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Gateways to Clinical Trials is a guide to the most recent clinical trials in current literature and congresses. The data in the following tables have been retrieved from the Clinical Trials Knowledge Area of Prous Science Integrity, the drug discovery and development portal, http://integrity.prous.com. This issue focuses on the following selection of drugs: Abiraterone acetate, acyline, adalimumab, adenosine triphosphate, AEE-788, AIDSVAX gp120 B/B, AK-602, alefacept, alemtuzumab, alendronic acid sodium salt, alicaforsen sodium, alprazolam, amdoxovir, AMG-162, aminolevulinic acid hydrochloride, aminolevulinic acid methyl ester, aminophylline hydrate, anakinra, anecortave acetate, anti-CTLA-4 MAb, APC-8015, aripiprazole, aspirin, atazanavir sulfate, atomoxetine hydrochloride, atorvastatin calcium, atrasentan, AVE-5883, AZD-2171; Betamethasone dipropionate, bevacizumab, bimatoprost, biphasic human insulin (prb), bortezomib, BR-A-657, BRL-55730, budesonide, busulfan; Calcipotriol, calcipotriol/betamethasone dipropionate, calcium folinate, capecitabine, capravirine, carmustine, caspofungin acetate, cefdinir, certolizumab pegol, CG-53135, chlorambucil, ciclesonide, ciclosporin, cisplatin, clofarabine, clopidogrel hydrogensulfate, clozapine, co-trimoxazole, CP-122721, creatine, CY-2301, cyclophosphamide, cypher, cytarabine, cytolin; D0401, darbepoetin alfa, darifenacin hydrobromide, DASB, desipramine hydrochloride, desloratadine, desvenlafaxine succinate, dexamethasone, didanosine, diquafosol tetrasodium, docetaxel, doxorubicin hydrochloride, drotrecogin alfa (activated), duloxetine hydrochloride, dutasteride; Ecallantide, efalizumab, efavirenz, eletriptan, emtricitabine, enfuvirtide, enoxaparin sodium, estramustine phosphate sodium, etanercept, ethinylestradiol, etonogestrel, etonogestrel/ethinylestradiol, etoposide, exenatide; Famciclovir, fampridine, febuxostat, filgrastim, fludarabine phosphate, fluocinolone acetonide, fluorouracil, fluticasone propionate, fluvastatin sodium, fondaparinux sodium; Gaboxadol, gamma-hydroxybutyrate sodium, gefitinib, gelclair, gemcitabine, gemfibrozil, glibenclamide, glyminox; Haloperidol, heparin sodium, HPV 16/HPV 18 vaccine, human insulin, human insulin; Icatibant, imatinib mesylate, indium 111 (111In) ibritumomab tiuxetan, infliximab, INKP-100, iodine (I131) tositumomab, IoGen, ipratropium bromide, ixabepilone; L-870810, lamivudine, lapatinib, laquinimod, latanoprost, levonorgestrel, licochalcone a, liposomal doxorubicin, lopinavir, lopinavir/ritonavir, lorazepam, lovastatin; Maraviroc, maribavir, matuzumab, MDL-100907, melphalan, methotrexate, methylprednisolone, mitomycin, mitoxantrone hydrochloride, MK-0431, MN-001, MRKAd5 HIV-1 gag/pol/nef, MRKAd5gag, MVA.HIVA, MVA-BN Nef, MVA-Muc1-IL-2, mycophenolate mofetil; Nelfinavir mesilate, nesiritide, NSC-330507; Olanzapine, olmesartan medoxomil, omalizumab, oral insulin, osanetant; PA-457, paclitaxel, paroxetine, paroxetine hydrochloride, PCK-3145, PEG-filgrastim, peginterferon alfa-2a, peginterferon alfa-2b, perillyl alcohol, pexelizumab, pimecrolimus, pitavastatin calcium, porfiromycin, prasterone, prasugrel, pravastatin sodium, prednisone, pregabalin, prinomastat, PRO-2000, propofol, prostate cancer vaccine; Rasagiline mesilate, rhBMP-2/ACS, rhBMP-2/BCP, rhC1, ribavirin, rilpivirine, ritonavir, rituximab, Ro-26-9228, rosuvastatin calcium, rosuvastatin sodium, rubitecan; Selodenoson, simvastatin, sirolimus, sitaxsentan sodium, sorafenib, SS(dsFv)-PE38, St. John's Wort extract, stavudine; Tacrolimus, tadalafil, tafenoquine succinate, talaglumetad, tanomastat, taxus, tegaserod maleate, telithromycin, tempol, tenofovir, tenofovir disoproxil fumarate, testosterone enanthate, TH-9507, thalidomide, tigecycline, timolol maleate, tiotropium bromide, tipifarnib, torcetrapib, trabectedin, travoprost, travoprost/timolol, treprostinil sodium; Valdecoxib, vardenafil hydrochloride hydrate, varenicline, VEGF-2 gene therapy, venlafaxine hydrochloride, vildagliptin, vincristine sulfate, voriconazole, VRX-496, VX-385; Warfarin sodium; Ximelagatran; Yttrium 90 (90Y) ibritumomab tiuxetan; Zanolimumab, zidovudine.
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PMID:Gateways to clinical trials. 1608 22

