MiR-1231 correlates tumor prognosis and inhibits cell growth in ovarian cancer.

OBJECTIVE: The purpose of this study was to investigate the expression characteristics of miR-1231 in ovarian cancer (OC), and to further explore its effects on cell proliferation capacity of OC cells. PATIENTS AND METHODS: Quantitative Real Time-Polymerase Chain Reaction (QRT-PCR) was performed to detect miR-1231 expression in 116 paired of OC and matched adjacent normal tissues. The association of miR-1231 expression and clinicopathological features and prognosis was analyzed. Furthermore, the effects of miR-1231 on cell proliferation and cell cycle of OC cells were evaluated by functional assays. RESULTS: In the study, the results exhibited that miR-1231 expression was lower in ovarian cancer tissues compared with adjacent normal tissues. Lower miR-1231 expression was associated with tumor clinical stage and lymph node invasion in patients. Survival plots by K-M survival analysis showed that lower miR-1231 expression predicted a poor outcome in ovarian cancer patients. Moreover, multivariate analysis implied that miR-1231 expression was an independent maker of overall survival (OS). Functional assays showed that upregulation of miR-1231 expression inhibited cell proliferation and cell cycle progression. CONCLUSIONS: We revealed that miR-1231 expression was lower in ovarian cancer tissues cell lines. Lower miR-1231 expression predicted a poor outcome in ovarian cancer patients and upregulation of miR-1231 expression inhibited cell growth.

Burden of diabetes, hyperglycaemia in China from to 2016: Findings from the 1990 to 2016, global burden of disease study.

AIMS: The prevalence of diabetes in China is among the highest in the world. For this reason, findings from the 2016 Global Burden of Disease (GBD) study were used to calculate the burden of hyperglycaemia and diabetes in China. METHODS: Following the general analytical strategy used in GBD 2016, diabetes prevalence and mortality were analyzed by age and gender. Trends in disability-adjusted life years (DALYs) due to diabetes were assessed in 33 province-level administrative units from 1990 to 2016, and similar data were provided for chronic kidney disease (CKD) related to diabetes and, as an overall summarizing measure, for hyperglycaemia expressed as high fasting plasma glucose (HFPG). RESULTS: From 1990 to 2016, all-age prevalence of diabetes rose from 3.7% to 6.6%, and all-age diabetes and diabetes-related CKD mortality rates increased by 63.5% and 33.3%, respectively, with both rates increasing more rapidly in diabetes patients aged 15-49 years than in any other age groups. In 2016, HFPG became China's sixth leading cause of DALYs, and the attributable DALYs burden was 1802.3/100,000 population. Although the number of diabetes DALYs increased by 95% from 1990 to 2016, age-standardized diabetes DALYs rates increased by only 2.3%. Also, from 1990 to 2016, rates of age-standardized DALYs due to diabetes decreased in 14 provinces, but increased in 19 provinces. High BMI Scores and diets low in whole grains, nuts and seeds were the most important risk factors for diabetes in 2016. CONCLUSION: Diabetes and hyperglycaemia constitute a huge health burden in China. The substantial increase in diabetes-related burden represents an ongoing challenge, given the rapidly ageing Chinese population. Thus, a targeted control and preventative strategy needs to be developed at risk factor level to reduce this burden.

Targeting the vulnerability to NAD+ depletion in B-cell acute lymphoblastic leukemia.

Although substantial progress has been made in the treatment of B-cell acute lymphoblastic leukemia (B-ALL), the prognosis of patients with either refractory or relapsed B-ALL remains dismal. Novel therapeutic strategies are needed to improve the outcome of these patients. KPT-9274 is a novel dual inhibitor of p21-activated kinase 4 (PAK4) and nicotinamide phosphoribosyltransferase (NAMPT). PAK4 is a serine/threonine kinase that regulates a variety of fundamental cellular processes. NAMPT is a rate-limiting enzyme in the salvage biosynthesis pathway of nicotinamide adenine dinucleotide (NAD) that plays a vital role in energy metabolism. Here, we show that KPT-9274 strongly inhibits B-ALL cell growth regardless of cytogenetic abnormalities. We also demonstrate the potent in vivo efficacy and tolerability of KPT-9274 in a patient-derived xenograft murine model of B-ALL. Interestingly, although KPT-9274 is a dual PAK4/NAMPT inhibitor, B-ALL cell growth inhibition by KPT-9274 was largely abolished with nicotinic acid supplementation, indicating that the inhibitory effects on B-ALL cells are mainly exerted by NAD+ depletion through NAMPT inhibition. Moreover, we have found that the extreme susceptibility of B-ALL cells to NAMPT inhibition is related to the reduced cellular NAD+ reserve. NAD+ depletion may be a promising alternative approach to treating patients with B-ALL.

