SOX2 (Sex-determining region Y (SRY)-Box2) has important functions during embryonic development and is involved in cancer stem cell (CSC) maintenance, in which it impairs cell growth and tumorigenicity. However, the function of SOX2 in pancreatic cancer cells is unclear. The objective of this study was to analyze SOX2 expression in human pancreatic tumors and determine the role of SOX2 in pancreatic cancer cells regulating CSC properties. In this report, we show that SOX2 is not expressed in normal pancreatic acinar or ductal cells. However, ectopic expression of SOX2 is observed in 19.3% of human pancreatic tumors. SOX2 knockdown in pancreatic cancer cells results in cell growth inhibition via cell cycle arrest associated with p21Cip1 and p27Kip1 induction, whereas SOX2 overexpression promotes S-phase entry and cell proliferation associated with cyclin D3 induction. SOX2 expression is associated with increased levels of the pancreatic CSC markers ALDH1, ESA and CD44. Importantly, we show that SOX2 is enriched in the ESA+/CD44+ CSC population from two different patient samples. Moreover, we show that SOX2 directly binds to the Snail, Slug and Twist promoters, leading to a loss of E-Cadherin and ZO-1 expression. Taken together, our findings show that SOX2 is aberrantly expressed in pancreatic cancer and contributes to cell proliferation and stemness/dedifferentiation through the regulation of a set of genes controlling G1/S transition and epithelial-to-mesenchymal transition (EMT) phenotype, suggesting that targeting SOX2-positive cancer cells could be a promising therapeutic strategy.

We characterize one transcription factor of DRE-binding proteins (TaDREB1) that was isolated from a drought-induced cDNA library of wheat (Triticum aestivum L.). TaDREB1 contains one conserved EREBP/AP2 domain, and shows similarity with Arabidopsis thaliana DREB family members in both overall amino-acid sequences and the secondary structure arrangement within the DNA-binding motifs. In yeast one-hybrid system, TaDREB1, can specially activate the genes fused with the promoter containing three tandemly repeated copies of the wild-type DRE sequence: TACCGACAT. In different wheat cultivars, the Ta DREB1 gene is induced by low temperature, salinity and drought; and the expression of Wcs120 that contains DRE motifs in its promoter is closely related to the expression of TaDREB1. These results suggest that TaDREB1 functions as a DRE-binding transcription factor in wheat. We also observed the dwarf phenotype in transgenic rice (T0) overexpressing TaDREB1.

While TRAIL is a promising anticancer agent due to its ability to selectively induce apoptosis in neoplastic cells, many tumors, including pancreatic ductal adenocarcinoma (PDA), display intrinsic resistance, highlighting the need for TRAIL-sensitizing agents. Here we report that TRAIL-induced apoptosis in PDA cell lines is enhanced by pharmacological inhibition of glycogen synthase kinase-3 (GSK-3) or by shRNA-mediated depletion of either GSK-3α or GSK-3β. In contrast, depletion of GSK-3β, but not GSK-3α, sensitized PDA cell lines to TNFα-induced cell death. Further experiments demonstrated that TNFα-stimulated IκBα phosphorylation and degradation as well as p65 nuclear translocation were normal in GSK-3β-deficient MEFs. Nonetheless, inhibition of GSK-3β function in MEFs or PDA cell lines impaired the expression of the NF-κB target genes Bcl-xL and cIAP2, but not IκBα. Significantly, the expression of Bcl-xL and cIAP2 could be reestablished by expression of GSK-3β targeted to the nucleus but not GSK-3β targeted to the cytoplasm, suggesting that GSK-3β regulates NF-κB function within the nucleus. Consistent with this notion, chromatin immunoprecipitation demonstrated that GSK-3 inhibition resulted in either decreased p65 binding to the promoter of BIR3, which encodes cIAP2, or increased p50 binding as well as recruitment of SIRT1 and HDAC3 to the promoter of BCL2L1, which encodes Bcl-xL. Importantly, depletion of Bcl-xL but not cIAP2, mimicked the sensitizing effect of GSK-3 inhibition on TRAIL-induced apoptosis, whereas Bcl-xL overexpression ameliorated the sensitization by GSK-3 inhibition. These results not only suggest that GSK-3β overexpression and nuclear localization contribute to TNFα and TRAIL resistance via anti-apoptotic NF-κB genes such as Bcl-xL, but also provide a rationale for further exploration of GSK-3 inhibitors combined with TRAIL for the treatment of PDA.

