Prognostic Significance of mRNA Expression RBBP8 or Its Methylation in Gliomas.

Retinoblastoma-binding protein 8 (RBBP8) affects the prognosis of patients with malignancies through various mechanisms. However, its function in gliomas is unknown. Our study explored the effects of RBBP8 on the prognosis of glioma patients, as well as its regulatory role in the glioma immune microenvironment. We used various bioinformatics methods to analyze the transcriptional profiles and methylation data of RBBP8 in gliomas from multiple databases. Our results showed that the mRNA and protein expression of RBBP8 in gliomas was higher than that in normal tissues and positively correlated with malignant clinical features such as age and WHO grade. A Kaplan-Meier analysis showed that patients with high RBBP8 expression had a poor prognosis. Cox regression demonstrated that RBBP8 was an independent risk indicator and had good diagnostic value for the poor prognosis of glioma. Importantly, RBBP8 was positively correlated with many well-known immune checkpoints (e.g., CTLA4 and PDL-1). Finally, a gene set enrichment analysis revealed that RBBP8 was remarkably enriched in cancer-related pathways such as cell cycle, DNA replication and so on. In conclusion, this study is the first to elaborate on the value of RBBP8 in the pathological process of glioma for anti-tumor immunotherapy. In addition, the expression of RBBP8 and its methylation site, cg05513509, may provide potential targets for glioma therapy.

ITGB3BP is a potential biomarker associated with poor prognosis of glioma.

Despite the growing recognition of ITGB3BP as an essential feature of various cancers, the relationship between ITGB3BP and glioma remains unclear. The main aim of this study was to determine the prognostic and diagnostic value of ITGB3BP in glioma. RNA-Seq and microarray data from 2222 glioma patients were included, and we found that the expression level of ITGB3BP in glioma tissues was significantly higher than that in normal brain tissues. Moreover, ITGB3BP can be considered an independent risk factor for poor prognosis and has great predictive value for the prognosis of glioma. Gene Set Enrichment Analysis results showed that ITGB3BP contributes to the poor prognosis of glioma by activating tumour-related signalling pathways. Some small-molecule drugs were identified, such as hexestrol, which may specifically inhibit ITGB3BP and be useful in the treatment of glioma. The TIMER database analysis results revealed a correlation between the expression of ITGB3BP and the infiltration of various immune cells in glioma. Our findings provide the first evidence that the up-regulation of ITGB3BP correlates with poor prognosis in human glioma. Thus, ITGB3BP is a potential new biomarker that can be used for the clinical diagnosis and treatment of glioma.

Cysteine cathepsin C: a novel potential biomarker for the diagnosis and prognosis of glioma.

BACKGROUND: Cysteine cathepsin C encoded by the CTSC gene is an important member of the cysteine cathepsin family that plays a key role regulation of many types of tumors. However, whether CTSC is involved in the pathological process of glioma has not yet been reported. We comprehensively analyzed data from multiple databases and for the first time revealed a role and specific mechanism of action of CTSC in glioma, identifying it as a novel and efficient biomarker for the diagnosis and treatment of this brain tumor. METHODS: The expression of CTSC in glioma and its relationship with clinical characteristics and prognosis of patients with glioma were analyzed at different levels by using clinical sample information from several databases. CTSC expression levels in glioma and normal brain tissues, as well as in glioma cells and normal brain cells, was validated by real-time quantitative polymerase chain reaction (RT-qPCR). Gene set enrichment analysis (GSEA) was used to reveal the signaling pathways that CTSC may participate in. The connectivity map was used to reveal small molecules that may inhibit CTSC expression in glioma, and the putative effect of these compounds was verified by RT-qPCR. RESULTS: Our analyses showed that the expression of CTSC in glioma was higher than that in non-cancerous cells. GSEA showed that CTSC expression may regulate the malignant development of glioma through Toll-like receptor signaling pathways, pathways in cancer, and extracellular matrix receptor interaction signaling pathways. And we proved piperlongumine and scopoletin could inhibit CTSC expression in glioma cells. CONCLUSIONS: CTSC may serve as an efficient molecular target for the diagnosis and therapy of glioma, thereby improving the poor prognosis of patients with glioma.

Identification of PYGL as a key prognostic gene of glioma by integrated bioinformatics analysis.

