Iodoarene-Catalyzed Cyclizations of Unsaturated Amides

The cyclization of N-alkenylamides catalyzed by iodoarenes under oxidative conditions is presented. Five-, six-, and seven-membered rings with a range of substitutions can be prepared by this route. Preliminary data from the use of chiral iodoarenes as precatalysts show that enantiocontrol is feasible

The Universal Real Projective Plane: LHC phenomenology at one Loop

The Real Projective Plane is the lowest dimensional orbifold which, when combined with the usual Minkowski space-time, gives rise to a unique model in six flat dimensions possessing an exact Kaluza Klein (KK) parity as a relic symmetry of the broken six dimensional Lorentz group. As a consequence of this property, any model formulated on this background will include a stable Dark Matter candidate. Loop corrections play a crucial role because they remove mass degeneracy in the tiers of KK modes and induce new couplings which mediate decays. We study the full one loop structure of the corrections by means of counter-terms localised on the two singular points. As an application, the phenomenology of the (2,0) and (0,2) tiers is discussed at the LHC. We identify promising signatures with single and di-lepton, top antitop and 4 tops: in the dilepton channel, present data from CMS and ATLAS may already exclude KK masses up to 250 GeV, while by next year they may cover the whole mass range preferred by WMAP data.Comment: 45 pages, 3 figure

Mechanisms of pain sensitization and the treatments

Hyperalgesia and allodynia, major symptoms of neuropathic pain can results after nerve injury or chronic inflammation. Trigeminal neuropathic pain resulting from alterations in peripheral and central noxious transmission systems often produced after nerve injury by pulpectomy or tooth-extraction or from temporomandibular joint inflammation. Neuropathic also occurs in some disease state, diabetic peripheral neuropathy, post-herpetic neuropathy and trigeminal neuralgia. Allodynia is characterized by long lasting pain evoked by essentially non-painful stimuli such as just light touch and tolerance to medication with conventional analgesics.Neuropathic pain is probably not a result of a single pathological mechanism, but the final product of an altered peripheral and central processing. Recent advances in pain research revealed that many factors derived from neurons and also non-neuronal neighboring residents participate in the initiation, development and maintenance. Among them, lipid mediators such as prostaglandins, lysophosphatidic acid and platelet-activating factor are recently found to play conspicuous roles for development of allodynia and hyperalgesia in spinal cord. Further advance by using cellular biological and molecular techniques would dig into the mechanisms underlying neuropathic pain and illustrate the new strategy and target candidate for drug development.There are also needs for tools and methods to assess neuropathic pain, common guidelines on classification, diagnosis and management, and evidence-based approach to the treatment of neuropathic pain

YM155 Induces EGFR Suppression in Pancreatic Cancer Cells

YM155, which inhibits the anti-apoptotic protein survivin, is known to exert anti-tumor effects in various cancers, including prostate and lung cancer. However, there are few reports describing the inhibitory effect of YM155 on human pancreatic cancers that highly express survivin. Here, we tested the effects of YM155 on a variety of cancer cell lines, including pancreatic cancer cells. We found that YM155 exerts an anti-proliferative effect in pancreatic cancer cells, inducing cell death through suppression of XIAP (X-linked inhibitor of apoptosis) as well as survivin without affecting the anti-apoptotic proteins Bcl-xL or Mcl-1. YM155 also inhibited tumor growth in vivo, reducing the size of pancreatic cancer cell line MIAPaCa-2 xenografts by 77.1% on day 31. Western blot analyses further showed that YM155 downregulated phosphoinoside 3-kinase (PI3K) expression and reduced the levels of phosphorylated (activated) extracellular signal-regulated kinase (ERK) and STAT3 (signal transducer and activator of transcription 3) in PANC-1 cells. Interestingly, we also found that YM155 downregulated the epidermal growth factor receptor (EGFR) in various cancer cell lines and induced the EGFR phosphorylation and ubiquitination of EGFR in PANC-1 cells. YM155 also modestly promoted the ubiquitination of survivin and XIAP. Therefore, YM155 acts through modulation of EGFR and survivin expression to subsequently reduce survival. We suggest that YM155 has potential as a therapeutic agent in the treatment of pancreatic cancer

Essential Role of the Small GTPase Ran in Postnatal Pancreatic Islet Development

The small GTPase Ran orchestrates pleiotropic cellular responses of nucleo-cytoplasmic shuttling, mitosis and subcellular trafficking, but whether deregulation of these pathways contributes to disease pathogenesis has remained elusive. Here, we generated transgenic mice expressing wild type (WT) Ran, loss-of-function Ran T24N mutant or constitutively active Ran G19V mutant in pancreatic islet β cells under the control of the rat insulin promoter. Embryonic pancreas and islet development, including emergence of insulin+ β cells, was indistinguishable in control or transgenic mice. However, by one month after birth, transgenic mice expressing any of the three Ran variants exhibited overt diabetes, with hyperglycemia, reduced insulin production, and nearly complete loss of islet number and islet mass, in vivo. Deregulated Ran signaling in transgenic mice, adenoviral over-expression of WT or mutant Ran in isolated islets, or short hairpin RNA (shRNA) silencing of endogenous Ran in model insulinoma INS-1 cells, all resulted in decreased expression of the pancreatic and duodenal homeobox transcription factor, PDX-1, and reduced β cell proliferation, in vivo. These data demonstrate that a finely-tuned balance of Ran GTPase signaling is essential for postnatal pancreatic islet development and glucose homeostasis, in vivo

Postnatal Expansion of the Pancreatic β-Cell Mass Is Dependent on Survivin

OBJECTIVE—Diabetes results from a deficiency of functional β-cells due to both an increase in β-cell death and an inhibition of β-cell replication. The molecular mechanisms responsible for these effects in susceptible individuals are mostly unknown. The objective of this study was to determine whether a gene critical for cell division and cell survival in cancer cells, survivin, might also be important for β-cells