A maternal low-protein diet impaired glucose metabolism and altered the lncRNA profiles of islets in adult offspring.

A maternal low-protein diet during pregnancy can increase children's susceptibility to diabetes mellitus in adulthood. However, whether long noncoding RNAs (lncRNAs) in islets participate in the development of diabetes in adult offspring following maternal protein restriction is not fully understood. Female mice were fed a low-protein (LP) diet or control diet throughout gestation and lactation. The male offspring were then randomly divided into two groups according to maternal diet: offspring from control diet group dams (Ctrl group) and offspring from LP group dams (LP group). We observed the glucose metabolism of adult offspring. A lncRNA microarray was constructed for the islets from the LP group and Ctrl group to explore the differently expressed lncRNAs. Gene ontology enrichment and Kyoto Encyclopedia of Genes and Genomes analyses were subsequently used to predict the functions of the differently expressed lncRNAs. The body weight from birth to 12 weeks of age was significantly lower in the LP offspring. Adult LP offspring exhibited impaired glucose tolerance and decreased insulin secretion, consistent with the reduction in ß-cell proliferation. According to the lncRNA microarray, four lncRNAs, three upregulated lncRNAs, and one downregulated lncRNA were differently expressed in LP offspring islets compared with Ctrl offspring. Gene ontology enrichment and Kyoto Encyclopedia of Genes and Genomes pathway analyses revealed that these differentially expressed lncRNAs were mostly associated with the hypoxia-inducible factor-1α signaling pathway. Additionally, we validated the expression of these four differentially expressed lncRNAs via quantitative real-time polymerase chain reaction. Our findings demonstrated the expression patterns of lncRNAs in islets from adult offspring of mothers who consumed a maternal low-protein diet.

The identification of liver metastasis- and prognosis-associated genes in pancreatic ductal adenocarcinoma.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is an often fatal malignancy with an extremely low survival rate. Liver metastasis, which causes high mortality, is the most common recurring metastasis for PDAC. However, the mechanisms underlying this liver metastasis and associated candidate biomarkers are unknown. METHODS: We performed mRNA profiling comparisons in 8 primary tumors (T) and 12 liver metastases (M) samples using the Gene Expression Omnibus (GEO) database. After determining differentially expressed genes (DEG), gene ontology (GO), pathway enrichment and protein-protein interaction (PPI) network analyses were performed to determine DEG functions. Then, Cytoscape was used to screen out significant hub genes, after which their clinical relevance was investigated using The Cancer Genome Atlas (TCGA) resources. Furthermore, prognosis-associated gene expression was validated using Oncomine and TCGA database. Lastly, associations between prognosis-associated genes, immune cells and immunological checkpoint genes were evaluated using the Tumor Immune Estimation Resource (TIMER). RESULTS: In total, 102 genes were related to liver metastasis and predominantly involved in cell migration, motility, and adhesion. Using Cytoscape, this number was narrowed down to 16 hub genes. Elevated mRNA expression levels for two of these genes, SPARC (P = 0.019) and TPM1 (P = 0.037) were significantly correlated with poor disease prognosis. For the remaining 14, expression was not related to overall patient survival. SPARC had higher expression in patients with metastatic PDAC than those with non-metastatic PDAC in TCGA dataset. SPARC and TPM1 levels were also positively correlated with the immune infiltration of specific cell types. Additionally, both genes exhibited strong co-expression associations with immune checkpoint genes. CONCLUSIONS: Combined, we suggest SPARC has high potential as biomarker to predict liver metastasis during PDAC. Additionally, both SPARC and TPM1 appeared to recruit and regulate immune-infiltrating cells during these pathophysiological processes.

Downregulation of Kcnq1ot1 attenuates ß-cell proliferation and insulin secretion via the miR-15b-5p/Ccnd1 and Ccnd2 axis.