Aim: PYGL has been reported to have carcinogenic effects in a variety of tumors. This study is the first to reveal the relationship between PYGL and the prognosis of glioma. Materials & methods: Analyzing the Chinese Glioma Genome Atlas database, the authors revealed the expression status and prognostic value of PYGL in gliomas and used quantitative real-time PCR to verify PYGL expression again. Subsequently, they used Gene Set Enrichment Analysis to explore the biological pathways that PYGL may participate in. The authors also used the tumor immune estimation resource database to explore the relationship between PYGL and tumor immune cells. Results: PYGL is involved in the malignant progression of glioma. Conclusions: PYGL can be used as a new biomarker and molecular target for evaluating the prognosis and immunotherapy of glioma.

Overexpression of GINS4 is associated with poor prognosis and survival in glioma patients.

BACKGROUND: GINS4, an indispensable component of the GINS complex, is vital for a variety of cancer. However, no known empirical research has focused on exploring relationships between GINS4 and glioma. Thus, this study aims to understand and explain the role of GINS4 in glioma. METHOD: First, we used the data in the CGGA, TCGA, GEO, GEPIA, and HPA databases to explore the expression level of GINS4 in glioma, the correlation between GINS4 expression and the clinical features of glioma, its impact on the survival of glioma patients, and verified the analysis results through RT-qPCR, IHC, and meta-analysis. Subsequently, GSEA enrichment analysis is used to find the potential molecular mechanism of GINS4 to promote the malignant process of glioma and the anti-glioma drugs that may target GINS4 screened by CMap analysis. Moreover, we further explored the influence of the GINS4 expression on the immune microenvironment of glioma patients through the TIMER database. RESULTS: Our results suggested that GINS4 was elevated in glioma, and the overexpression of GINS4 was connected with a vast number of clinical features. The next, GINS4 as an independent prognostic factor, which can result in an unfavorable prognosis of glioma. Once more, GINS4 may be participating in the oncogenesis of glioma through JAK-STAT signaling pathways, etc. 6-thioguanine, Doxazosin, and Emetine had potential value in the clinical application of drugs targeting GINS4. Finally, the expression exhibited a close relationship with some immune cells, especially Dendritic cells. CONCLUSION: GINS4 is an independent prognostic factor that led to a poor prognosis of glioma. The present study revealed the probable underlying molecular mechanisms of GINS4 in glioma and provided a potential target for improving the prognosis of glioma.

Overexpressed XRCC2 as an independent risk factor for poor prognosis in glioma patients.

BACKGROUND: XRCC2, a homologous recombination-related gene, has been reported to be associated with a variety of cancers. However, its role in glioma has not been reported. This study aimed to find out the role of XRCC2 in glioma and reveal in which glioma-specific biological processes is XRCC2 involved based on thousands of glioma samples, thereby, providing a new perspective in the treatment and prognostic evaluation of glioma. METHODS: The expression characteristics of XRCC2 in thousands of glioma samples from CGGA and TCGA databases were comprehensively analyzed. Wilcox or Kruskal test was used to analyze the expression pattern of XRCC2 in gliomas with different clinical and molecular features. The effect of XRCC2 on the prognosis of glioma patients was explored by Kaplan-Meier and Cox regression. Gene set enrichment analysis (GSEA) revealed the possible cellular mechanisms involved in XRCC2 in glioma. Connectivity map (CMap) was used to screen small molecule drugs targeting XRCC2 and the expression levels of XRCC2 were verified in glioma cells and tissues by RT-qPCR and immunohistochemical staining. RESULTS: We found the overexpression of XRCC2 in glioma. Moreover, the overexpressed XRCC2 was associated with a variety of clinical features related to prognosis. Cox and meta-analyses showed that XRCC2 is an independent risk factor for the poor prognosis of glioma. Furthermore, the results of GSEA indicated that overexpressed XRCC2 could promote malignant progression through involved signaling pathways, such as in the cell cycle. Finally, doxazosin, quinostatin, canavanine, and chrysin were identified to exert anti-glioma effects by targeting XRCC2. CONCLUSIONS: This study analyzed the expression pattern of XRCC2 in gliomas and its relationship with prognosis using multiple datasets. This is the first study to show that XRCC2, a novel oncogene, is significantly overexpressed in glioma and can lead to poor prognosis in glioma patients. XRCC2 could serve as a new biomarker for glioma diagnosis, treatment, and prognosis evaluation, thus bringing new insight into the management of glioma.

