COMMD10 inhibits HIF1α/CP loop to enhance ferroptosis and radiosensitivity by disrupting Cu-Fe balance in hepatocellular carcinoma.

BACKGROUND & AIMS: Copper (Cu) is an essential trace element whose serum levels have been reported to act as an effective indicator of the efficacy of radiotherapy. However, little is known about the role of Cu in radiotherapy. In this study we aimed to determine this role and investigate the precise mechanism by which Cu or Cu-related proteins regulate the radiosensitivity of hepatocellular carcinoma (HCC). METHODS: The expression and function of Cu and copper metabolism MURR1 domain 10 (COMMD10) were assessed via a Cu detection assay, immunostaining, real-time PCR, western blot, a radiation clonogenic assay and a 5-ethynyl-2'-deoxyuridine assay. Ferroptosis was determined by detecting glutathione, lipid peroxidation, malondialdehyde and ferrous ion (Fe) levels. The in vivo effects of Cu and COMMD10 were examined with Cu/Cu chelator treatment or lentivirus modification of COMMD10 expression in radiated mouse models. RESULTS: We identified a novel role of Cu in promoting the radioresistance of HCC cells. Ionizing radiation (IR) induced a reduction of COMMD10, which increased intracellular Cu and led to radioresistance of HCC. COMMD10 enhanced ferroptosis and radiosensitivity in vitro and in vivo. Mechanistically, low expression of COMMD10 induced by IR inhibited the ubiquitin degradation of HIF1α (by inducing Cu accumulation) and simultaneously impaired its combination with HIF1α, promoting HIF1α nuclear translocation and the transcription of ceruloplasmin (CP) and SLC7A11, which jointly inhibited ferroptosis in HCC cells. In addition, elevated CP promoted HIF1α expression by reducing Fe, forming a positive feedback loop. CONCLUSIONS: COMMD10 inhibits the HIF1α/CP loop to enhance ferroptosis and radiosensitivity by disrupting Cu-Fe homeostasis in HCC. This work provides new targets and treatment strategies for overcoming radioresistance in HCC. LAY SUMMARY: Radiotherapy benefits patients with unresectable or advanced hepatocellular carcinoma (HCC), but its effectiveness is hampered by radioresistance. Herein, we uncovered a novel role for copper in promoting the radioresistance of HCCs. This work has revealed new targets and potential treatment strategies that could be used to sensitize HCC to radiotherapy.

Research Status and Progress of Nutritional Support Therapy for Ovarian Cancer.

Ovarian cancer is one of the most fatal gynecological cancers. For most ovarian cancer patients, nutritional risk or malnutrition may accompany them for life. Regular nutritional risk screening, timely nutritional assessment and necessary nutritional treatment play an extremely important role in the process of comprehensive treatment of ovarian cancer. The nutritional status and influence of ovarian cancer patients, preoperative screening and assessment of nutritional risk, preoperative and postoperative nutritional treatment indicate that nutritional treatment of ovarian cancer is one of the key factors in the treatment of cancer. We have summarized the status and progress of nutritional support therapy for ovarian cancer. We are aimed to improve the understanding of the impact of nutritional support therapy for ovarian cancer and to guide the clinical work.

MicroRNA-139 inhibits pancreatic-cancer carcinogenesis by suppressing RalB via the Ral/RAC/PI3K pathway.

Micro-ribonucleic acids (miRNAs) are a class of conserved small non-coding RNAs (sncRNAs) that post-transcriptionally regulate their downstream target genes. Existing evidence indicates that abnormal expression of mRNAs results in the occurrence and development of pancreatic cancer (PC). In this study, we explored the potential role of miRNA-139 (miR-139) as a biomarker in the monitoring and treatment of PC. We demonstrated that expression of miR-139 was significantly downregulated in PC cells and tissues. In addition, both in vitro and in vivo experiments showed that miR-139 significantly inhibited the growth, migration, and invasion of PC cells. We carried out microarray analysis and transcriptome sequencing to find the potential target of miR-139 in PC cells, and the results showed that miR-139 targeted Ras-like proto-oncogene B (RalB). Luciferase reporter experiments verified that high level of RalB could reverse the proliferation and invasion of PC cells overexpressing miR-139. Using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses, we found that miR-139 likely affected PC cell cycle by targeting RalB via the Ral/protein kinase B (Akt) serine/threonine kinase 1 (RAC)/phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) pathway, thus affecting cell proliferation. This presumption was further confirmed in our in vitro and in vivo experiments. Our examination of PC tissues suggested that the expression of miR-139 was negatively correlated with that of RalB. Taken together, our results implied that miR-139 could suppress tumor growth and metastasis in PC by targeting RalB, revealing the potential role of miR-139 as a biomarker for the monitoring and treatment of PC.