Neuropilin-1 contributes to esophageal squamous cancer progression via promoting P65-dependent cell proliferation.

Neuropilin-1 (NRP1) is a non-kinase receptor recently implicated in tumor progression. Here we revealed that over-expression of NRP1 correlates with poor prognosis in esophageal squamous cell carcinoma (ESCC). NRP1-knockdown suppressed ESCC cell proliferation and xenograft tumor growth. Reduced NRP1 expression downregulated P65 mRNA and protein expression, and ectopic expression of P65-restored cell proliferation in NRP1-silenced cells. NRP1 regulates P65 transcription by activating cAMP responsive element binding protein (CREB). NRP1 interacted with and activated epidermal growth factor receptor (EGFR), and b1/b2 domain of NRP1 is responsible for the activation of EGFR. We also found that EGFR regulated CREB transcriptional activity via AKT. These data suggest that NRP1 is an upstream regulator in the P65-dependent proliferation signaling pathway and a candidate therapeutic target for ESCC.

Effects of Bacillus fermentation on the protein microstructure and anti-nutritional factors of soybean meal.

This study evaluated the effects of Bacillus fermentation on soybean meal protein (SBMP) microstructure and major anti-nutritional factors (ANFs) in soybean meal (SBM). The Bacillus siamensis isolate JL8 producing high yield of protease at 519·1 U g-1 was selected for the laboratory production of fermented soybean meal (FSBM). After 24 h fermentation, the FSBM showed better properties compared with those of SBM, the ANFs such as glycinin, ß-conglycinin and trypsin inhibitor significantly decreased by 86·0, 70·3 and 95·01%, while in vitro digestibility and absorbability increased by 8·7 and 18·9% respectively. Scanning electron microscopy (SEM) image of fermented soybean meal protein showed smaller aggregates and looser network than that of SBMP. Secondary structure examination of proteins revealed fermentation significantly decreased the content of ß-sheet structure by 43·2% and increased the random coil structure by 59·9%. It is demonstrated that Bacillus fermentation improved the nutritional quality of SBM through degrading ANFs and changing the microstructure of SBMP. SIGNIFICANCE AND IMPACT OF THE STUDY: There is limited information about the structural property changes of soybean protein during fermentation. In this study, physicochemical analysis of soybean meal protein showed evidence that the increase in in vitro digestibility and absorbability of fermented soybean meal reflected the decrease in ß-conformation and destruction of original structure in soybean meal protein. The results directly gained the understanding of nutritional quality improvement of soybean meal by Bacillus fermentation, and supply the potential use of Bacillus siamensis for fermented soybean meal production.

Ordering of mutations in acute myeloid leukemia with partial tandem duplication of MLL (MLL-PTD).

Partial tandem duplication of MLL (MLL-PTD) characterizes acute myeloid leukemia (AML) patients often with a poor prognosis. To understand the order of occurrence of MLL-PTD in relation to other major AML mutations and to identify novel mutations that may be present in this unique AML molecular subtype, exome and targeted sequencing was performed on 85 MLL-PTD AML samples using HiSeq-2000. Genes involved in the cohesin complex (STAG2), a splicing factor (U2AF1) and a poorly studied gene, MGA were recurrently mutated, whereas NPM1, one of the most frequently mutated AML gene, was not mutated in MLL-PTD patients. Interestingly, clonality analysis suggests that IDH2/1, DNMT3A, U2AF1 and TET2 mutations are clonal and occur early, and MLL-PTD likely arises after these initial mutations. Conversely, proliferative mutations (FLT3, RAS), typically appear later, are largely subclonal and tend to be unstable. This study provides important insights for understanding the relative importance of different mutations for defining a targeted therapeutic strategy for MLL-PTD AML patients.