Methyl-CpG-Binding Domain Protein 3 Promotes Seizures by Recruiting Methyltransferase DNMT1 to Enhance TREM2 Methylation.

Epilepsy represents a hazardous neurological disorder, underpinned by a pathophysiological process that is yet to be fully understood. Here, we aimed to elucidate the effect of methyl-CpG-binding domain protein 3 (MBD3) on hippocampal neuronal damage in epileptic mice by targeting the phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) pathway. The expression of MBD3 was determined by Western blot in a hippocampal neuronal culture (HNC) epileptic model established using the low Mg2+ECF culture method. The interaction between MBD3 and DNA methyltransferase 1 (DNMT1) was determined via co-immunoprecipitation and mass spectrometry analysis. Bisulfite modification and sequencing was performed to evaluate the degree of methylation of triggering receptor expressed on myeloid cells 2 (TREM2). The viability and apoptosis of hippocampal neurons were detected by CCK-8 and TUNEL assays, respectively. Finally, the effect of MBD3 was verified in vivo. MBD3 was highly expressed in the HNC model of epilepsy, with its interaction with DNMT1 found to promote the hypermethylation of TREM2 at site cg25748868. Additionally, decreased TREM2 and inhibited PI3K/Akt pathway was observed in the HNC epileptic model. Simultaneous inhibition of MBD3 and DNMT1 decreased the methylation level at cg25748868, up-regulated TREM2 expression, and activated the PI3K/Akt pathway, thereby arresting neuronal damage. Inhibition of MBD3 reduced the level of epileptic seizures, down-regulated cg25748868 methylation, activated TREM2-mediated signaling pathways, and alleviated hippocampal neuronal damage in the acute seizure mouse models. The present study unveiled that MBD3 and DNMT1 synergistically enhanced hypermethylation of cg25748868 in TREM2, and promoted the onset of epilepsy via inhibition of the PI3K/Akt pathway.

Long non-cording RNA XIST promoted cell proliferation and suppressed apoptosis by miR-423-5p/HMGA2 axis in diabetic nephropathy.

This research studied the effect of long non-coding RNA X-inactive-specific transcript (XIST) on DN. The effect of high glucose (HG) on the expression of XIST and miR-423-5p was detected by quantitative real-time PCR (qRT-PCR) in human kidney (HK) cells (human glomerular mesangial cells (HMCs) and human kidney-2 (HK-2) cells). The effect of XIST depletion and miR-423-5p inhibition or overexpression on high mobility group protein A2 (HMGA2) protein level was examined by western blot in HG-induced HK cells. The impacts of XIST depletion on viability and apoptosis were assessed by 3-(4, 5-dimethyl-2-thiazolyl)-2, 5-diphenyl-2-H-tetrazolium bromide (MTT) and flow cytometry assays in HG-induced HK cells. We found the expression of XIST and HMGA2 protein was significantly upregulated in DN tissues and cells. Moreover, HG treatment induced the upregulation of XIST and HMGA2 protein level in HK cells. Besides, both XIST depletion and HMGA2 depletion decreased cell proliferation but increased apoptosis in HG-treated HK cells. Furthermore, HMGA2 upregulation or miR-423-5p inhibition partly eliminated the effects of XIST depletion on cell proliferation, apoptosis of HG-treated HK cells. Interestingly, HMGA2 upregulation partly reversed miR-423-5p overexpression-mediated suppression on viability and promotion on apoptosis in HG-treated HK cells. Mechanistically, XIST sponged miR-423-5p to regulate HMGA2 expression in DN cells. Taken together, XIST depletion suppressed proliferation and promoted apoptosis via miR-423-5p/HMGA2 axis in HG-treated HK cells, which may provide a potential therapeutic target for DN.

Fasting serum total bile acid levels are associated with insulin sensitivity, islet ß-cell function and glucagon levels in response to glucose challenge in patients with type 2 diabetes.