[Evaluation study on a new method of dietary assessment with instant photography applied in urban pregnant women in Nanjing city].

OBJECTIVE: To evaluate the usefulness and efficiency of a novel dietary method among urban pregnant women. METHODS: Sixty one pregnant women were recruited from the ward and provided with a meal accurately weighed before cooking. The meal was photographed from three different angles before and after eating. The subjects were also interviewed for 24 h dietary recall by the investigators. Food weighting, image quantification and 24 h dietary recall were conducted by investigators from three different groups, and the messages were isolated from each other. Food consumption was analyzed on bases of classification and total summation. Nutrient intake from the meal was calculated for each subject. The data obtained from the dietary recall and the image quantification were compared with the actual values. Correlation and regression analyses were carried out on values between weight method and image quantification as well as dietary recall. RESULTS: Total twenty three kinds of food including rice, vegetables, fish, meats and soy bean curd were included in the experimental meal for the study. Compared with data from 24 h dietary recall (r = 0.413, P < 0.05), food weight estimated by image quantification (r = 0.778, P < 0.05, n = 308) were more correlated with weighed data, and show more concentrated linear distribution. Absolute difference distribution between image quantification and weight method of all food was 77.23 ± 56.02 (P < 0.05, n = 61), which was much small than the difference (172.77 ± 115.18) between 24 h recall and weight method. Values of almost all nutrients, including energy, protein, fat, carbohydrate, vitamin A, vitamin C, calcium, iron and zine calculated based on food weight from image quantification were more close to those of weighed data compared with 24 h dietary recall (P < 0.01). The results found by the Bland Altman analysis showed that the majority of the measurements for nutrient intake, were scattered along the mean difference line and close to the equality line (difference = 0). The plots show fairly good agreement between estimated and actual food consumption. It indicate that the differences (including the outliers) were random and did not exhibit any systematic bias, being consistent over different levels of mean food amount. On the other hand, the questionnaire showed that fifty six pregnant women considered the image quantification was less time-consuming and burdened than 24 h recall. Fifty eight of them would like to use image quantification to know their dietary status. CONCLUSION: The novel method which called instant photography (image quantification) for dietary assessment is more effective than conventional 24 h dietary recall and it also can obtain food intake values close to weighed data.

Screening and identification of CNIH4 gene associated with cell proliferation in gastric cancer based on a large-scale CRISPR-Cas9 screening database DepMap.

BACKGROUND: Gastric cancer is a common malignant tumor of digestive tract. The study aimed to identify candidate genes associated with the proliferation and survival of gastric cancer cell through CRISPR-cas9 screening data, which may provide new therapeutic targets for gastric cancer patients. METHODS: Candidate genes related to gastric cancer cell viability by CRISPR-cas9 screening from Depmap and genes differentially expressed between gastric cancer tissues and normal gastric tissues from TCGA were overlapped. WGCNA and KEGG analysis was conducted to performed to identify key pathways and genes. Using CMap, we identified small molecules that might reverse candidate gene expression of gastric cancer. LASSO regression was used to construct a signature to predict overall survival of gastric cancer patients. CCK8 assay was performed to assess the effects of candidate gene on gastric cancer cell proliferation. RESULTS: A total of 710 candidate genes related to gastric cancer cell viability in the DepMap were identified and overlapped with differentially expressed genes in TCGA database, which were enriched in the cell cycle pathway. CMap analysis suggested that molecule drug LY294002 might be a novel choice for gastric cancer treatment. Using Cox univariate analysis and Lasso analysis, we developed a prognostic model including 12 candidate genes, and conducted subgroup analysis and external validation. Moreover, knockdown of the key candidate gene CNIH4 inhibited the proliferation of gastric cancer cells. CONCLUSION: Cell cycle pathway and CNIH4, identified by CRISPR-cas9 screening, were a key pathway and gene that regulate cell viability in gastric cancer. CNIH4 has significant prognostic values and can serve as a new target for gastric cancer patient treatment.