ZNF750 is a lineage-specific tumour suppressor in squamous cell carcinoma.

ZNF750 controls epithelial homeostasis by regulating epidermal-differentiation genes, a role underscored by its pathogenic mutations in esophageal squamous cell cancers (SCCs). However, the precise role of ZNF750 in SCC cell biology remains unclear. In this study, we report that ZNF750 is exclusively deleted, mutated and underexpressed in human SCCs, and low ZNF750 expression is associated with poor survival. Restoration of wildtype, but not mutant ZNF750 protein uniquely inhibited the malignant phenotypes of SCC cells both in vitro and in vivo. Notably, ZNF750 promoted the expression of a long non-coding RNA (TINCR), which mediated both cancer-inhibition and differentiation-induction effects of ZNF750. In addition, ZNF750 potently suppressed cell migration by directly inhibiting the transactivation of LAMC2. Together, our findings characterize ZNF750 as a crucial SCC-specific suppressor and uncover its novel anticancer-associated functions.

Correlation between hyoid bone position and airway dimensions in Chinese adolescents by cone beam computed tomography analysis.

This study aimed to investigate the correlation between upper airway dimensions and hyoid bone position in Chinese adolescents based on cone beam computed tomography (CBCT) images. CBCT images from a total of 254 study subjects were included. The upper airway and hyoid bone parameters were measured by Materialism's interactive medical image control system (MIMICS) v.16.01 (Materialise, Leuven, Belgium). The airway dimensions were evaluated in terms of volume, cross-sectional area (CSA), mean CSA, length, anteroposterior dimension of the cross-section (AP), lateral dimension of the cross-section (LAT), and LAT/AP ratio. The hyoid bone position was evaluated using eight linear parameters and two angular parameters. Facial characteristics were evaluated using three linear parameters and three angular parameters. Most hyoid bone position parameters (especially the distance between the hyoid bone and hard palate) were significantly associated with most airway dimension parameters. Significant correlations were also observed between the different facial characteristic parameters and hyoid bone position parameters. Most airway dimension parameters showed significant correlations with linear facial parameters, but they displayed significant correlations with only a few angular facial parameters. These findings provide an understanding of the static relationship between the hyoid bone position and airway dimensions, which may serve as a reference for surgeons before orthodontic or orthognathic surgery.

Microtubule-associated protein 4 is an important regulator of cell invasion/migration and a potential therapeutic target in esophageal squamous cell carcinoma.

Cell invasion and migration significantly contribute to tumor metastasis. Microtubule-associated protein 4 (MAP4) protein is one member of microtubule-associate proteins family. It is responsible for stabilization of microtubules by modulation of microtubule dynamics. However, there is little information about the involvement of MAP4 in human cancer. Here we show that MAP4 serves as a regulator of invasion and migration in esophageal squamous cancer cells. By activating the ERK-c-Jun-vascular endothelial growth factor A signaling pathway, MAP4 promotes cell invasion and migration in vitro, tumor growth and metastasis in mouse models. Immunohistochemical staining of operative tissues indicated that MAP4 expression was associated with tumor stage, lymph node metastasis and shorter survival of the patients with esophageal squamous cell carcinoma (ESCC). Multivariate Cox regression analysis showed that MAP4 is an independent prognostic indicator. In the serial sections of ESCC tissues, there was a positive correlation between MAP4 and vascular endothelial growth factor A expression. Notably, an intratumoral injection of MAP4-small interfering RNA (siRNA) remarkably inhibited the growth of the tumors that formed by the MAP4-expressing ESCC cells in nude mice, and a combination of MAP4-siRNA and Bevacizumab significantly enhanced the inhibition effect. Our data suggest that MAP4 is probably a useful prognostic biomarker and a potential therapeutic target for the disease.