Gateways to Clinical Trials are a guide to the most recent clinical trials in current literature and congresses. The data in the following tables have been retrieved from the Clinical Trials Knowledge Area of Prous Science Integrity, the drug discovery and development portal, http://integrity. prous.com. This issue focuses on the following selection of drugs: 131I-chTNT; Abatacept, adalimumab, alemtuzumab, APC-8015, aprepitant, atazanavir sulfate, atomoxetine hydrochloride, azimilide hydrochloride; Bevacizumab, bortezomib, bosentan, buserelin; Caspofungin acetate, CC-4047, ChAGCD3, ciclesonide, clopidogrel, curcumin, Cypher; Dabigatran etexilate, dapoxetine hydrochloride, darbepoetin alfa, darusentan, denosumab, DMXB-Anabaseine, drospirenone, drospirenone/estradiol, duloxetine hydrochloride, dutasteride; Edodekin alfa, efaproxiral sodium, elaidic acid-cytarabine, erlotinib hydrochloride, ertapenem sodium, escitalopram oxalate, eszopiclone, etonogestrel/testosterone decanoate, exenatide; Fulvestrant; Gefitinib, glycine, GVS-111; Homoharringtonine; ICC-1132, imatinib mesylate, iodine (I131) tositumomab, i.v. gamma-globulin; Levetiracetam, levocetirizine, lintuzumab, liposomal nystatin, lumiracoxib, lurtotecan; Manitimus, mapatumumab, melatonin, micafungin sodium, mycophenolic acid sodium salt; Oblimersen sodium, OGX-011, olmesartan medoxomil, omalizumab, omapatrilat, oral insulin; Parathyroid hormone (human recombinant), pasireotide, peginterferon alfa-2a, peginterferon alfa-2b, peginterferon alfa-2b/ribavirin, phVEGF-A165, pimecrolimus, pitavastatin calcium, plerixafor hydrochloride, posaconazole, pramlintide acetate, prasterone, pregabalin, PT-141; Quercetin; Ranolazine, rosuvastatin calcium, rubitecan, rupatadine fumarate; Sardomozide, sunitinib malate; Tadalafil, talactoferrin alfa, tegaserod maleate, telithromycin, testosterone transdermal patch, TH-9507, tigecycline, tiotropium bromide, tipifarnib, tocilizumab, treprostinil sodium; Valdecoxib, vandetanib, vardenafil hydrochloride hydrate, voriconazole.
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PMID:Gateways to clinical trials. 1639 22

We describe a novel TCR-transgenic mouse line, TCR7, where MHC class II-restricted, CD4+ T cells are specific for the subdominant H-2b epitope (HEL74-88) of hen egg lysozyme (HEL), and displayed an increased frequency in the thymus and in peripheral lymphoid compartments over that seen in non-transgenic littermate controls. CD4+ T cells responded vigorously to HEL or HEL74-88 epitope presented on APC and could develop into Th1 or Th2 cells under appropriate conditions. Adoptive transfer of TCR7 Ly5.1 T cells into Ly5.2 rat insulin promoter (RIP)-HEL transgenic recipient hosts did not lead to expansion of these cells or result in islet infiltration, although these TCR7 cells could expand upon transfer into mice expressing high levels of HEL in the serum. Islet cell infiltration only occurred when the TCR7 cells had been polarized to either a Th1 or Th2 phenotype prior to transfer, which led to insulitis. Progression from insulitis to autoimmune diabetes only occurred in these recipients when Th1 but not Th2 TCR7 cells were transferred and CTLA-4 signaling was simultaneously blocked. These findings show that regulatory pathways such as CTLA-4 can hold in check already differentiated autoreactive effector Th1 cells, to inhibit the transition from tolerance to autoimmune diabetes.
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PMID:Breakpoints in immunoregulation required for Th1 cells to induce diabetes. 1695 44