Identification of key pathways and genes in nasopharyngeal carcinoma based on WGCNA.

OBJECTIVE: We aim to identify the potential genes and signaling pathways associated with the nasopharyngeal carcinoma (NPC) prognosis using Weighted Gene Co-Expression Network Analysis (WGCNA). METHODS: Gene Expression Omnibus (GEO) query was utilized to download two NPC mRNA microarray data. WGCNA was conducted on differentially expressed genes (DEGs) to obtain tumor-associated gene modules. Genes in core modules were intersected with DEGs for gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional enrichment analysis. GSE102349 dataset was devoted to identifying prognostic hub genes by survival analysis and the results were confirmed by quantitative polymerase chain reaction (qPCR). RESULTS: Co-expression networks were built, and we detected 12 gene modules. The Brown module and Magenta module were extremely associated with NPC samples. GO functional analysis and KEGG pathway analysis was carried out to the genes in the Brown and Magenta modules. Our data indicated that DEGs in Brown module and Magenta module were correlated with the biological regulation, metabolic process, reproduction, and cellular proliferation. Twenty-six hub genes were obtained and were considered to be closely related to NPC. GSE102349 dataset was devoted to identifying prognostic hub genes by survival analysis. The expression of IL33, MPP3 and SLC16A7 in GSE102349 dataset was significantly correlated with the progression-free survival (PFS). The results of qPCR indicated a strong correlation between SLC16A7 expression and the overall survival (OS). CONCLUSIONS: WGCNA contributed to the detection of gene modules and identification of hub genes and crucial genes. These crucial genes might be potential targets for pharmaceutic therapies with potential clinical significance.

Survival analysis and nomogram for pulmonary sarcomatoid carcinoma: an SEER analysis and external validation.

OBJECTIVE: Uncommon and particularly deadly, pulmonary sarcomatoid carcinoma (PSC) is an aggressive type of lung cancer. This research aimed to create a risk categorisation and nomogram to forecast the overall survival (OS) of patients with PSC. METHODS: To develop the model, 899 patients with PSC were taken from the Surveillance, Epidemiology, and End Results database from the USA. We also used an exterior verification sample of 34 individuals with PSC from Fujian Provincial Hospital in China. The Cox regression hazards model and stepwise regression analysis were done to screen factors in developing a nomogram. The nomogram's ability to discriminate was measured employing the area under a time-dependent receiver operating characteristic curve (AUC), the concordance index (C-index) and the calibration curve. Decision curve analysis (DCA) and integrated discrimination improvement (IDI) were used to evaluate the nomogram to the tumour-node-metastasis categorisation developed by the American Joint Committee on Cancer (AJCC-TNM), eighth edition, and an additional sample confirmed the nomogram's accuracy. We further developed a risk assessment system based on nomogram scores. RESULTS: Six independent variables, age, sex, primary tumour site, pathological group, tumour-node-metastasis (TNM) clinical stage and therapeutic technique, were chosen to form the nomogram's basis. The nomogram indicated good discriminative ability with the C-index (0.763 in the training cohort and 0.746 in the external validation cohort) and time-dependent AUC. Calibration plots demonstrated high congruence between the prediction model and real-world evidence in both the validation and training cohorts. Nomogram outperformed the AJCC-TNM eighth edition classification in both DCA and IDI. Patients were classified into subgroups according to their risk ratings, and significant differences in OS were observed between them (p<0.001). CONCLUSION: We conducted a survival analysis and nomogram for PSC. This developed nomogram holds potential to serve as an efficient tool for clinicians in prognostic modelling.