Type 2 diabetes (T2D) is characterized by islet ß-cell dysfunction and impaired suppression of glucagon secretion of α-cells in response to oral hyperglycaemia. Bile acid (BA) metabolism plays a dominant role in maintaining glucose homeostasis. So we evaluated the association of fasting serum total bile acids (S-TBAs) with insulin sensitivity, islet ß-cell function and glucagon levels in T2D. Total 2,952 T2D patients with fasting S-TBAs in the normal range were recruited and received oral glucose tolerance tests for determination of fasting and postchallenge glucose, C-peptide and glucagon. Fasting and systemic insulin sensitivity were assessed by homeostasis model assessment (HOMA) and Matsuda index using C-peptide, i.e., ISHOMA-cp and ISIM-cp, respectively. Islet ß-cell function was assessed by the insulin-secretion-sensitivity-index-2 using C-peptide (ISSI2cp). The area under the glucagon curve (AUCgla) was used to assess postchallenge glucagon. The results showed ISHOMA-cp, ISIM-cp and ISSI2cp decreased, while AUCgla notably increased, across ascending quartiles of S-TBAs but not fasting glucagon. Moreover, S-TBAs were inversely correlated with ISHOMA-cp, ISIM-cp and ISSI2cp (r = -0.21, -0.15 and -0.25, respectively, p < 0.001) and positively correlated with AUCgla (r = 0.32, p < 0.001) but not with fasting glucagon (r = 0.033, p = 0.070). Furthermore, after adjusting for other clinical covariates by multiple linear regression analyses, the S-TBAs were independently associated with ISHOMA-cp (ß = -0.04, t = -2.82, p = 0.005), ISIM-cp (ß = -0.11, t = -7.05, p < 0.001), ISSI2cp (ß = -0.15, t = -10.26, p < 0.001) and AUCgla (ß = 0.29, t = 19.08, p < 0.001). Increased fasting S-TBAs are associated with blunted fasting and systemic insulin sensitivity, impaired islet ß-cell function and increased glucagon levels in response to glucose challenge in T2D.

The 150-kDa oxygen-regulated protein (ORP150) regulates proteinuria in diabetic nephropathy via mediating VEGF.

The 150-kDa oxygen-regulated protein (ORP150) belongs to a family of the heat shock protein implicated in the cellular response to environmental stress. Previous data demonstrated that ORP150 regulates the secretion of vascular endothelial growth factor (VEGF) to drive progression of angiogenesis associated with proliferative diabetic retinopathy. However, the expression and biological functions of serum ORP150 levels in diabetic nephropathy (DN) remain unclear. In this study, we reported for the first time that ORP150 was up-regulated in serum of patients with DN. Moreover, we observed the dramatic increase in serum ORP150 accompanied with the elevated levels of proteinuria and serum VEGF levels in DN, indicating the possible involvement of ORP150 in regulation of albuminuria via mediating VEGF in DN. Employing the streptozotocin (STZ) to construct the DN model, we confirmed the positive correlation of ORP150 with VEGF in vivo. Monoclonal anti-ORP150 antibodies treatment significantly decreased the secretion of VEGF and albuminuria in STZ-induced DN models. Consequently, our data suggested that ORP150 levels were positively correlated with proteinuria burden via mediating VEGF in DN. It may be considered as a novel diagnostic and therapeutic target.

KIAA1199, a Target of MicoRNA-486-5p, Promotes Papillary Thyroid Cancer Invasion by Influencing Epithelial-Mesenchymal Transition (EMT).

BACKGROUND KIAA1199 has been reported to be associated with malignant progression and poor clinical outcomes in various human malignancies. However, its clinical role and molecular function remain unknown in papillary thyroid cancer (PTC). MATERIAL AND METHODS The Cancer Genome Atlas (TCGA) was used to investigate the expression profiles of KIAA1199 and miR-486-5p in PTC. Immunohistochemistry was used to validate the protein expression of KIAA1199 in PTC. The Weighted Gene Co-expression Network Analysis (WGCNA) and Gene Set Enrichment Analysis (GSEA) were used to explore the potential pathway underling KIAA1199 in PTC. In vitro and in vivo experiments were performed to investigate the biological role of KIAA1199 in PTC progression. Luciferase reporter assays and Western blot analysis were performed to determine whether KIAA1199 is a downstream target of miR-486-5p. RESULTS We found that KIAA1199 was aberrantly elevated in PTC tissues compared with normal tissues, and upregulation of KIAA1199 was positively correlated with more advanced clinical variables. Additionally, bioinformatic analysis indicated that KIAA1199 was involved in cell migration and invasion. KIAA1199 silencing inhibited the invasive ability of PTC cells by affecting epithelial-mesenchymal transition (EMT) in vitro and in vivo. Furthermore, miR-486-5p was identified as an upstream microRNA that directly targets the 3'-UTR region of KIAA1199. CONCLUSIONS The miR-486-5p/KIAA1199/EMT axis might play a critical role in PTC invasion and metastasis and offers a potential therapeutic strategy for PTC.