Type 1 diabetes (T1D) is caused by the destruction of insulin-producing islet beta cells. CD8 T cells are prevalent in the islets of T1D patients and are the major effectors of beta cell destruction in nonobese diabetic (NOD) mice. In addition to their critical involvement in the late stages of diabetes, CD8 T cells are implicated in the initiation of disease. NOD mice, in which the beta2-microglobulin gene has been inactivated by gene targeting (NOD.beta2M-/-), have a deficiency in CD8 T cells and do not develop insulitis, which suggests that CD8 T cells are required for the initiation of T1D. However, neither in humans nor in NOD mice have the immunological requirements for diabetogenic CD8 T cells been precisely defined. In particular, it is not known in which cell type MHC class I expression is required for recruitment and activation of CD8 T cells. Here we have generated transgenic NOD mice, which lack MHC class I on mature professional antigen-presenting cells (pAPCs). These "class I APC-bald" mice developed periislet insulitis but not invasive intraislet insulitis, and they never became diabetic. Recruitment to the islet milieu does not therefore require cognate interaction between CD8 T cells and MHC class I on mature pAPCs. Conversely, such an interaction is critically essential to allow the crucial shift from periislet insulitis to invasive insulitis. Importantly, our findings demonstrate unequivocally that CD8 T cells cannot be primed to become diabetogenic by islet beta cells alone.
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PMID:Beta cells cannot directly prime diabetogenic CD8 T cells in nonobese diabetic mice. 1722 43

Islet function is regulated by a number of different signals. A main signal is generated by glucose, which stimulates insulin secretion and inhibits glucagon secretion. The glucose effects are modulated by many factors, including hormones, neurotransmitters and nutrients. Several of these factors signal through guanine nucleotide-binding protein (G protein)-coupled receptors (GPCR). Examples of islet GPCR are GPR40 and GPR119, which are GPCR with fatty acids as ligands, the receptors for the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), the receptors for the islet hormones glucagon and somatostatin, the receptors for the classical neurotransmittors acetylcholine (ACh; M(3) muscarinic receptors) and noradrenaline (beta(2)- and alpha(2)-adrenoceptors) and for the neuropeptides pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal polypeptide (VIP; PAC(1) and VPAC(2) receptors), cholecystokinin (CCK(A) receptors) and neuropeptide Y (NPY Y1 receptors). Other islet GPCR are the cannabinoid receptor (CB(1) receptors), the vasopressin receptors (V1(B) receptors) and the purinergic receptors (P(2Y) receptors). The islet GPCR couple mainly to adenylate cyclase and to phospholipase C (PLC). Since important pharmacological strategies for treatment of type 2 diabetes are stimulation of insulin secretion and inhibition of glucagon secretion, islet GPCR are potential drug targets. This review summarizes knowledge on islet GPCR.
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PMID:G-protein-coupled receptors and islet function-implications for treatment of type 2 diabetes. 1790 Jul

In pancreatic beta-cells, the pituitary adenylate cyclase-activating polypeptide (PACAP) exerts a potent insulin secretory effect via PAC(1) and VPAC receptors (Rs) through the Galpha(s)/cAMP/protein kinase A pathway. Here, we investigated the mechanisms linking PAC(1)R to ERK1/2 activation in INS-1E beta-cells and pancreatic islets. PACAP caused a transient (5 min) increase in ERK1/2 phosphorylation via PAC(1)Rs and promoted nuclear translocation of a fraction of cytosolic p-ERK1/2. Both protein kinase A- and Src-dependent pathways mediated this transient ERK1/2 activation. Moreover, PACAP potentiated glucose-induced long-lasting ERK1/2 activation. Blocking Ca(2+) influx abolished glucose-induced ERK1/2 activation and PACAP potentiating effect. Glucose stimulation during KCl depolarization showed that, in addition to the triggering signal (rise in cytosolic [Ca(2+)]), the amplifying pathway was also involved in glucose-induced sustained ERK1/2 activation and was required for PACAP potentiation. The finding that at 30 min glucose-induced p-ERK1/2 was detected in both cytosol and nucleus while the potentiating effect of PACAP was only observed in the cytosol, suggested the involvement of the scaffold protein beta-arrestin. Indeed, beta-arrestin 1 (beta-arr1) depletion (in beta-arr1 knockout mouse islets or in INS-1E cells by siRNA) completely abolished PACAP potentiation of long-lasting ERK1/2 activation by glucose. Finally, PACAP potentiated glucose-induced CREB transcriptional activity and IRS-2 mRNA expression mainly via the ERK1/2 signaling pathway, and likewise, beta-arr1 depletion reduced the PACAP potentiating effect on IRS-2 expression. These results establish for the first time that PACAP potentiates glucose-induced long-lasting ERK1/2 activation via a beta-arr1-dependent pathway and thus provide new insights concerning the mechanisms of PACAP and glucose actions in pancreatic beta-cells.
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PMID:beta-Arrestin 1 is required for PAC1 receptor-mediated potentiation of long-lasting ERK1/2 activation by glucose in pancreatic beta-cells. 1907 39