[Study of the correlation between the colorectal cancer Chinese medicine syndrome types and (excision repair cross-complementing 1, ERCC1) gene polymorphisms].

OBJECTIVE: To explore the correlation between excision repair cross-complementing 1 (ERCC1) C8092A and C19007T gene polymorphisms and different Chinese medicine (CM) syndrome types of colorectal cancer (CC). METHODS: Ninety-nine patients with CC were syndrome typed as dampness-heat accumulation syndrome, qi stagnation with blood stasis syndrome, Pi-Shen yang deficiency syndrome, and Gan-Shen yin deficiency syndrome. The gene polymorphisms of excision repair cross-complementing 1 (ERCC1) C8092A and C19007T in different CM syndrome types of CC were examined by polymorphisms chain reaction amplification and direct sequencing, and analyzed statistically. RESULTS: The frequencies of C8092A genotype and allele in different CM syndrome types had no statistical difference (P > 0.05). The frequencies of C19007T genotype and allele in different CM syndrome types had statistical difference (P < 0.05). Of them, there was no statistical difference in the frequencies between dampness-heat accumulation syndrome and qi stagnation with blood stasis syndrome, or between Pi-Shen yang deficiency syndrome and Gan-Shen yin deficiency syndrome (P > 0.05). There was statistical difference between dampness-heat accumulation syndrome and Pi-Shen yang deficiency syndrome as well as Gan-Shen yin deficiency syndrome (P < 0.05). There was statistical difference between qi stagnation with blood stasis syndrome and Pi-Shen yang deficiency syndrome as well as Gan-Shen yin deficiency syndrome (P < 0.05). CONCLUSION: ERCC1 C19007T gene polymorphisms might be associated with CM syndrome types of CC, which needed to be further studied.

Multiomics Integrative Analysis Identifying EPC1 as a Prognostic Biomarker in Head and Neck Squamous Cell Carcinoma.

Background: Biomarker research in head and neck squamous cell carcinoma (HNSCC) is constantly revealing promising findings. An enhancer of polycomb homolog 1 (EPC1) was found to play a procancer role in nasopharyngeal carcinoma (NPC), but its role in HNSCC with strong heterogeneity is still unclear. Herein, we investigated the prognostic significance and related mechanisms of EPC1 in HNSCC. Methods: The Kaplan-Meier plotter was used to evaluate the prognostic significance of EPC1. Based on a range of published public databases, the multiomics expression of EPC1 in HNSCC was explored to investigate the mechanisms affecting prognosis. Results: According to the clinical data, high EPC1 expression in HNSCC was a predictor of patient prognosis (hazard ratio (HR) = 0.64; 95% confidence interval (CI) 0.49-0.83; P < 0.01). EPC1 expression varied among clinical subtypes and was related to key factors, such as TP53 and human papillomavirus (HPV) (P < 0.05). At the genetic level, EPC1 expression level may be associated with protein phosphorylation, cell adhesion, cancer-related pathways, etc. For the noncoding region, a competing endogenous RNA network was constructed, and 6 microRNAs and 12 long noncoding RNAs were identified. At the protein level, a protein-protein interaction (PPI) network related to EPC1 expression was constructed and found to be involved in HPV infection, endocrine resistance, and multiple cancer pathways. At the immune level, EPC1 expression was correlated with a variety of immune cells and immune molecules, which together constituted the immune microenvironments of tumors. Conclusion: High EPC1 expression may predict a better prognosis in HNSCC, as it is more frequently found in HNSCC with HPV infection. EPC1 may participate in the genomics, transcriptomics, proteomics, and immunomics of HNSCC, and the results can provide a reference for the development of targeted drugs and evaluation of patient prognosis.

Development and validation of a deep learning model to predict survival of patients with esophageal cancer.

