Background: The nationwide BioCrohn Registry (Biological Registry with Crohn's Disease Patients in Germany) of the German Competence-Network IBD is a five-year prospective registry of patients suffering from Crohn's disease (CD) in Germany.Up to October 2012, about 1,400 patients were included by 58 different gastroenterology practices and hospitals with IBD-experience.This 24 months follow-up interim analysis reports in particular the anti-TNF data of 620 early disease CD-patients.Methods: Within the framework of this non-interventional prospective online documentation, data on the course of disease, on psychosocial disease burden, on health economics and on the genetic profile will be examined.Until the end of 2012 the registry aims at including 1,500 patients with 5 years of follow-up.Results: 620 early disease CD-patients (course of disease: <3 years) were analyzed (average age: 33 years; female: 55%).The following therapies were observed.The use of immunosuppressants and/or anti-TNF increased in the 24months course up to 73.9% (6 months), 78.9% (12 months) and 82.8% after two years (34.5% anti-TNF after 24 months).

Einleitung: Die BioCrohn-Studie ist eine prospektive deutschlandweite Registrierung von Morbus Crohn (MC)-Patienten über fünf Jahre. Die MC-Patienten werden einerseits bei der Einleitung einer anti-TNF-α-Therapie, auch zur Dokumentation von potentiellen Nebenwirkungen, und andererseits als frühe MC-Patienten dokumentiert, um so prospektiv eine Vergleichsgruppe aufzubauen. Bis März 2012 sind über 1200 Patienten von 58 gastroenterologischen Praxen und Krankenhausambulanzen mit CED-Erfahrung eingeschlossen worden.

Purpose: Aurora kinases play a crucial role in cell-cycle control. Uncontrolled expression of aurora kinases causes aneuploidy and tumor growth. As conservative treatment options for advanced gastroenteropancreatic neuroendocrine tumors (GEP-NET) are disappointing, aurora kinases may be an interesting target for novel therapeutic strategies. Experimental Design: Human GEP-NETs were tested for aurora kinase expression. The efficacy of the new aurora kinase inhibitor danusertib was evaluated in two human GEP-NET cell lines (BON1 and QGP) in vitro and in vivo. Results: The majority of ten insulinomas and all 33 nonfunctional pancreatic or midgut GEP-NETs expressed aurora A despite a mostly high degree of cell differentiation. Both human GEP-NET cell lines expressed aurora kinase A and B, and high Ser10 phosphorylation of histone H3 revealed increased aurora B activity. Remarkably, danusertib led to cell-cycle arrest and completely inhibited cell proliferation of the GEP-NET cells in vitro. Decreased phosphorylation of histone H3 indicated effective aurora B inhibition. In a subcutaneous murine xenograft model, danusertib significantly reduced tumor growth in vivo compared with controls or mice treated with streptozotocine/5-fluorouracil. As a consequence, decreased levels of tumor marker chromogranin A were found in mouse serum samples. In a newly developed orthotopic model for GEP-NET liver metastases by intrasplenic tumor cell transplantation, dynamic MRI proved significant growth inhibition of BON1- and QGP-derived liver metastases. Conclusions: These results show that danusertib may impose a new therapeutic strategy for aurora kinase expressing metastasized GEP-NETs. Clin Cancer Res; 18(17); 4621–32. ©2012 AACR.

responses involve PKD acting as a downstream effector.Recently, we extended previous models of PKD regulation by identifying a novel mechanism that leads to late, PKC-independent PKD activation.However, the precise role of biphasic PKD activation in cell proliferation and ERK activation in response to GPCR agonists and other stimuli has not been elucidated.Aim: In order to elucidate the biological significance of biphasic PKD activation, we examined the mechanisms of early and late PKD activation in Swiss 3T3 cells, a well-established model system in which PKD signaling promotes long-term biological responses, including ERK signaling and mitogenesis.Results: Treatment of Swiss 3T3 cells overexpressing PKD with the preferential PKC inhibitors GF 109203X or Gö 6983 blocked rapid (10 min) PKD catalytic activation induced by bombesin stimulation, but this inhibition was greatly diminished at later times of bombesin stimulation (e.g. 120 min).Similar results were obtained in cells stimulated with vasopressin, i.e. via a different Gq-coupled receptor agonist.These results imply that PKD activation induced via endogenously expressed bombesin receptors is mediated by early PKC-dependent and late PKC-independent mechanisms.To gain insight into the transphosphorylation and /or autophosphorylation mechanisms involved, we used Western blot analysis with site-specific antibodies that detect the phosphorylated state of the activation loop residues Ser744 and Ser748.Our results indicate that transphosphorylation is a major mechanism targeting Ser744 and autophosphorylation is a predominant mechanism for Ser748 in cells stimulated with GPCR agonists.The pathways leading to the phosphorylation of these residues depend on the time of GPCR stimulation.PKD phosphorylation on Ser744 depended on PKC at early times of bombesin stimulation but was PKC-independent at longer times of bombesin stimulation.Prolongation of ERK signaling and DNA synthesis in PKD overexpressing 3T3 cells were not diminished by treatment with PKC inhibitors, indicating that these events are facilitated by PKD through a PKC-independent pathway.Conclusion: The present studies identify a novel mechanism induced by GPCR activation that leads to late, PKC-independent PKD activation and mitogenic signaling.

