Trophinin-associated protein expression correlates with shorter survival of patients with glioma: a study based on multiple data fusion analysis.

BACKGROUND: Trophinin-associated protein (TROAP) mediates embryonic transfer, regulates microtubules, and is associated with the biological behavior of various cancers. However, there is limited information on the role of TROAP in glioma. METHODS AND RESULTS: We obtained clinical information on 1948 patients with glioma from The Cancer Genome Atlas, Gene Expression Omnibus and the Chinese Glioma Genome Atlas. Basal assays were used to measure changes in TROAP expression levels in high-grade glioma cell lines and in normal human astrocytes. Quantitative reverse transcription polymerase chain reaction assays showed that TROAP expression was higher in glioma cell lines than in normal astrocytes. The expression level of TROAP in 749 glioma was significantly higher than that in 228 normal brain tissues using Student's t test. The expression of TROAP has a positive relationship with the clinical characteristics of poor prognosis, such as WHO grade, age and has negatively correlated with the indicators of beneficial prognosis, such as IDH mutation and 1p19q co-deletion. Kaplan-Meier survival curves, single multifactor analysis were used to analyze correlations between TROAP and clinical features and prognosis of gliomas. In addition, TROAP overexpression was an independent risk factor for glioma and was associated with reduced overall survival of patients with glioma particularly in patients with WHO grade III and grade IV glioma. Gene set enrichment analysis showed that homologous recombination, cell cycle, and p53 signaling pathways were enriched in samples overexpressing TROAP. CONCLUSION: TROAP is a potential risk factor associated with poor prognosis in patients with glioma and may act as a highly specific biomarker, offering the possibility of individualized glioma treatment.

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.

Precise microdeletion detection of Prader-Willi Syndrome with array comparative genome hybridization.

OBJECTIVE: Prader-Willi Sydrome (PWS) is a human disorder related to genomic imprinting defect on 15q11-13. It is characterized by a series of classic features such as hypotonia, hyperphagia, obesity, osteoporosis, typical facial and body dysmorphosis, hypogonadism, mental and behaviour disorders. Our study was designed to precisely detect the microdeletions, which accounts for 65%-70% of the PWS. METHODS: Physical and laboratory examinations were firstly performed to diagnose PWS clinically, and to discover novel clinical features. Then the patient was screened with bisulfite-specific sequencing and precisely delineated through high-density array CGH. RESULTS: With the bisulfite-specific sequencing, the detected CpG island in the PWS critical region was found homozygously hypermethylated. Then with array CGH, a 2.22 Mb type II microdeletion was detected, covering a region from MKRN3, MAGEL2, NDN, PWRN2, PWRN1, C12orf2, SNURF-SNRPN, C/D snoRNAs, to distal of UBE3A. CONCLUSIONS: Array CGH, after the fast screening of Bisulfite-specific sequencing, is a feasible and precise method to detect microdeletions in PWS patients. A novel feature of metacarpophalangeal joint rigidity was also presented, which is the first time reported in PWS.

The relationship between insulin sensitivity and heart rate-corrected QT interval in patients with type 2 diabetes.

BACKGROUND: Reduced insulin sensitivity not only contributes to the pathogenesis of type 2 diabetes but is also linked to multiple metabolic risk factors and cardiovascular diseases (CVD). A prolonged heart rate-corrected QT interval (QTc interval) is related to ventricular arrhythmias and CVD mortality and exhibits a high prevalence among type 2 diabetes patients. The aim of the study was to investigate the relationship between insulin sensitivity and the QTc interval in patients with type 2 diabetes. METHODS: This cross-sectional observational study recruited 2927 patients with type 2 diabetes who visited the Affiliated Haian Hospital and Second Affiliated Hospital of Nantong University. The insulin sensitivity index (Matsuda index, ISIMatsuda) derived from 75-g OGTT and other metabolic risk factors were examined in all patients. The QTc interval was estimated using a resting 12-lead electrocardiogram, and an interval longer than 440 ms was considered abnormally prolonged. RESULTS: The QTc interval was significantly and negatively correlated with the ISIMatsuda (r = -0.296, p < 0.001), and when the multiple linear regression analysis was adjusted for anthropometric parameters, metabolic risk factors, and current antidiabetic treatments, the QTc interval remained significantly correlated with the ISIMatsuda (ß = -0.23, t = -12.63, p < 0.001). The proportion of patients with prolonged QTc interval significantly increased from 12.1% to 17.9%, 25.6% and 37.9% from the fourth to third, second and first quartile of the ISIMatsuda, respectively. After adjusting for anthropometric parameters by multiple logistic regression analysis, the corresponding odd ratios (ORs) for prolonged QTc interval of the first, second and third quartiles versus the fourth quartile of ISIMatsuda were 3.11 (95% CI 2.23-4.34), 2.09 (1.51-2.88) and 1.53 (1.09-2.14), respectively, and p for trend was <0.001. CONCLUSIONS: Reduced insulin sensitivity is associated with an increase in the QTc interval in patients with type 2 diabetes.

The association of long-term glycaemic variability versus sustained chronic hyperglycaemia with heart rate-corrected QT interval in patients with type 2 diabetes.