Objective: To compare the performance of a deep learning survival network with the tumor, node, and metastasis (TNM) staging system in survival prediction and test the reliability of individual treatment recommendations provided by the network. Methods: In this population-based cohort study, we developed and validated a deep learning survival model using consecutive cases of newly diagnosed stage I to IV esophageal cancer between January 2004 and December 2015 in a Surveillance, Epidemiology, and End Results (SEER) database. The model was externally validated in an independent cohort from Fujian Provincial Hospital. The C statistic was used to compare the performance of the deep learning survival model and TNM staging system. Two other deep learning risk prediction models were trained for treatment recommendations. A Kaplan-Meier survival curve was used to compare survival between the population that followed the recommended therapy and those who did not. Results: A total of 9069 patients were included in this study. The deep learning network showed more promising results in predicting esophageal cancer-specific survival than the TNM stage in the internal test dataset (C-index=0.753 vs. 0.638) and external validation dataset (C-index=0.687 vs. 0.643). The population who received the recommended treatments had superior survival compared to those who did not, based on the internal test dataset (hazard ratio, 0.753; 95% CI, 0.556-0.987; P=0.042) and the external validation dataset (hazard ratio, 0.633; 95% CI, 0.459-0.834; P=0.0003). Conclusion: Deep learning neural networks have potential advantages over traditional linear models in prognostic assessment and treatment recommendations. This novel analytical approach may provide reliable information on individual survival and treatment recommendations for patients with esophageal cancer.

The Protective Effects of Inulin-Type Fructans Against High-Fat/Sucrose Diet-Induced Gestational Diabetes Mice in Association With Gut Microbiota Regulation.

Background: Inulin-type fructans (ITF) have been used as prebiotics to alleviate glucose and lipid metabolism disorders. However, few studies evaluated the microbial mechanism of ITF in improving maternal metabolic status during pregnancy. Methods: C57BL/6J mice were fed a high-fat/sucrose diet (HFD) for 4 weeks before and throughout pregnancy to induce a model of gestational diabetes mellitus (GDM). Body weight, glycolipid metabolic parameters, and fecal short-chain fatty acids (SCFAs) were assessed in the experimental process. The effects of ITF on the fecal microbiota were analyzed by 16S rRNA gene amplicon sequencing. Results: Pregnant HFD-fed mice displayed significant insulin resistance and dyslipidemia. ITF (3.33 g/kg/day) treatment improved glucose and lipid metabolism disorder parameters in HFD-induced GDM mice and alleviated fat accumulation and glucose intolerance. The alpha diversity of the gut microbial community was increased in ITF mice, while the beta diversity returned to the level of normal chow diet (NCD) mice. Interestingly, Verrucomicrobia, Bifidobacterium, and Akkermansia were obviously enriched, while Dubosiella was obviously lessened after inulin treatment. Further analysis indicated that Dubosiella was positively correlated with markers of glycolipid metabolism disorders, whereas the ITF-supplemented diet partially reversed the changes. Conclusion: Our results suggest that the ITF treatment may alleviate glucose and lipid metabolism disorders with the mediation of gut microbiota.

Concordance Study of a 520-Gene Next-Generation Sequencing-Based Genomic Profiling Assay of Tissue and Plasma Samples.

INTRODUCTION: Next-generation sequencing (NGS) enables simultaneous detection of actionable somatic variants and estimation of genomic signatures such as tumor mutational burden (TMB) or microsatellite instability (MSI) status, which empowers therapeutic decisions in clinical oncology. OBJECTIVE: Our retrospective study investigated the clinical performance of somatic variant detection in paired tissue and blood samples using a large targeted gene panel, the OncoScreen Plus, which interrogates 520 cancer-related genes. METHODS: We analyzed sequencing data derived from paired tissue and blood samples of 3005 patients spanning 20 solid tumor types, including lung (n = 1971), gastrointestinal (n = 625), breast (n = 120) and gynecological (n = 110), genitourinary (n = 38), and other cancers (n = 141). RESULTS: Across tumor types, the OncoScreen Plus panel achieved a high tissue detection rate, with an average of 97.9%. The average plasma detection rate was 72.2%, with an average tissue concordance rate of 36.6%. Considering all variant types, the plasma assay yielded an average sensitivity/true positive rate of 45.7%, with a positive predictive value of 64.7% relative to tissue assay. Pearson correlation analysis revealed a strong correlation in TMB estimated from blood and tissue samples (correlation coefficient 0.845, R2 = 0.756). MSI-high status was identified in five tumor types, including endometrial cancer (28.6%), colorectal cancer (2.5%), ovarian cancer (2.0%), gastric cancer (1.5%), and lung adenocarcinoma (0.2%). CONCLUSION: Paired tumor and blood samples from a large cohort of patients spanning 20 tumor types demonstrated that the OncoScreen Plus is a reliable pan-cancer panel for the accurate detection of somatic variants and genomic signatures that could guide individualized treatment strategies to improve the care of patients with advanced cancer.