Sarcopenia Contributes to the Progression of Nonalcoholic Fatty Liver Disease- Related Fibrosis: A Meta-Analysis.

BACKGROUNDS AND AIMS: Previous studies have investigated that sarcopenia is associated with nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis, and fibrosis in NAFLD. The study aims to investigate the risk for NAFLD, especially NAFLD-related significant fibrosis among subjects with sarcopenia. METHODS: We searched electronic databases until 30, September 2017 and reviewed literature extensively. Effect estimates were pooled using random effect models regarding the risk for NAFLD and fixed effect models concerning the risk for significant fibrosis among sarcopenia patients. Sensitivity analysis was performed for the risk of NAFLD. RESULTS: We identified 6 studies. Our results showed that subjects with sarcopenia exhibited an increased risk for NAFLD compared to those without sarcopenia (OR 1.29, 95% CI 1.12-1.49) with heterogeneity among the individual studies (I2 = 61%). And the risk for NAFLD-related significant fibrosis appeared to be more pronounced in sarcopenia patients (OR 1.57, 95% CI 1.29-1.90) with an I2 of 0%. Sensitivity analysis revealed that neither the direction nor the magnitude of the estimated pooled results for NAFLD was obviously affected. Furthermore, the pooled ORs were both close to initial analysis when omitting the study by Hong et al. [Hepatology 2014; 59: 1772-1778] (OR 1.24, 95% CI 1.11-1.39, I2 = 47%) or by Hashimoto et al. [Endocr J 2016; 63: 877-884] (OR 1.33, 95% CI 1.11-1.59, I2 = 67%), which were considered sources of heterogeneity. CONCLUSIONS: Our analysis demonstrated that sarcopenia served not only as a risk factor for the onset of NAFLD but also related to the progression of NAFLD-related significant fibrosis.

Serum adropin levels are decreased in Chinese type 2 diabetic patients and negatively correlated with body mass index.

Adropin has been identified as potent regulatory hormone implicated in insulin sensitivity and the maintenance of energy homeostasis. The aim of current study was to investigate serum adropin concentrations of type 2 diabetes mellitus (T2DM) patients in the fasting status, especially those overweight/obese and evaluate the relationships between adropin levels and metabolic parameters. A total of 116 T2DM patients and 60 controls with normal glucose tolerance (NGT) were recruited to the study. Adropin concentration was determined using commercial ELISA kits. Anthropometric characteristics were collected and biochemistry, glycosylated hemoglobin A1c (HbA1c) and fasting insulin (FIns) were detected by clinical laboratory. Insulin resistance was estimated by homeostasis model 2 assessment of insulin resistance (HOMA2-IR). Serum adropin levels in Chinese T2DM patients were decreased compared with the controls [3.8 (3.0-5.5) vs. 5.5 (3.7-7.9) ng/mL, p < 0.01]. Meanwhile, overweight/obese patients had more considerably reduced levels of adropin. Adropin level was negatively correlated with body mass index (BMI), high-sensitive C reactive protein (hs-CRP), triglycerides (TG), fasting plasma glucose (FPG), FIns, HOMA2-IR and HbA1c, while positively with high-density lipoprotein cholesterol (HDL-C) in study participants (p < 0.01). The correlations of adropin with glucolipid variables (TG, HDL-C, FPG, FIns, HOMA2-IR, HbA1c) still existed after adjusting the effect of BMI. Besides, HOMA2-IR and HbA1c were independent factors associated with serum adropin levels. Binary logistic regression analyses showed that adropin was significantly associated with T2DM after removing confounding factors (p < 0.01). Receiver operating characteristic (ROC) curve demonstrated adropin concentration of 5.8 ng/mL could be used as a possible optimal cut-off value to identify T2DM from non-T2DM with sensitivity of 81.9% and specificity of 46.7%. Serum adropin concentrations are decreased in Chinese T2DM patients, especially those overweight/obese. Adropin, associated with glucolipid homeostasis and insulin sensitivity, may implicate in the pathogenesis of T2DM.

