Common activation of canonical Wnt signaling in pancreatic adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDA) is an extremely aggressive malignancy, which carries a dismal prognosis. Activating mutations of the Kras gene are common to the vast majority of human PDA. In addition, recent studies have demonstrated that embryonic signaling pathway such as Hedgehog and Notch are inappropriately upregulated in this disease. The role of another embryonic signaling pathway, namely the canonical Wnt cascade, is still controversial. Here, we use gene array analysis as a platform to demonstrate general activation of the canonical arm of the Wnt pathway in human PDA. Furthermore, we provide evidence for Wnt activation in mouse models of pancreatic cancer. Our results also indicate that Wnt signaling might be activated downstream of Hedgehog signaling, which is an early event in PDA evolution. Wnt inhibition blocked proliferation and induced apoptosis of cultured adenocarcinoma cells, thereby providing evidence to support the development of novel therapeutical strategies for Wnt inhibition in pancreatic adenocarcinoma

A screen for regulators of survival of motor neuron protein levels

The motor neuron disease spinal muscular atrophy (SMA) results from mutations that lead to low levels of the ubiquitously expressed protein survival of motor neuron (SMN). An ever-increasing collection of data suggests that therapeutics that elevate SMN may be effective in treating SMA. We executed an image-based screen of annotated chemical libraries and discovered several classes of compounds that were able to increase cellular SMN. Among the most important was the RTK–PI3K–AKT–GSK-3 signaling cascade. Chemical inhibitors of glycogen synthase kinase 3 (GSK-3) and short hairpin RNAs (shRNAs) directed against this target elevated SMN levels primarily by stabilizing the protein. It was particularly notable that GSK-3 chemical inhibitors were also effective in motor neurons, not only in elevating SMN levels, but also in blocking the death that was produced when SMN was acutely reduced by an SMN-specific shRNA. Thus, we have established a screen capable of detecting drug-like compounds that correct the main phenotypic change underlying SMA.Stem Cell and Regenerative Biolog

Promoting the Use of Elective Single Embryo Transfer in Clinical Practice.

BACKGROUND: The transfer of multiple embryos after in vitro fertilization (IVF) increases the risk of twins and higher-order births. Multiple births are associated with significant health risks and maternal and neonatal complications, as well as physical, emotional, and financial stresses that can strain families and increase the incidence of depression and anxiety disorders in parents. Elective single embryo transfer (eSET) is among the most effective methods to reduce the risk of multiple births with IVF. MAIN BODY: Current societal guidelines recommend eSET for patientsprognosis, yet even this approach is not widely applied. Many patients and clinicians have been reluctant to adopt eSET due to studies reporting higher live birth rates with the transfer of two or more embryos rather than eSET. Additional barriers to eSET include risk of treatment dropout after embryo transfer failure, patient preference for twins, a lack of knowledge about the risks and complications associated with multiple births, and the high costs of multiple IVF cycles. This review provides a comprehensive summary of strategies to increase the rate of eSET, including personalized counseling, access to educational information regarding the risks of multiple pregnancies and births, financial incentives, and tools to help predict the chances of IVF success. The use of comprehensive chromosomal screening to improve embryo selection has been shown to improve eSET outcomes and may increase acceptance of eSET. CONCLUSIONS: eSET is an effective method for reducing multiple pregnancies resulting from IVF. Although several factors may impede the adoption of eSET, there are a number of strategies and tools that may encourage the more widespread adoption of eSET in clinical practice

Regulated beta-cell regeneration in the adult mouse pancreas

Several studies have shown that the adult pancreas possesses a limited potential for beta-cell regeneration upon tissue injury. One of the difficulties in studying P-cell regeneration has been the lack of a robust, synchronized animal model system that would allow controlled regulation of beta-cell loss and subsequent proliferation in adult pancreas. Here we present a transgenic mouse regeneration model in which the c-Myc transcription factor/mutant estrogen receptor (cMycER(TAM)) fusion protein can be specifically activated in mature P-cells. We have studied these transgenic mice by immunohistochemical and biochemical methods to assess the ablation and posterior regeneration of P-cells. Activation of the cMycER(TAM) fusion protein results in synchronous and selective P-cell apoptosis followed by the onset of acute diabetes. Inactivation of c-Myc leads to gradual regeneration of insulin-expressing cells and reversal of diabetes. Our results demonstrate that the mature pancreas has the ability to fully recover from almost complete ablation of all existing beta-cells. Our results also suggest the regeneration of beta-cells is mediated by replication of P-cells rather than neogenesis from pancreatic ducts

The majorization approach to multidimensional scaling for Minkowski distances

Multidimensional scaling, Distance analysis, Majorization, Minkowski distances,

The tunneling method for global optimization in multidimensional scaling

multidimensional scaling, iterative majorization, global optimization, tunneling method,

Common activation of canonical Wnt signaling in pancreatic adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDA) is an extremely aggressive malignancy, which carries a dismal prognosis. Activating mutations of the Kras gene are common to the vast majority of human PDA. In addition, recent studies have demonstrated that embryonic signaling pathway such as Hedgehog and Notch are inappropriately upregulated in this disease. The role of another embryonic signaling pathway, namely the canonical Wnt cascade, is still controversial. Here, we use gene array analysis as a platform to demonstrate general activation of the canonical arm of the Wnt pathway in human PDA. Furthermore, we provide evidence for Wnt activation in mouse models of pancreatic cancer. Our results also indicate that Wnt signaling might be activated downstream of Hedgehog signaling, which is an early event in PDA evolution. Wnt inhibition blocked proliferation and induced apoptosis of cultured adenocarcinoma cells, thereby providing evidence to support the development of novel therapeutical strategies for Wnt inhibition in pancreatic adenocarcinoma