FCGR2A Could Function as a Prognostic Marker and Correlate with Immune Infiltration in Head and Neck Squamous Cell Carcinoma.

OBJECTIVE: We aim to investigate the correlation between FCGR2A mRNA level and prognosis of head and neck squamous cancer (HNSC) in public databases. In addition, we investigated the correlation between FCGR2A expression and clinicopathological characteristics and tumor-infiltrating immune cells in HNSC patients. METHODS: FCGR2A mRNA expression in multiple cancers was analyzed based on Gene Expression Profiling Interactive Analysis. A protein-protein interaction network was obtained based on the STRING database. The 10 proteins most closely related to FCGR2A (i.e., CD3G, PLCG2, LAT, LYN, SYK, FCGR3A, PIK3R1, HCK, ITGAM, and ITGB2) were screened, followed by establishing the protein-protein interaction network. The correlation between FCGR2A expression and immunocytes was investigated, together with the effects of FCGR2A on the metastasis, recurrence, and survival of HNSC. RESULTS: FCGR2A expression in several carcinoma tissues was significantly higher than that of adjacent tissues. Significant differences were noticed in the HNSC samples and the adjacent tissue samples except the seven samples of grade 4. There were statistical differences between the FCGR2A expression in tissues of grade 1, grade 2, and grade 3 (P < 0.05). In the tissues of grade 4, the expression of FCGR2A was the lowest. The FCGR2A protein was a type of II-a receptor in γFc of the low-affinity immunoglobulin, which could bind with the Fc region of the immunoglobulin γ. There was a correlation between the FCGR2A gene and the distal HNSC metastasis. FCGR2A gene expression was correlated with the survival and prognosis. The GSE65858 dataset was selected for the validation. The FCGR2A expression was significantly correlated with total survival (P = 0.0107) and progression-free survival (P = 0.0362). CONCLUSIONS: Our findings shed light on the importance of FCGR2A in HNSC and illustrated a potential relationship between FCGR2A and tumor-immune interactions.

Expression and Biological Functions of EPC1 in Nasopharyngeal Carcinoma.

BACKGROUND: Comb homolog enhancer 1 (EPC1) gene is one of the important members of epigenetic inhibitor PCG family. It shows carcinogenic potential in a variety of malignant tumors, but the expression and role of EPC1 in nasopharyngeal carcinoma are unclear. The aim of this study was to explore the expression and function of enhancer of polycomb homolog 1 (EPC1) in nasopharyngeal carcinoma (NPC). METHODS: The differential expression of EPC1 in the cancer tissues and cell lines of NPC was examined by quantitative real-time reverse transcription-polymerase chain reaction (qRT-PCR). EPC1 expression, cell proliferation, and apoptosis were detected in NPC cell lines after EPC1 silencing, and the levels of the epithelial-mesenchymal transition (EMT)-related proteins E-cadherin and vimentin were detected in NPC cells after EPC1 silencing. The study was performed at Fujian Provincial Hospital, Fujian, China, from 2018 to 2019. RESULTS: We found that EPC1 was significantly upregulated in the cancer tissues and cell lines of NPC (P<0.001). Furthermore, knockdown of EPC1 inhibited the growth and metastasis of NPC cells. E-cadherin and vimentin were detected in NPC cells after EPC1 was knocked out. It was confirmed that inhibition of EPC1 resulted in increased E-cadherin expression (P<0.001) and decreased vimentin expression (P<0.001), suggesting that inhibition of EPC1 could inhibit the EMT in NPC cells. CONCLUSION: EPC1 expression was upregulated in NPC tissues and cell lines. Knockout of EPC1 effectively inhibited the growth of NPC cells, induced apoptosis, and inhibited invasion and metastasis. Inhibition of EPC1 could inhibit the EMT in NPC cells. All of the above findings support the viewpoint that EPC1 plays a pro-cancer role in NPC.