Role of Ketotifen on metabolic profiles, inflammation and oxidative stress in diabetic rats.

We aim to explore effects of Ketotifen on metabolic profiles, inflammation and oxidative stress. Sprague Dawley (SD) male rats were randomly divided into normal control group (NC) and experimental groups, and experimental group rats were fed with high-sugar and fat diet for 6 weeks. Then, experimental group rats were divided into diabetes group (DM) and ketotifen treatment group (KT). KT group was given ketotifen via Intragastric for 8 weeks with the dosage of 0.09 mg/kg/d. Fasting plasma glucose (FPG) was measured using glucose oxidase-phenol amino phenazone method. Fasting insulin (FINS), total cholesterol (TC), triglyceride (TG), low-density lipoprotein (LDL), high-density lipoprotein (HDL), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) were tested by enzyme-linked immunosorbent assay. Malondialdehyde (MDA) and superoxide dismutase (SOD) were quantified by spectrophotometer method. Before Ketotifen administration, compared with NC group, DM and KT groups showed significantly high levels of body weight, FPG, FINS, HOMA-IR, TC, TG, LDL, IL-6, TNF-α and MDA, and lower levels of HDL and SOD (All p <0.05). After 4 weeks of Ketotifen administration, levels of body weight, FPG, FINS, HOMA-IR, TC, TG, LDL, IL-6, TNF-α in KT group decreased significantly, and levels of HDL and SOD elevated significantly (All p <0.05). After 8 weeks of Ketotifen administration, levels of body weight, FPG, FINS, HOMA-IR, TC, TG, LDL, IL-6, TNF-α and MDA in KT group decreased more obviously, and levels of HDL and SOD elevated significantly further (All p <0.05). Ketotifen improved metabolic profiles, and ameliorated status of inflammation and oxidative stress.

Associations Between CYP3A5 (c.6986A>G) Gene Polymorphism and Kidney Impairment in Hypertensive Adults Without Cystatin C Elevation.

OBJECTIVE: This study aimed to explore the potential role of CYP3A5 (c. 6986A>G) gene polymorphism in predicting kidney function impairment in patients with hypertension who did not have elevated serum cystatin C. METHODS: We recruited a group of patients with hypertension who did not have elevated cystatin C and analyzed the CYP3A5 (c. 6986A>G) gene polymorphism. Chi-square tests were used to compare the clinical characteristics and genotypic distribution between the two groups. Logistic regression analysis was used to explore the association between CYP3A5 (c.6986A>G) gene polymorphism and renal function impairment in hypertension with non-elevated cystatin. RESULTS: In patients with hypertension who participated in the study, there was a significant association between CYP3A5 (c. 6986A>G) gene polymorphism and kidney function impairment (p < 0.05). Patients with the CYP3A5 (c. 6986A>G) mutation display a greater risk of kidney function impairment. CONCLUSION: CYP3A5 (c. 6986A>G) gene AA homozygote polymorphism significantly increases risk of kidney function impairment in patients with hypertension with normal cystatin C. However, further studies are needed to validate this association and to further understand the mechanism of CYP3A5 (c. 6986A>G) gene polymorphism in kidney function impairment in patients with hypertension.

WD repeat domain 76 predicts poor prognosis in lower grade glioma and provides an original target for immunotherapy.

BACKGROUND: The WD40 repeat (WDR) domain provides scaffolds for numerous protein-protein interactions in multiple biological processes. WDR domain 76 (WDR76) has complex functionality owing to its diversified interactions; however, its mechanism in LGG has not yet been reported. METHODS: Transcriptomic data from public databases were multifariously analyzed to explore the role of WDR76 in LGG pathology and tumor immunity. Laboratory experiments were conducted to confirm these results. RESULTS: The results first confirmed that high expression of WDR76 in LGG was not only positively associated with clinical and molecular features of malignant LGG, but also served as an independent prognostic factor that predicted shorter survival in patients with LGG. Furthermore, high expression of WDR76 resulted in the upregulation of oncogenes, such as PRC1 and NUSAP1, and the activation of oncogenic mechanisms, such as the cell cycle and Notch signaling pathway. Finally, WDR76 was shown to be involved in LGG tumor immunity by promoting the infiltration of immune cells, such as M2 macrophages, and the expression of immune checkpoints, such as PDCD1 (encoding PD-1). CONCLUSIONS: This study shows for the first time the diagnostic and prognostic value of WDR76 in LGG and provides a novel personalized biomarker for future targeted therapy and immunotherapy. Thus, WDR76 may significantly improve the prognosis of patients with LGG.