Gastrin-induced release of calcitonin from medullary thyroid carcinomas (MTC) is based on the expression of the cholecystokinin(2)-receptor (CCK(2)R) in these tumors. Recently, we have shown that the CCK(2)R is expressed not only in MTC but also in C-cells within the normal thyroid gland. The functions of the CCK(2)R in MTC and C-cells are largely unknown. We therefore explored the effects of gastrin-induced CCK(2)R stimulation in the highly differentiated MTC cell line, TT. CCK(2)R expression in TT-cells is detectable by RT-PCR as well as immunocytochemistry. Stimulation of the CCK(2)R by gastrin induces immediate release of calcitonin from TT-cells. Moreover, quantitative (LightCycler) RT-PCR demonstrates that gastrin stimulates transcription of the calcitonin and chromogranin A genes in TT-cells. TT-cell proliferation, assessed by counting of viable cells and (3)H-thymidine uptake, is markedly increased by gastrin. This effect is inhibited by the CCK(2)R-specific antagonist L-365,260. Our findings suggest physiological functions for the CCK(2)R in calcitonin-secretion and gene expression as well as a pathophysiological role in MTC proliferation. CCK(2)R antagonists might have therapeutic potential in these tumors.

The Cholecystokinin type 1 and type 2 receptors (CCK-1R and CCK-2R) share >50% amino acid identity, as well as subnanomolar affinity for the endogenous peptide cholecystokinin octapeptide (CCK-8). Although it is likely that these two receptor subtypes share amino acids that confer CCK-8 affinity, it has been difficult to identify such residues. We have examined the role of several transmembrane domain (TMD) IV residues that are common to both CCK receptor subtypes. In both the CCK-1R and CCK-2R, we demonstrate that alanine substitution of two TMD IV residues, which are highly conserved among all known CCK receptor subtypes and species homologs, significantly decrease CCK-8 affinity. Despite the observed decrease in peptide binding, the mutant receptors maintain close to wild-type affinity for the respective subtype selective nonpeptide ligands, 3H-labeled L-364,714 (CCK-1R) and 3H-labeled L-365,260 (CCK-2R), suggesting conserved tertiary structure of these mutants. Assessment of CCK-8-induced inositol phosphate production at each of the mutant CCK receptors revealed normal peptide efficacy. In contrast, peptide potencies are reduced in parallel with the observed decreases in affinity. Taken together, these findings suggest that important peptide affinity determinants are localized on TMD IV, a region that has not previously been considered a major contributor to ligand affinity in either CCK receptors or other G protein-coupled peptide receptors.

Cholecystokinin (CCK) and gastrin belong to one family of gastrointestinal peptides that regulate a variety of functions in the gastrointestinal tract and in the central nervous system. On the basis of pharmacological, physiological and molecular studies, receptors for these peptides can be divided into at least two different types: CCKA- and CCKB-receptors. CCKA- and CCKB-receptors are both G-protein coupled receptors and are highly conserved between species. Molecular techniques have revealed a distinct species- and tissue-specific variation in receptor expression and pharmacology. In addition, previously unknown targets for CCK and gastrin such as the kidney were identified. This review discusses the physiological functions of the hormones CCK and gastrin and their receptors. The molecular structure of these receptors and the results of recent structure-function analysis are reviewed.

Research Article| January 01 1996 Japan in 1995: A Year of Natural and Other Disasters Michael Blaker Michael Blaker Search for other works by this author on: This Site PubMed Google Scholar Asian Survey (1996) 36 (1): 41–52. https://doi.org/10.2307/2645554 Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Facebook Twitter LinkedIn Email Tools Icon Tools Get Permissions Cite Icon Cite Search Site Citation Michael Blaker; Japan in 1995: A Year of Natural and Other Disasters. Asian Survey 1 January 1996; 36 (1): 41–52. doi: https://doi.org/10.2307/2645554 Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu toolbar search search input Search input auto suggest filter your search All ContentAsian Survey Search This content is only available via PDF. Copyright 1996 The Regents of the University of California Article PDF first page preview Close Modal You do not currently have access to this content.

The microenvironment at chemical receptor sites is important for ligand-receptor interaction as it can influence the entry, residence time or exit of odorant and sapid molecules. The perireceptor milieu at apical taste cell microvilli consists of taste pore mucus and secretions from salivary glands. The majority of taste buds are sheltered in epithelial folds of the foliate and circumvallate papillae where saliva is provided predominantly by the lingual von Ebner's glands (VEGs). To investigate possible saliva-tastant interactions, we have characterized a prominent 18 kDa secretory protein expressed in human, rat and pig VEGs. The human and rat VEG proteins share 60% sequence identity and, by virtue of their protein and gene structure, can be assigned to the lipocalin superfamily of lipophilic ligand carrier proteins. VEG proteins might function as transporters of hydrophobic molecules, for example bitter substances, like the nasal odorant-binding proteins that belong to the same protein family. Because binding experiments using various bitter substances have so far failed, and in light of the species-specific expression, other functions for VEG proteins must be considered. These include the protection of taste epithelia, pheromone transport and lipid binding.

Von Ebner's glands (VEG) are small lingual salivary glands. Their ducts open into trenches of circumvallate and foliate papillae, thus influencing the milieu where the interaction between taste receptor cells and sapid molecules takes place. The major secretions of human VEG is a protein with a molecular mass of 18 kDa. The human VEG protein crossreacts with antibodies raised against the rat VEG protein, indicating sequence similarity between the rat and human VEG proteins. This was subsequently confirmed by N-terminal protein sequencing. A cDNA clone, isolated from a human VEG library, contained an insert of 735 bp including an open reading frame that encodes the human VEG protein of 176 amino acids. Comparison of the human and rat VEG proteins revealed an overall identity of 60%. Immunocytochemistry, in situ hybridization and in vitro translation studies demonstrated the human VEG protein to be highly and exclusively expressed in VEG. The VEG proteins are members of the lipocalin protein superfamily and, together with the rat odorant binding protein II, they constitute a new subfamily. Sequence similarity to proteins such as the retinol binding protein and the odorant binding protein which are lipophilic ligand carriers, suggests a possible function for the human VEG protein in taste perception.