Dietary supplementation of inulin alleviates metabolism disorders in gestational diabetes mellitus mice via RENT/AKT/IRS/GLUT4 pathway.

BACKGROUND: Gestational diabetes mellitus (GDM) has significant short and long-term health consequences for both the mother and child. There is limited but suggestive evidence that inulin could improve glucose tolerance during pregnancy. This study assessed the effect of inulin on glucose homeostasis and elucidated the molecular mechanisms underlying the inulin-induced antidiabetic effects during pregnancy. METHOD: Female C57BL/6 mice were randomized to receive either no treatment, high-dose inulin and low-dose inulin for 7 weeks with measurement of biochemical profiles. A real-time2 (RT2) profiler polymerase chain reaction (PCR) array involved in glycolipid metabolism was measured. RESULTS: Inulin treatment facilitated glucose homeostasis in a dose-dependent manner by decreasing fasting blood glucose, advanced glycation end products and total cholesterol, and improving glucose tolerance. Suppressing resistin (RETN) expression was observed in the inulin treatment group and the expression was significantly correlated with fasting blood glucose levels. The ratios of p-IRS to IRS and p-Akt to Akt in liver tissue and the ratio of p-Akt to Akt in adipose tissue as well as the expression level of GLUT4 increased significantly after inulin treatment. CONCLUSIONS: Our findings indicated improvement of glucose and lipid metabolism by inulin was to activate glucose transport through the translocation of GLUT4 which was mediated by insulin signaling pathway repairment due to decreased expression of RETN and enhanced phosphorylation of IRS and Akt in GDM mice.

Interferon-Induced Protein 44 Correlated With Immune Infiltration Serves as a Potential Prognostic Indicator in Head and Neck Squamous Cell Carcinoma.

Interferon-induced protein 44 (IFI44) containing a guanosine-5'-triphosphate (GTP) binding domain was reported to play a significant role in the immune response to autoimmune disease. However, its roles involved in cancers remain unclear. Here, we detected the expression of IFI44 in The Cancer Genome Atlas (TCGA) Pan-cancer and generally explored the effect of IFI44 on immune infiltration in the tumor microenvironment (TME). The results displayed that IFI44 was mainly located in the cytoplasm and overexpressed in head and neck squamous cell carcinoma (HNSC) samples compared with normal tissues. Survival analysis exhibited that IFI44 was remarkably associated with the clinical outcomes, particularly in lymph node-positive and locally advanced HNSC patients. Biological analysis showed that IFI44 was correlated with such immune biological processes as antigen-presenting and nuclear factor (NF)-kappa B signaling pathways. Immune signature analysis demonstrated that the expression of IFI44 was positively correlated with the infiltration of CD4+ cells and macrophages as well as neutrophils in HNSC. Taken together, these data suggested that IFI44 was abnormally expressed in cancer tissues and indicated the potential impact of IFI44 on the tumor immune infiltration in HNSC.

Radiosensitivity-Related Genes and Clinical Characteristics of Nasopharyngeal Carcinoma.

MATERIALS AND METHODS: Clinicopathological data of 185 patients with NPC treated at Nanfang Hospital of Southern Medical University between January 2013 and December 2014 were retrospectively analyzed. SPSS statistical software was used to analyze the clinicopathological data related to radiotherapy efficacy. Three patients who achieved complete remission and three with disease progression after CRT were selected. Differentially expressed genes (DEGs) were screened via mRNA microarray analysis of primary diagnostic endoscopy specimens. RESULTS: The peripheral blood leukocyte count, platelet count, and EBV-DNA copy number in NPC patients who were resistant to radiotherapy were higher than those in NPC patients who were sensitive to radiotherapy. The RobustRankAggreg (RRA) analysis method identified 392 DEGs, and the 66 most closely related genes among the DEGs were identified from the PPI network. CONCLUSION: The results of this study indicate that screening for DEGs and pathways in NPC using integrated in silico analyses can help identify a series of genetic and clinical signatures for NPC patients treated with neoadjuvant chemotherapy followed by concurrent chemoradiotherapy.