OBJECTIVES: Prolonged heart rate-corrected QT(QTc) interval is related to ventricular arrhythmia and cardiovascular mortality, with considerably high prevalence of type 2 diabetes. Additionally, long-term glycaemic variability could be a significant risk factor for diabetic complications in addition to chronic hyperglycaemia. We compared the associations of long-term glycaemic variability versus sustained chronic hyperglycaemia with the QTc interval among type 2 diabetes patients. METHODS: In this cross-sectional study, 2904 type 2 diabetes patients were recruited who had undergone at least four fasting plasma glucose (FPG) and 2-hour postprandial plasma glucose (PPG) measurements (at least once for every 3 months, respectively) during the preceding year. Long-term glycaemic variabilities of FPG and 2-hour PPG were assessed by their standard deviations (SD-FPG and SD-PPG, respectively), and chronic fasting and postprandial hyperglycaemia were assessed by their means (M-FPG and M-PPG, respectively). HbA1c was also determined upon enrolment to assess current overall glycaemic control. QTc interval was estimated from resting 12-lead electrocardiograms, and more than 440 ms was considered abnormally prolonged. RESULTS: Patients with prolonged QTc interval (≥440 ms) had greater M-FPG, M-PPG, SD-PPG and HbA1c than those with normal QTc interval but comparable SD-FPG. QTc interval was correlated with M-FPG, M-PPG, SD-PPG and HbA1c (r = 0.133, 0.153, 0.245 and 0.207, respectively, p = 0.000) but not with SD-FPG (r = 0.024, p = 0.189). After adjusting for metabolic risk factors via multiple linear regression analysis, SD-PPG, M-PPG and HbA1c (t = 12.16, 2.69 and 10.16, respectively, p = 0.000) were the major independent contributors to the increased QTc interval. The proportion of prolonged QTc interval increased significantly from 10.9% to 14.2% to 26.6% for the first (T1) to second (T2) to third (T3) tertiles of SD-PPG. After adjusting via multiple logistic regression analysis, the odd ratios of prolonged QTc interval of the T2 and T3 versus the T1 of SD-PPG were 1.15 (95% CI, 0.82-1.60) and 2.62 (1.92-3.57), respectively. CONCLUSIONS: Increased long-term variability of PPG is a strong independent risk factor for prolonged QTc interval in type 2 diabetes patients, in addition to long-term postprandial hyperglycaemia and current HbA1c.

Effect of advanced glycosylation end products (AGEs) on proliferation of human bone marrow mesenchymal stem cells (MSCs) in vitro.

This study aims to explore the effect of advanced glycosylation end products (AGEs) on proliferation of human bone marrow mesenchymal stem cells in vitro and the underlying mechanism. Bone marrow cell proliferation was determined by WST-8 assay using Cell Counting Kit-8 under the intervention of AGEs. In addition, the content of maldondialdehyde (MDA) and the activity of superoxide dismutase (SOD) were also measured. The proliferation activity of mesenchymal stem cells (MSCs) was significantly inhibited when AGEs were added to culture medium, and this effect was dose-dependent and time-dependent. As the concentration of AGEs-bovine serum albumin increased, the content of intracellular MDA was significantly increased, but the activity of SOD in cell homogenates was significantly suppressed, which also showed a dose-dependent manner. AGEs could significantly inhibit the proliferation of MSCs in vitro by improving the oxidative stress in MSCs and breaking the homeostasis of intracellular environment.

Obesity and low target attainment rates in Chinese with type 2 diabetes.

BACKGROUND: Although it is known that the prevalence of type 2 diabetes and obesity is increasing in China, there is little research into how obese or non-obese patients may differ in their attainment of treatment goals for type 2 diabetes. To do this, we assessed the attainment of American Diabetes Association (ADA)-recommended goals in Chinese with type 2 diabetes stratified by body mass index (BMI). METHODS: This cross-sectional study enrolled 520 Chinese with type 2 diabetes to find out if they had attained the following ADA-recommended goals: HbA1c<7%, SBP<130 mm Hg, DBP<80 mm Hg, LDL-C<100mg/dl, TG<150 mg/dl, HDL-C>40 mg/dl for men and >50mg/dl for women. RESULTS: Only 44.4% of all participants achieved the blood pressure goal, 20.8% the HbA1c goal, 44.8% the LDL-C goal, 43.3% the HDL-C goal, and 66.8% the triglyceride goal. Obese patients were less likely than normal weight patients to achieve the blood pressure goal (OR, 0.474; 95% CI, 0.231-0.973; p = 0.01), the HDL goal (OR, 0.365; 95% CI, 0.163-0.817; p = 0.01), or the triglyceride goal (OR, 0.416; 95% CI, 0.212-0.817; p = 0.01), after adjusting for confounders. Compared to normal weight participants, the obese patients had a significantly higher prescription rates for statin, metformin and anti-hypertensive drugs. CONCLUSION: Obese diabetic patients were less likely to achieve the blood pressure, LDL-C, HDL-C and triglyceride targets even when they were receiving several drugs to help them meet their target treatment goals. More strategies are needed to improve the treatment of Chinese with type 2 diabetes, particularly those who are obese.