AIM: To examine the effect of lncRNA Kcnq1ot1 on pancreatic ß cells in the development of diabetes. METHODS: The expression levels of Kcnq1ot1 were detected in the islets of diabetes mouse models and the serum of patients with type 2 diabetes by qRT-PCR. CCK8, Ki67 staining, immunohistochemical analyses, glucose-stimulated insulin secretion and intraperitoneal glucose tolerance test were performed to detect the effect of Kcnq1ot1 on ß-cell proliferation and insulin secretion in vitro and in vivo. The relationship between Kcnq1ot1 and miR-15b-5p was predicted by bioinformatics prediction, which was confirmed by luciferase reporter assay. RESULTS: Kcnq1ot1 was more abundant in the pancreas. The expression of Kcnq1ot1 was decreased in the islets of db/db mice and diet-induced obese mice and in the serum of patients with type 2 diabetes. Silencing Kcnq1ot1 inhibited the ß-cell proliferation concomitant with a reduction in the levels of Ccnd1 and Ccnd2. Insulin synthesis and secretion were impaired, along with the decreased expression of Ins1, Ins2, and insulin-related transcription factors. Moreover, Kcnq1ot1 knockdown in vivo reduced glucose tolerance and decreased insulin secretion, consistent with the reduction in the relative islet area and Ki67-positive ß-cells detected by immunochemistry and immunofluorescence staining, respectively. Mechanistically, Kcnq1ot1 directly targeted miR-15b-5p which regulated ß-cell proliferation and insulin secretion through Ccnd1 and Ccnd2. Notably, the suppression of miR-15b-5p attenuated the inhibition of Min6 proliferation and insulin production induced by Kcnq1ot1 knockdown. CONCLUSION: Kcnq1ot1 regulated ß-cell proliferation and insulin secretion via the miR-15b-5p/Ccnd1 and Ccnd2 axis, which is worthy of further investigation considering its potential in diabetes treatment.

Bioinformatic identification of differentially expressed genes regulated by DNA-methylation in glioblastoma.

DNA methylation-driven differentially expressed genes (DEGs) play potentially important roles in glioblastoma (GBM). In the present study, we applied bioinformatic analyses to identify key methylation-regulated DEGs (MeDEGs) in glioblastoma and elucidate their functions. Gene expression and methylation profile data from glioblastoma samples along with clinical information were obtained from GEO and TCGA databases. A total of 65 genes were identified as MeDEGs from the aforementioned data. Subsequently, gene ontology and kyoto encyclopaedia of genes and genomes enrichment analyses of these MeDEGs exhibited that MeDEGs were mostly enriched in several tumour-related terms such as 'activation of cysteine-type endopeptidase activity involved in apoptotic process' and 'phospholipid scrambling'. Kaplan-Meier survival analysis demonstrated significant correlation of CASP1, CFH and TTLL7 hyper-methylation with patient prognosis. Finally, CASP1 protein could indirectly interact with CFH protein, but interaction of TTLL7 protein with CASP1 or CFH protein was not evident. Based on gene set enrichment analysis, hyper-methylation of CASP1, CFH and TTLL7 were found enriched in tumour-related KEGG terms, such as 'RNA degradation', 'apyruvate metabolism' and 'nitrogen metabolism'. Methylation levels of CASP1, CFH and TTLL7 were addressed to negatively correlate with their mRNA levels in GBM cell lines. In sum, the present identification of MeDEGs associated with overall survival put forth potential molecular targets for translation towards improved diagnosis and treatment of GBM, and specifically, methylation levels of CASP1, CFH and TTLL7 genes could serve as key prognostic biomarkers in GBM.

Expression of HER2 and BRCA1 Correlates with Prognosis in Patients with Breast Cancer After Radiotherapy: A Case-Control Study.