Machine learning algorithm-based biomarker exploration and validation of mitochondria-related diagnostic genes in osteoarthritis.

The role of mitochondria in the pathogenesis of osteoarthritis (OA) is significant. In this study, we aimed to identify diagnostic signature genes associated with OA from a set of mitochondria-related genes (MRGs). First, the gene expression profiles of OA cartilage GSE114007 and GSE57218 were obtained from the Gene Expression Omnibus. And the limma method was used to detect differentially expressed genes (DEGs). Second, the biological functions of the DEGs in OA were investigated using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. Wayne plots were employed to visualize the differentially expressed mitochondrial genes (MDEGs) in OA. Subsequently, the LASSO and SVM-RFE algorithms were employed to elucidate potential OA signature genes within the set of MDEGs. As a result, GRPEL and MTFP1 were identified as signature genes. Notably, GRPEL1 exhibited low expression levels in OA samples from both experimental and test group datasets, demonstrating high diagnostic efficacy. Furthermore, RT-qPCR analysis confirmed the reduced expression of Grpel1 in an in vitro OA model. Lastly, ssGSEA analysis revealed alterations in the infiltration abundance of several immune cells in OA cartilage tissue, which exhibited correlation with GRPEL1 expression. Altogether, this study has revealed that GRPEL1 functions as a novel and significant diagnostic indicator for OA by employing two machine learning methodologies. Furthermore, these findings provide fresh perspectives on potential targeted therapeutic interventions in the future.

Potential value of expression of receptor accessory protein 4 for evaluating the prognosis of lower-grade glioma patients.

BACKGROUND: REEP4 is involved in the regulation of the biological process of mitosis. Lower grade glioma (LGG), as a malignant tumor, is accompanied by abnormalities in mitosis, but there have been no reports of REEP4 so far. METHODS: We collected transcriptome data, DNA methylation data and the clinical characteristics of thousands of patients with LGG. Various big data analysis methods and molecular biology experiments were employed to reveal the impact of REEP4 on the pathological process of LGG. RESULTS: It was found that the expression of REEP4 was significantly elevated and negatively regulated by its methylation site. Therefore, both the high expression of REEP4 and low methylation state of cg16311504 showed that the patients are correlated with lower patient survival rate. In addition, high REEP4 expression participates in the regulation of various cancer-related cellular signaling pathways, such as the cell cycle, MAPK signaling pathway, NOD-like receptor signaling pathway, etc. More importantly, the level of immune cell infiltration significantly increased in the high expression group of REEP4 in the LGG tumor microenvironment and REEP4 has a high positive correlation with PD-L1 and other immune checkpoints. CONCLUSIONS: In brief, this study is the first to introduce REEP4 in malignant tumors, which can be used as an independent risk factor that participates in the malignant process of LGG. More importantly, REEP4 has the potential to become a new star in the field of anti-tumor treatment.

A 5:2 Intermittent Fasting Meal Replacement Diet and Glycemic Control for Adults With Diabetes: The EARLY Randomized Clinical Trial.