Identification of putative target genes for amplification within 11q13.2 and 3q27.1 in esophageal squamous cell carcinoma

BACKGROUND: Genomic aberration is a common feature of human cancers and also is one of the basic mechanisms that lead to overexpression of oncogenes and underexpression of tumor suppressor genes. Our study aims to identify frequent genomic changes and candidate copy number driving genes in esophageal squamous cell carcinoma (ESCC). METHODS: We used array comparative genomic hybridization to identify recurrent genomic alterations and screened the candidate targets of selected amplification regions by quantitative and semi-quantitative RT-PCR. RESULTS: Thirty-four gains and 16 losses occurred in more than 50 % of ESCCs. High-level amplifications at 7p11.2, 8p12, 8q24.21, 11q13.2-q13.3, 12p11.21, 12q12 and homozygous deletions at 2q22.1, 8p23.1-p21.2, 9p21.3 and 14q11.2 were also identified. 11q13.2 was a frequent amplification region, in which five genes including CHKA, GAL, KIAA1394, LRP5 and PTPRCAP were overexpressed in tumor tissues than paracancerous normal tissues. The expression of ALG3 at 3q27.1 was higher in ESCCs, especially in patients with lymph node metastasis. CONCLUSIONS: Target gene identification of amplifications or homozygous deletions will help to reveal the mechanism of tumor formation and explore new therapy method (AU)

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Identification of putative target genes for amplification within 11q13.2 and 3q27.1 in esophageal squamous cell carcinoma.

BACKGROUND: Genomic aberration is a common feature of human cancers and also is one of the basic mechanisms that lead to overexpression of oncogenes and underexpression of tumor suppressor genes. Our study aims to identify frequent genomic changes and candidate copy number driving genes in esophageal squamous cell carcinoma (ESCC). METHODS: We used array comparative genomic hybridization to identify recurrent genomic alterations and screened the candidate targets of selected amplification regions by quantitative and semi-quantitative RT-PCR. RESULTS: Thirty-four gains and 16 losses occurred in more than 50 % of ESCCs. High-level amplifications at 7p11.2, 8p12, 8q24.21, 11q13.2-q13.3, 12p11.21, 12q12 and homozygous deletions at 2q22.1, 8p23.1-p21.2, 9p21.3 and 14q11.2 were also identified. 11q13.2 was a frequent amplification region, in which five genes including CHKA, GAL, KIAA1394, LRP5 and PTPRCAP were overexpressed in tumor tissues than paracancerous normal tissues. The expression of ALG3 at 3q27.1 was higher in ESCCs, especially in patients with lymph node metastasis. CONCLUSIONS: Target gene identification of amplifications or homozygous deletions will help to reveal the mechanism of tumor formation and explore new therapy method.

Altered protein profile of lymphocytes in an antigen-specific model of colitis: a comparative proteomic study.

OBJECTIVE: Lymphocytes are deeply involved in the initiation and perpetuation of inflammatory response in inflammatory bowel disease (IBD) and lymphocyte-derived proteins are associated with the pathogenesis of the disease. The aim of this study was to identify the altered protein profiles of lymphocytes from rats with colitis. METHODS: Colitis models were induced by colonic administration of trinitrobenzene sulfonic acid (TNBS) in 50% ethanol in male SD rats. Seven days after administration of TNBS/ethanol, lymphocytes were harvested from mesenteric lymph nodes (MLNs) and proteins were extracted. Two-dimensional polyacrylamide gel electrophoresis and PDQuest 2D-image-analysis software were used to display and analyze the protein spots. The differentially-expressed proteins were identified by tryptic in-gel digestion and mass spectrometry. Real-time RT-PCR was used for selected transcripts to validate the findings of the proteomics analysis. RESULTS: A total of 1,100 protein spots including 26 proteins with at least a two-fold difference in abundance between colitis and control groups were identified. Among all the detected spots, 17 were up-regulated and 9 were down-regulated. It was found that the altered proteins included the regulators of the cell cycle and cell proliferation, signal transduction factors, inflammatory factors, apoptosis-related proteins and metabolic enzymes. CONCLUSIONS: In lymphocytes of rats with TNBS-induced colitis, 26 altered proteins were identified. They involve inflammation, apoptosis, metabolism, and regulation of the cell cycle, cell proliferation, and signal transduction.