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Pancreatic ductal adenocarcinoma (PDAC) is characterized by the deregulation of the hedgehog signaling pathway. The Sonic Hedgehog ligand (Shh), absent in the normal pancreas, is highly expressed in pancreatic tumors and is sufficient to induce neoplastic precursor lesions in mouse models. We investigated the mechanism of Shh signaling in PDAC(More)
INTRODUCTION -Catenin function is essential for the canonical arm of the Wnt signaling pathway (reviewed by Willert and Nusse, 1998). In the absence of Wnt ligand, cytoplasmic pools of -catenin are highly unstable because of multiple phosphorylations in the N terminus of the protein that target the protein for degradation. However, when the Wnt co-receptors(More)
A recent study has shown that deletion of beta-catenin within the pancreatic epithelium results in a loss of pancreas mass. Here, we show that ectopic stabilization of beta-catenin within mouse pancreatic epithelium can have divergent effects on both organ formation and growth. Robust stabilization of beta-catenin during early organogenesis drives changes(More)
To investigate the role of the Sry/hydroxymethylglutaryl box (Sox) transcription factors in the development of the pancreas, we determined the expression pattern of Sox factors in the developing mouse pancreas. By RT-PCR, we detected the presence of multiple Sox family members in both the developing pancreas and mature islets and then focused on two(More)
Previous studies have suggested that defects in pancreatic epithelium caused by activation of the Hedgehog (Hh) signaling pathway are secondary to changes in the differentiation state of the surrounding mesenchyme. However, recent results describe a role of the pathway in pancreatic epithelium, both during development and in adult tissue during neoplastic(More)
Akt protein kinase has been shown to play a pivotal role in diverse cell functions, including motility, apoptosis, growth and metabolism. How it differentially regulates these diverse functions is of significant interest. Three isoforms have been well characterized, Akt1, 2, and 3, encoded by separate genes, but showing high homology over the entire coding(More)
OBJECTIVE Current studies indicate that Hedgehog (Hh) signaling must be excluded during early stages of pancreas formation. However, conflicting evidence suggests that Hh signaling may be active later during pancreas formation and that it is required for insulin production and secretion in cultured beta-cell lines. The objective of this study was to address(More)
AIM/HYPOTHESIS Recent studies indicate that tyrosine kinase inhibitors, including imatinib, can reverse hyperglycemia in non-obese diabetic (NOD) mice, a model of type 1 diabetes (T1D). Imatinib inhibits c-Abl, c-Kit, and PDGFRs. Next-generation tyrosine kinase inhibitors for T1D treatment should maintain activities required for efficacy while sparing(More)
Type-1 diabetes (T1D) is an autoimmune disease targeting insulin-producing beta cells, resulting in dependence on exogenous insulin. To date, significant efforts have been invested to develop immune-modulatory therapies for T1D treatment. Previously, IL-2 immunotherapy was demonstrated to prevent and reverse T1D at onset in the non-obese diabetic (NOD)(More)
Expression of PD-L1, the ligand for T-cell inhibitory receptor PD-1, is one key immunosuppressive mechanism by which cancer avoids eradication by the immune system. Therapeutic use of blocking antibodies to PD-L1 or its receptor PD-1 has produced unparalleled, durable clinical responses, with highest likelihood of response seen in patients whose tumour or(More)