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Objective To determine whether the recently published A global reference for fetal-weight and birthweight percentiles (Global Reference) improves small-(SGA), appropriate-(AGA), and large-for-gestational-age (LGA) definitions in predicting infant mortality.Design Population-based cohort study. Population Singleton births with birthweight >500 g born at 24-41 weeks of gestation.Methods We compared infant mortality rates of SGA, AGA, and LGA infants classified by three different references: the Global Reference; a commonly used birthweight reference; and Hadlock's ultrasound reference.Main outcome measures Infant mortality rates.Results Among 33 997 719 eligible liveborn singleton births, 25% of preterm and 9% of term infants were classified differently for SGA, AGA, and LGA by the Global Reference and the birthweight reference. The Global Reference indicated higher mortality rates in preterm SGA and preterm LGA infants than the birthweight reference. The mortality rate was considerably higher in infants classified as preterm SGA by the Global Reference but not by the birthweight reference, compared with the corresponding infants classified by the birthweight reference but not by the Global Reference (105.7 versus 12.9 per 1000, RR 8.17, 95% CI 7.38-9.06). Yet, the differences in mortality rates were much smaller in term infants than in preterm infants. Black infants had a particularly higher mortality rate than other races in AGA and LGA preterm and term infants.Conclusions In respect to the commonly used birthweight reference, the Global Reference increases the identification of infant deaths by improved classification of abnormal newborn size at birth, and these advantages were more obvious in preterm than in term infants.

Sir -The prognosis and survival rates of patients with systemic lupus erythematosus (SLE) have improved over the years1; thus, an increasing number of women with SLE are reaching the age of menopause. In addition, the use of cyclophosphamide therapy and the disease itself increase the risk of premature ovarian failure in these patients.2 Therefore, as our LUMINA (Lupus in Minorities: Nature versus Nurture) cohort matures, we have been intrigued by the accrual of damage in our postmenopausal women. Previously, we have examined damage accrual in our cohort patients whose disease started before and after the menopause and concluded that it was age rather than the menopause that accounted for damage accrual in the postmenopausal women.3 With a larger number of LUMINA cohort patients, and more years of observation having occurred, we sought to re-examine this matter. We, therefore, examined the role of menopause versus age by regressing age on menopause so that the effect of menopause per se could be better determined.The current analyses were limited to the women in the LUMINA cohort. Briefly, at entry into the cohort (T0), patients had disease duration ≤5 years, were ≥16 years of age and were of defined ethnicity (Hispanic from Texas and Puerto Rico, African American, or Caucasian).

Objectives: To compare the image quality, radiation dose and diagnostic accuracy of 320-detector CT coronary angiography with prospective and retrospective electrocardiogram (ECG) gating in a single heartbeat. Methods: Two independent reviewers separately scored image quality of coronary artery segment for 480 cardiac CT studies in a prospective group and a retrospective group (240 patients with a heart rate ,65 beats per minute in each group). The two groups matched well for clinical characteristics and CT parameters. There was good agreement for image quality scores of coronary artery segment between the independent reviewers (k50.73). Of the 7023 coronary artery segments, the image quality scores of the prospective group and retrospective group were not significantly different (p.0.05). The mean radiation dose was 10.0¡3.5 mSv (range 6.2-21.6 mSv) for prospective ECG gating at 65-85% of R-R interval (the interval between the R-wave of one heartbeat to the Rwave of the next). The mean radiation dose for retrospective ECG-triggered modulated scans was 23.2¡3.4 mSv (range 17-27.4 mSv). The mean radiation dose was 57% lower for prospective gating than for retrospective gating (p,0.01). Results: Compared with coronary angiography, the results for prospective vs retrospective ECG gating were 92% vs 90% for sensitivity (p50.23), 89% vs 91% for specificity (p50.19), 90% vs 93% for positive predictive value (p50.25) and 92% vs 95% for negative predictive value (p50.21) for lesions with $50% stenosis, respectively. Conclusion: 320-detector CT coronary angiography performed with prospective ECG gating has similar subjective image quality scores, but a 57% lower radiation dose than retrospective ECG gating in a single heartbeat.

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