Background: This study aims to explore the associations of human epidermal growth factor receptor 2 (HER2) and breast cancer susceptibility gene 1 (BRCA1) expression levels with prognosis and radiation sensitivity in patients with breast cancer. Materials and Methods: Breast cancer tissues, adjacent normal breast tissues, and benign breast lesions were initially obtained from 256 breast cancer patients as well as an additional 245 patients with breast lesions. Reverse transcriptase-quantitative polymerase chain reaction (RT-qPCR) was conducted to assess the expression of HER2 and BRCA1 in the collected tissues. Immunohistochemistry was performed to examine HER2 and BRCA1-positive expression levels in the tissues. The relationship between HER2 and BRCA1 expression levels and radiation sensitivity as well breast cancer prognosis was assessed by the Spearman correlation analysis and Kaplan-Meier survival analysis. Results: Compared with adjacent normal breast tissues and benign breast lesions, the breast cancer tissues exhibited high expression of HER2 mRNA and protein, and low expression of BRCA1 mRNA and protein. Patients with positive HER2 expression had a significantly shorter survival time, and survival time of patients with positive BRCA1 expression was markedly longer, which were consistent with RT-qPCR results. After radiotherapy, the local failure rate of HER2-positive patients was higher than that of the negative ones, while that of BRCA1-positive patients was lower than that of the negative ones. Conclusions: This study suggested that breast cancer patients with high HER2 expression and low BRCA1 expression were less sensitive to radiotherapy with poor prognosis in breast cancer.

A Risk Signature Consisting of Eight m6A Methylation Regulators Predicts the Prognosis of Glioma.

Glioma progression seriously correlates to the epigenetic context. This study aims to identify glioma subtypes by clustering analysis of patients using the multi-omics data of N6-methyladenosine (m6A) methylation regulators and to construct a risk signature for investigating the role of m6A methylation regulators in the prognosis of glioma. Multi-omics data of glioma and normal control tissues were obtained through The Cancer Genome Atlas (TCGA) database. The clustering analysis of multi-omics data of patients was conducted using the R package iClusterPlus software. The risk model was constructed by univariate and multivariate Cox analysis, and the glioma expression data and related clinical data were obtained by Chinese Glioma Genome Atlas (CGGA) datasets to verify the risk model. By analyzing the glioma data in TCGA, we found that the risk signature could be constructed according to the eight genes with m6A methylation modification function, including ALKBH5, HNRNPA2B1, IGF2BP2, IGF2BP3, RBM15, WTAP, YTHDF1, and YTHDF2. Meanwhile, we found that IGF2BP2 and IGF2BP3 were highly expressed in glioma subtypes with high-risk scores and closely related to the prognosis of glioma patients. m6A methylation regulators, especially IGF2BP2 and IGF2BP3, play important roles in the malignant progression of glioma. The risk signature constructed by eight m6A methylation regulators can predict the prognosis of glioma. IGF2BP2 and IGF2BP3 may be the key regulatory factors of m6A methylation regulators involved in the occurrence and development of glioma, and can serve as molecular markers for the prognosis of glioma.

Fabrication of One-Dimensional Organic Nanofiber Networks via Electrophoretic Deposition for a Nonvolatile Memory Device.

Despite many advanced growth methodologies for organic nanofibers (ONFs), the lack of efficient and scalable ONF-based film preparation technologies has long been a hindrance in their practical application in organic electronic devices. Here, a typical cathode electrophoretic deposition (C-EPD) technology was developed to controllably produce ONFs and their corresponding thin films. Using the solvent effect and an external electric field force during the C-EPD process, a one-dimensional ONF network was formed, which exhibits compact molecular packing and superior optoelectronic properties in the thin-film state. Prototype sandwich-structure memory devices based on these ONF films exhibited a binary nonvolatile memory performance significantly superior than that of the bulk materials. This study provides an efficient and scalable ONF fabrication technology for high-performance electronic devices in various potential applications.

