Hedgehog signalling-an essential pathway during embryonic pancreatic development, the misregulation of which has been implicated in several forms of cancer-may also be an important mediator in human pancreatic carcinoma [1][2][3][4][5][6][7][8] . Here we report that sonic hedgehog, a secreted hedgehog ligand, is abnormally expressed in pancreatic adenocarcinoma and its precursor lesions: pancreatic intraepithelial neoplasia (PanIN). Pancreata of Pdx-Shh mice (in which Shh is misexpressed in the pancreatic endoderm) develop abnormal tubular structures, a phenocopy of human PanIN-1 and -2. Moreover, these PanIN-like lesions also contain mutations in K-ras and overexpress HER-2/neu, which are genetic mutations found early in the progression of human pancreatic cancer. Furthermore, hedgehog signalling remains active in cell lines established from primary and metastatic pancreatic adenocarcinomas. Notably, inhibition of hedgehog signalling by cyclopamine induced apoptosis and blocked proliferation in a subset of the pancreatic cancer cell lines both in vitro and in vivo. These data suggest that this pathway may have an early and critical role in the genesis of this cancer, and that maintenance of hedgehog signalling is important for aberrant proliferation and tumorigenesis.Sonic hedgehog (SHH) is misexpressed in human adenocarcinoma and its precursor lesions. SHH expression was determined using in situ hybridization to detect SHH messenger RNA and immunohistochemistry (IHC) to detect the protein with an antibody directed against Competing interests statementThe authors declare that they have no competing financial interests. . Pancreatic tissues were obtained from 20 specimens resected for pancreatic cancer. Control pancreatic tissues with no evidence of abnormality or autolysis upon histological evaluation were obtained from autopsy specimens or from pancreatic resections for trauma. In normal adult human pancreata, no SHH was detected in the islets, acini or ductal epithelium (Fig. 1a). However, evaluation of pancreata from patients with adenocarcinoma reveals that SHH is aberrantly expressed in 70% of specimens. Normal ductal epithelium does not express detectable levels of SHH (Fig. 1b); however, as the ductal epithelium shows increasing degrees of atypia, PanIN-1 to -3 ( Fig. 1c-e), a higher expression of SHH is observed. SHH expression is also detected in the malignant epithelium of adenocarcinoma samples (Fig. 1f). This expression pattern was also confirmed by our in situ hybridization for SHH mRNA ( Supplementary Fig. 1). NIH Public AccessLoss of regulation in this pathway has been implicated in several human cancers 10,11 . Thus in order to determine the potential role of SHH misexpression in the adult human pancreas, pancreata from transgenic mice (gift of H. Edlund) in which Shh misexpression was driven by the pancreatic-specific Pdx-1 promoter were histologically and immunohistochemically analysed.A total of four pancreata from three-week-old Pdx-Shh mice were histologically evaluated by a gastro...

OBJECTIVETo describe the prevalence of biochemical B12 deficiency in adults with type 2 diabetes taking metformin compared with those not taking metformin and those without diabetes, and explore whether this relationship is modified by vitamin B12 supplements.RESEARCH DESIGN AND METHODSAnalysis of data on U.S. adults ≥50 years of age with (n = 1,621) or without type 2 diabetes (n = 6,867) from the National Health and Nutrition Examination Survey (NHANES), 1999–2006. Type 2 diabetes was defined as clinical diagnosis after age 30 without initiation of insulin therapy within 1 year. Those with diabetes were classified according to their current metformin use. Biochemical B12 deficiency was defined as serum B12 concentrations ≤148 pmol/L and borderline deficiency was defined as >148 to ≤221 pmol/L.RESULTSBiochemical B12 deficiency was present in 5.8% of those with diabetes using metformin compared with 2.4% of those not using metformin (P = 0.0026) and 3.3% of those without diabetes (P = 0.0002). Among those with diabetes, metformin use was associated with biochemical B12 deficiency (adjusted odds ratio 2.92; 95% CI 1.26–6.78). Consumption of any supplement containing B12 was not associated with a reduction in the prevalence of biochemical B12 deficiency among those with diabetes, whereas consumption of any supplement containing B12 was associated with a two-thirds reduction among those without diabetes.CONCLUSIONSMetformin therapy is associated with a higher prevalence of biochemical B12 deficiency. The amount of B12 recommended by the Institute of Medicine (IOM) (2.4 μg/day) and the amount available in general multivitamins (6 μg) may not be enough to correct this deficiency among those with diabetes.

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Background Red blood cell (RBC) folate concentrations are a potential biomarker of folate-sensitive neural tube defect (NTD) risk in the population. The purpose of this analysis was to describe women in the U.S. population with RBC folate concentrations below those associated with optimal NTD prevention. Methods We used data from the 2007 to 2012 National Health and Nutrition Examination Survey (NHANES) to assess the RBC folate status of U.S. women of childbearing age relative to risk categories for NTD risk based on RBC folate concentrations. We defined suboptimal RBC folate concentrations as those associated with a prevalence of _9 NTDs per 10,000 live births. Results Among nonpregnant women age 12 to 49 years, 22.8% (95% Confidence Interval: 21.1, 24.6) had suboptimal RBC folate concentrations. Women had greater odds of having a suboptimal RBC folate concentration if they did not use dietary supplements containing folic acid; had mandatorily fortified enriched cereal grain products as their only source of folic acid; were non-Hispanic black or Hispanic; or were current smokers. Conclusion Based on RBC folate concentrations, we would predict that the majority of U.S. women of reproductive age are not at increased risk for folate sensitive NTDs in the presence of mandatory folic acid fortification. Prevention policies and programs can be aimed at population subgroups identified as having higher predicted risk for folate-sensitive NTDs based on RBC folate concentrations.