Metformin prevents LYRM1-induced insulin resistance in 3T3-L1 adipocytes via a mitochondrial-dependent mechanism.

We previously proposed that LYR motif containing 1 (LYRM1)-induced mitochondrial reactive oxygen species (ROS) production contributes to obesity-related insulin resistance. Metformin inhibits ROS production and promotes mitochondrial biogenesis in specific tissues. We assessed the effects of metformin on insulin resistance in LYRM1-over-expressing 3T3-L1 adipocytes. Metformin enhanced basal and insulin-stimulated glucose uptake and GLUT4 translocation, reduced IRS-1 and Akt phosphorylation and ROS levels, and affected the expression of regulators of mitochondrial biogenesis in LYRM1-over-expressing adipocytes. Metformin may ameliorate LYRM1-induced insulin resistance and mitochondrial dysfunction in part via a direct antioxidant effect and in part by activating the adenosine monophosphate-activated protein kinase (AMPK)-PGC1/NRFs pathway.

MiR-146b is a regulator of human visceral preadipocyte proliferation and differentiation and its expression is altered in human obesity.

Visceral obesity is an independent risk factor for metabolic syndrome, and abnormal fat accumulation is linked to increases in the number and size of adipocytes. MiR-146b was a miRNA highly expressed in mature adipocytes while very lowly expressed in human mesenchymal stem cells (hMSCs) and human visceral preadipocytes (vHPA). In this paper, we mainly focused on the roles of miR-146b in adipogenesis. We found miR-146b could inhibit the proliferation of visceral preadipocytes and promote their differentiation. MiR-146b in human visceral adipocytes inhibited the expression of KLF7, a member of the Kruppel-like transcription factors, as demonstrated by a firefly luciferase reporter assay, indicating that KLF7 is a direct target of the endogenous miR-146b. MiR-146b expression was significantly altered in visceral and subcutaneous adipose tissues in human overweight and obese subjects, and in the epididymal fat tissues and brown fat tissues of diet-induced obese mice. Our data indicates that miR-146b may be a new therapeutic target against human visceral obesity and metabolic dysfunction.

Knockdown of LYRM1 rescues insulin resistance and mitochondrial dysfunction induced by FCCP in 3T3-L1 adipocytes.

LYR motif-containing 1 (LYRM1) was recently discovered to be involved in adipose tissue homeostasis and obesity-associated insulin resistance. We previously demonstrated that LYRM1 overexpression might contribute to insulin resistance and mitochondrial dysfunction. Additionally, knockdown of LYRM1 enhanced insulin sensitivity and mitochondrial function in 3T3-L1 adipocytes. We investigated whether knockdown of LYRM1 in 3T3-L1 adipocytes could rescue insulin resistance and mitochondrial dysfunction induced by the cyanide p-trifluoromethoxyphenyl-hydrazone (FCCP), a mitochondrion uncoupler, to further ascertain the mechanism by which LYRM1 is involved in obesity-associated insulin resistance. Incubation of 3T3-L1 adipocytes with 1 µM FCCP for 12 h decreased insulin-stimulated glucose uptake, reduced intracellular ATP synthesis, increased intracellular reactive oxygen species (ROS) production, impaired insulin-stimulated Glucose transporter type 4 (GLUT4) translocation, and diminished insulin-stimulated tyrosine phosphorylation of Insulin receptor substrate-1 (IRS-1) and serine phosphorylation of Protein Kinase B (Akt). Knockdown of LYRM1 restored insulin-stimulated glucose uptake, rescued intracellular ATP synthesis, reduced intracellular ROS production, restored insulin-stimulated GLUT4 translocation, and rescued insulin-stimulated tyrosine phosphorylation of IRS-1 and serine phosphorylation of Akt in FCCP-treated 3T3-L1 adipocytes. This study indicates that FCCP-induced mitochondrial dysfunction and insulin resistance are ameliorated by knockdown of LYRM1.