Identification of Key Prognostic Biomarker and Its Correlation with Immune Infiltrates in Pancreatic Ductal Adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is an extremely malignant tumor. The immune profile of PDAC and the immunologic milieu of its tumor microenvironment (TME) are unique; however, the mechanism of how the TME engineers the carcinogenesis of PDAC is not fully understood. This study is aimed at better understanding the relationship between the immune infiltration of the TME and gene expression and identifying potential prognostic and immunotherapeutic biomarkers for PDAC. Analysis of data from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) databases identified differentially expressed genes (DEGs), including 159 upregulated and 53 downregulated genes. Gene Ontology analysis and Kyoto Encyclopedia of Genes and Genomes enrichment were performed and showed that the DEGs were mainly enriched for the PI3K-Akt signaling pathway and extracellular matrix organization. We used the cytoHubba plugin of Cytoscape to screen out the most significant ten hub genes by four different models (Degree, MCC, DMNC, and MNC). The expression and clinical relevance of these ten hub genes were validated using Gene Expression Profiling Interactive Analysis (GEPIA) and the Human Protein Atlas, respectively. High expression of nine of the hub genes was positively correlated with poor prognosis. Finally, the relationship between these hub genes and tumor immunity was analyzed using the Tumor Immune Estimation Resource. We found that the expression of SPARC, COL6A3, and FBN1 correlated positively with infiltration levels of six immune cells in the tumors. In addition, these three genes had a strong coexpression relationship with the immune checkpoints. In conclusion, our results suggest that nine upregulated biomarkers are related to poor prognosis in PDAC and may serve as potential prognostic biomarkers for PDAC therapy. Furthermore, SPARC, COL6A3, and FBN1 play an important role in tumor-related immune infiltration and may be ideal targets for immune therapy against PDAC.

CONUT Score or/and Peripheral Blood CD4+/CD8+ Ratio-Based Web Dynamic Nomograms to Predict the Individualized Survival of Patients with Advanced Osteosarcoma.

BACKGROUND: Nutritional and immune status is paramount for the overall survival (OS) of patients with advanced osteosarcoma. Comprehensive prognostic predictors based on the two indices are scarce. This study aimed to construct and validate individualized web dynamic nomograms based on CONUT score or/and peripheral blood CD4+/CD8+ ratio for OS in patients with advanced osteosarcoma. MATERIALS AND METHODS: The clinical data of 376 advanced osteosarcoma patients from January 2000 to December 2019 were retrospectively collected. Data from the 301 patients (diagnosed in the first 15 years) were used as the development set and data from the remaining 75 patients were assigned as the validation set. Multivariate Cox regression analyses were conducted and three prediction models were constructed, namely, CD4+/CD8+ ratio univariate model (model 1), CONUT score univariate model (model 2), and CD4+/CD8+ ratio plus CONUT score (model 3). These models were visualized by conventional nomograms and individualized web dynamic nomograms, and their performances were further evaluated by C-index, calibration curve, receiver operating characteristic (ROC) curve, and decision curve analysis (DCA), respectively. RESULTS: In multivariate Cox analysis, age, metastasis, ALP, CD4+/CD8+ ratio, chemotherapy, and CONUT score were identified as independent prognostic factors for OS. The calibration curves of the three models all showed good agreement between the actual observation and nomogram prediction for 1-year overall survival. In the development set, the C-index and area under the curve (AUC) of model 3 (0.837, 0.848) were higher than that of model 1 (0.765, 0.773) and model 2 (0.712, 0.749). Similar trends were observed in the validation set. The net benefits of model 3 were better than the other two models within the threshold probability of 36-80% in DCA. CONCLUSION: CONUT score and peripheral CD4+/CD8+ ratio are easily available, reliable, and economical prognostic predictors for survival prediction and stratification in patients with advanced osteosarcoma, but the two predictors combined can establish a better prognosis prediction model.

Controllable and Versatile Electrophoretic Deposition Technology for Monolithic Organic Memory Devices.

