We detected increased LC3-II lipidation, autophagosome formation, upregulation of Beclin-1 and ATG5, and downregulation of P62/SQSTM1 in the resistant group. Inhibition of JQ1-induced autophagy by pharmacologic inhibitors 3-MA and CQ enhanced the inhibition of proliferation and significantly increased the apoptosis in the JQ1-resistant group, which was also verified by in vivo experiments, indicating that JQ1-induced autophagy played a cytoprotective role. Inactivation of Akt (Ser473)/mTOR(Ser2448) pathway was associated with JQ1-induced autophagy in the resistant group. Overexpression of Akt1 suppressed autophagy and increased the anti-tumour effect of JQ1. CONCLUSION: These findings revealed that JQ1-induced pro-survival autophagy might be a potential mechanism in the resistance of ovarian cancer cells to BET inhibition by JQ1. Combination of JQ1 and autophagy inhibitors could be an effective therapeutic strategy for overcoming BET inhibitor resistance in ovarian cancer.