A functional Notch–survivin gene signature in basal breast cancer

INTRODUCTION: Basal-type, or triple-negative, breast cancer (lacking estrogen receptor, progesterone receptor, and human epidermal growth factor receptor-2 expression) is a high-risk disease for which no molecular therapies are currently available. We studied genetic signatures of basal breast cancer potentially suitable for therapeutic intervention. METHODS: We analyzed protein expression of the Notch-1 intracellular domain and survivin by immunohistochemistry in a series of basal breast cancer patients. A hierarchical clustering and overall survival analysis was carried out on a microarray mRNA database of 232 breast cancer patients. Fifteen published mRNA datasets containing estrogen receptor-negative or estrogen receptor-positive samples were subjected to meta-analysis for co-segregated gene expression. Experiments of plasmid transfection and gene silencing were carried out in estrogen receptor-negative MDA-MB-231 breast cancer cells. RESULTS: The developmental signaling regulator Notch-1 was highly expressed in breast cancer, compared with normal tissue, and was segregated with basal disease. Higher Notch-1 levels correlated with progressively abbreviated overall survival, and with increased expression of survivin, a tumor-associated cell death and mitotic regulator implicated in stem cell viability. Analysis of Pearson\u27s correlation coefficient indicated that Notch-1 and survivin co-segregated in basal breast cancer. Notch-1 stimulation in MDA-MB-231 cells increased survivin expression, whereas silencing Notch reduced survivin levels. CONCLUSIONS: A Notch-1-survivin functional gene signature is a hallmark of basal breast cancer, and may contribute to disease pathogenesis. Antagonists of Notch and survivin currently in the clinic may be tested as novel molecular therapy for these recurrence-prone patients

Genetic dissection of quantitative trait loci for flag leaf size in bread wheat (Triticum aestivum L.)

Flag leaf size is a crucial trait influencing plant architecture and yield potential in wheat. A recombinant inbred line (RIL) population derived from the cross of W7268 and Chuanyu 12 was employed to identify quantitative trait loci (QTL) controlling flag leaf length (FLL), flag leaf width (FLW), and flag leaf area (FLA) in six environments and the best linear unbiased estimator (BLUE) datasets. Using a 55 K SNP-based genetic map, six major and stable QTL were detected with 6.33–53.12% of explained phenotypic variation. Except for QFlw.cib-4B.3, the other five major QTL were co-located within two intervals on chromosomes 2B and 2D, namely QFll/Fla.cib-2B and QFll/Flw/Fla.cib-2D, respectively. Their interactions and effects on the corresponding traits and yield-related traits were also assessed based on flanking markers. QFll/Fla.cib-2B showed pleiotropic effects on spikelet number per spike (SNS). QFlw.cib-4B.3 and QFll/Flw/Fla.cib-2D had effects on grain number per spike (GNS) and thousand-grain weight (TGW). Comparison analysis suggested that QFll/Fla.cib-2B was likely a new locus. Two candidate genes, TraesCS2B03G0222800 and TraesCS2B03G0230000, associated with leaf development within the interval of QFll/Fla.cib-2B were identified based on expression-pattern analysis, gene annotation, ortholog analysis, and sequence variation. The major QTL and markers reported here provide valuable information for understanding the genetic mechanism underlying flag leaf size as well as breeding utilization in wheat

The clinical implications of fasting serum insulin levels in patients with insulin-treated type 2 diabetes: a cross-sectional survey

ObjectiveThis study aimed to investigate the clinical implications of fasting serum insulin (FINS) levels in subjects with type 2 diabetes who were receiving insulin therapy.MethodsA total of 1,553 subjects with type 2 diabetes [774 subjects who had never received insulin treatment (N-INS) and 779 subjects who were receiving insulin therapy (constant insulin treatment, C-INS)] admitted to the Department of Endocrinology and Metabolism of Peking University People’s Hospital were enrolled in this study. Their FINS levels were measured and those with hyperinsulinemia were identified. The underlying mechanisms of hyperinsulinemia were revealed by measuring insulin antibodies (IAs) and analyzing changes in FINS levels before and after polyethylene glycol (PEG) precipitation. In addition, the clinical characteristics of patients with different types of hyperinsulinemia were compared.ResultsHigher FINS levels and a higher incidence (43.8%, 341/779) of hyperinsulinemia (FINS > 15μIU/mL) were observed in subjects with C-INS than in subjects with N-INS. Among subjects with C-INS and hyperinsulinemia, 66.9% (228/341) were IAs positive, and the incidence of IAs was found to be positively associated with FINS level. By performing PEG precipitation, we found that all subjects without IAs (i.e., those with real hyperinsulinemia) and 31.1% of subjects (71/228) with IAs (i.e., those with both real and IAs-related hyperinsulinemia) still had hyperinsulinemia after PEG precipitation, whereas FINS levels in the other 68.9% of subjects (157/228) with IAs were normal (IAs-related hyperinsulinemia) after PEG precipitation. Comparisons between the groups showed that subjects with real hyperinsulinemia showed more obvious insulin resistance characteristics, including higher lipid levels, BMIs, and homoeostasis model assessment2-estimated insulin resistance (HOMA2-IR) index, and were more likely to have hypertension, obesity, and metabolic syndromes (p < 0.05). However, the risk of hypoglycemia and glucose variability increased significantly in subjects with IAs compared with those without IAs. A cutoff of FINS to serum C-peptide ratio (≥ 9.3μIU/ng) could be used to screen IAs in clinical practice with 83.3% sensitivity and 70% specificity.ConclusionsIt is necessary to measure FINS in subjects with C-INS to distinguish between types of hyperinsulinemia, which should help to tailor treatment regimens