Scaling up organic nanofilm deposition from the laboratory scale to the industrial scale is an important challenge for the booming organic electronics. Herein, we propose a high-efficiency technology for organic nanofilm deposition called electrophoretic deposition (EPD). EPD was used to produce scalable films based on an ingenious molecular design by introducing the pyridinium group and flexible substituents to versatile solution-processable organic salts. EPD films with an area of 104 mm2 and controllable film thickness ranging from 50 nm to 1.55 µm can be easily fabricated using an organic solvent under different deposition conditions. Compared with traditional spin-coated films, the superior electrochemical and mechanical properties of EPD films are ascribed to their compact molecular packing, high purity, and uniform morphology. Evaluation of 2745 device units integrated into a 104 mm2 monolithic organic memory device showed that 95% of the device units possessed excellent binary data-storage performance with high stability and reproducibility, small reading bias (1.0 V), and large ON/OFF ratio (>103). Furthermore, decoating tests of EPD-based films and devices by the process of reverse EPD with switched electrode polarity suggested the potential application for information storage security and active environmental protection by simultaneously separating and recycling metal electrodes and organic materials.

[Clinical Trials for Treatment of Allergic Rhinitis with Heat Sensitive Moxibustion and Its Regularity of Heat-sensitization Acupoint Distribution].

OBJECTIVE: To observe the clinical effect of heat sensitive moxibustion (HSM) and its regularity of acupoint heat-sensitization in the treatment of allergic rhinitis (AR) patients. METHODS: Seventy patients with AR were randomly divided into HSM and manual acupuncture groups (n＝35/group). For patients of the HSM group, acupoints Yintang (EX-HN 3), bilateral Yingxiang (LI 20), Shangxing (GV 23), Tongtian (BL 7), Feishu (BL 13), Hegu (LI 4), etc. were used, and for patients of the manual acupuncture group, bilateral LI 20 and LI 4, Bitong (EX-HN 8) and EX-HN 3 were needled and stimulated with uniform reinforcing-reducing needling method. The treatment was conducted once every other day, for 20 days, with 3 days' interval between two 10 days. The symptoms of sneezing, running nose, nasal obstruction, and nasal itching were scored as 1, 2 and 3 points according to their severity. The signs of turbinate-nose cavity bottom/nasal septum correlation, morphological state (swelling or not) of inferior nasal concha and color of nasal mucosa, appearance (deviation or polyp) of the middle turbinate and nasal septum were scored as 1, 2 and 3 points according to their severity. The total score equaled to symptom score plus nasal sign score. The distribution of heat sensitization acupoints for effectively improving AR were recorded. RESULTS: The total effective rate of 82.86%(29/35) in the HSM group had no marked difference in comparison with that of 74.29%(26/35) in the manual acupuncture group (P>0.05). After the treatment, the total scores of symptoms and nasal signs of both HSM and manual acupuncture groups were significantly reduced in comparison with their own individual pre-treatment (P<0.01), and those in the HSM group were significantly decrased than those in the manual acupuncture group (P<0.05). In 35 patients of the HSM group, among the detected 57 acupoints, the most frequently sensitive acupoints were LI 20, EX-HN 3, EX-HN 8, Shangyintang, BL 13, Shenque(CV 8), GV 23, Fengchi(GB 20), Die'e and Dazhui (GV 14) in sequence, mainly covering the Governor Vessel, Large Intestine Meridian of Hand-yangming(LI), and Bladder Meridian of Foot-taiyang(BL), and characterized by heat conduction, heat diffusion, diathermancy, non-thermal (mainly itching) sensation, thermal sensation mainly in the deep tissue and in the distant part rather than in the body surface and the local part. CONCLUSIONS: HSM has a positive effect on improvement of AR, when applied, acupoints LI 20, EX-HN 3, EX-HN 8, Shangyintang, BL 13, CV 8, GV 23, GB 20, Die'e and GV 14 are highly recommended.