Importance: An intermittent fasting plan consisting of 2 nonconsecutive fasting days and 5 days of habitual intake per week and meal replacement diet (5:2 MR) could provide additional benefits to patients with type 2 diabetes. Objective: To evaluate the effect of the 5:2 MR on glycemic control among patients with early type 2 diabetes compared with metformin and empagliflozin. Design, Setting, and Participants: The EARLY (Exploration of Treatment of Newly Diagnosed Overweight/Obese Type 2 Diabetes Mellitus) study is a randomized, open-label, active parallel-controlled clinical trial conducted between November 13, 2020, and December 29, 2022, in 9 centers across China. A total of 509 eligible patients underwent screening, out of which 405 were randomly assigned to 3 groups and included in the intention-to-treat analysis. Interventions: Patients were randomly allocated in a 1:1:1 ratio to receive either metformin, empagliflozin, or 5:2 MR. The treatment was 16 weeks, with an 8-week follow-up. Main Outcomes and Measures: The primary end point was the change in hemoglobin A1c (HbA1c) level from baseline to 16 weeks. Secondary end points included changes in body weight, anthropometric measurements, and biochemical parameters. Results: Of the 405 randomized participants (265 men [65.4%]; mean [SD] age, 45.5 [11.0] years; mean [SD] body mass index, 29.5 [4.1]; and mean [SD] HbA1c level, 7.9% [0.6%]), 332 completed the 16-week treatment. From baseline to week 16, participants in the 5:2 MR group showed the greatest reduction in HbA1c (least-squares mean [LSM], -1.9% [SE, 0.2%]), significantly greater than patients receiving metformin (LSM, -1.6% [SE, 0.2%]; adjusted LSM difference, -0.3% [95% CI, -0.4% to -0.1%]) and empagliflozin (LSM, -1.5% [SE, 0.2%]; adjusted LSM difference, -0.4% [95% CI, -0.6% to -0.2%]). At week 16, the mean weight loss in the 5:2 MR group (LSM, -9.7 kg [SE, 2.2 kg]) was greater than that in the metformin group (LSM, -5.5 kg [SE, 2.3 kg]) and empagliflozin group (LSM, -5.8 kg [SE, 2.3 kg]). Conclusions and Relevance: This randomized clinical trial of Chinese adults with overweight or obesity and with early type 2 diabetes found that 5:2 MR could improve glycemic outcomes and weight loss in the short term compared with metformin or empagliflozin, making it a promising initial intervention and early management for type 2 diabetes. Trial Registration: Chinese Clinical Trial Registry Identifier: ChiCTR2000040656.

Relationship between circulating thrombospondin-1 messenger ribonucleic acid and microribonucleic acid-194 levels in Chinese patients with type 2 diabetic kidney disease: The outcomes of a case-control study.

AIMS/INTRODUCTION: We investigated the relationship of circulating TSP-1 mRNA and miR-194 with diabetic kidney disease's degree. MATERIALS AND METHODS: We enrolled 167 hospitalized type 2 diabetes patients in the endocrinology department. Patients were split into three groups according to urinary microalbumin: A, B and C. The control group comprised healthy outpatients (n = 163). The quantities of microribonucleic acid (miR)-194 and thrombospondin-1 (TSP-1) messenger ribonucleic acid (mRNA) in the participants' circulation were measured using a quantitative real-time polymerase chain reaction. RESULTS: Circulating TSP-1 mRNA (P = 0.024) and miR-194 (P = 0.029) expressions significantly increased in type 2 diabetes patients. Circulating TSP-1 mRNA (P = 0.040) and miR-194 (P = 0.007) expression levels differed significantly among the three groups; circulating TSP-1 mRNA expression increased with urinary microalbumin. However, miR-194 declined in group B and increased in group C. Circulating TSP-1 mRNA was positively correlated with cystatin-c (r = 0.281; P = 0.021) and microalbumin/creatinine ratio (UmALB/Cr; r = 0.317; P = 0.009); miR-194 was positively correlated with UmALB/Cr (r = 0.405; P = 0.003). Stepwise multivariate linear regression analysis showed cystatin-c (ß = 0.578; P = 0.021) and UmALB/Cr (ß = 0.001; P = 0.009) as independent factors for TSP-1 mRNA; UmALB/Cr (ß = 0.005; P = 0.028) as an independent factor for miR194. Areas under the curve for circulating TSP-1 mRNA and miR194 were 0.756 (95% confidence interval 0.620-0.893; sensitivity 0.69 and specificity 0.71, P < 0.01) and 0.584 (95% confidence interval 0.421-0.748; sensitivity 0.54 and specificity 0.52, P < 0.01), respectively. CONCLUSIONS: Circulating TSP-1 mRNA and miR-194 expressions significantly increased in type 2 diabetes patients. The microalbumin group had lower levels of miR-194 (a risk factor that is valuable for type 2 diabetes kidney disease evaluation).