Epidemiological studies report that high sucrose consumption is associated with increased risk of colon cancer. One hypothesis is that this association is mediated by elevated circulatory insulin and IGF levels promoting intestinal proliferation. To test this hypothesis, APC(Min) mice and their wild type littermates were fed, starting at 4 wk of age, sucrose or cornstarch as the sole carbohydrate source in the absence or presence of low levels of dietary sulindac for 10 or 16 wk, respectively. APC(Min) mice fed sucrose had an increased tumor number in the proximal third of the small intestine in both studies and a higher incidence of papillary colon tumors in the 16-wk feeding study (P < or = 0.05). Mice fed sucrose (relative to cornstarch) had higher body weights and greater Ki67-labeling indexes in colonic epithelium than mice fed cornstarch in both feeding studies (P < or = 0.05). Furthermore, mice fed sucrose had higher serum glucose and liver IGF-I mRNA concentrations (P < or = 0.05) and tended to have higher serum insulin levels (P = 0.08). These results support the hypothesis that high dietary sucrose intake promotes intestinal proliferation and tumorigenesis by increasing circulating levels of insulin and IGF-I.
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PMID:High sucrose diets promote intestinal epithelial cell proliferation and tumorigenesis in APC(Min) mice by increasing insulin and IGF-I levels. 1911 78

To reach the mammalian gut, enteric bacteria must pass through the stomach. Many such organisms survive exposure to the harsh gastric environment (pH 1.5-4) by mounting extreme acid-resistance responses, one of which, the arginine-dependent system of Escherichia coli, has been studied at levels of cellular physiology, molecular genetics and protein biochemistry. This multiprotein system keeps the cytoplasm above pH 5 during acid challenge by continually pumping protons out of the cell using the free energy of arginine decarboxylation. At the heart of the process is a 'virtual proton pump' in the inner membrane, called AdiC, that imports L-arginine from the gastric juice and exports its decarboxylation product agmatine. AdiC belongs to the APC superfamily of membrane proteins, which transports amino acids, polyamines and organic cations in a multitude of biological roles, including delivery of arginine for nitric oxide synthesis, facilitation of insulin release from pancreatic beta-cells, and, when inappropriately overexpressed, provisioning of certain fast-growing neoplastic cells with amino acids. High-resolution structures and detailed transport mechanisms of APC transporters are currently unknown. Here we describe a crystal structure of AdiC at 3.2 A resolution. The protein is captured in an outward-open, substrate-free conformation with transmembrane architecture remarkably similar to that seen in four other families of apparently unrelated transport proteins.
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PMID:Structure of a prokaryotic virtual proton pump at 3.2 A resolution. 1957 61

Colorectal carcinoma is among the most common malignancies. The tumour cells may arise from mutations in genes encoding proteins involved in the regulation of cell survival and proliferation. Recent evidence disclosed the sensitivity of colon carcinoma to the expression of ubiquitous serum and glucocorticoid inducible kinase-1 (SGK1). The kinase is activated by insulin and growth factors via the phosphatidylinositide-3-kinase (PI3K) and the 3-phosphoinositide dependent kinase (PDK1). SGK1 regulates channels, carriers and Na(+)/K(+)-ATPase, enzymes such as glycogen-synthase-kinase-3 (GSK3) and ubiquitin-ligase Nedd4-2, as well as several transcription factors. SGK1 regulates transport, hormone release, neuroexcitability, inflammation, cell proliferation and apoptosis. SGK1 contributes to metabolic syndrome and the pathophysiology of neurodegeneration, allergy, peptic ulcer, fibrosing disease and response to ischemia. SGK1 is upregulated in some tumours but downregulated in others. SGK1-sensitive mechanisms fostering tumour growth include activation of K(+) channels and Ca(2+) channels, Na(+)/H(+) exchanger, amino acid transporters and glucose transporters, upregulation of the nuclear factor NFkappaB and beta-catenin as well as downregulation of the transcription factors Foxo3a/FKHRL1 and p53. SGK1 enhances survival, invasiveness, motility, epithelial to mesenchymal transition and adhesiveness of tumour cells. Following deficiency of APC (adenoma polyposis coli) or chemical cancerogenesis, SGK1 knockout mice develop less intestinal tumours than their wild-type littermates and pharmacological SGK1 inhibition counteracts growth of prostate cancer cells.
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PMID:Colorectal carcinoma cells--regulation of survival and growth by SGK1. 2054 Oct 34

Weight gain is increasingly recognized as an unwanted side effect of atypical antipsychotic drugs. To explore the mechanisms underlying this side effect, we examined the effects of olanzapine, an atypical antipsychotic drug, on cellular proliferation and differentiation in the adult mouse hypothalamus. A 6-week treatment with olanzapine resulted in a significant increase in body weight. The sizes and numbers of olanzapine-treated mouse adipocytes were significantly larger than those of control mice. No significant differences were observed in the levels of blood insulin, cholesterol, triglyceride, leptin, and ghrelin among olanzapine-, haloperidol-treated and control mice with an exception that adiponectin was significantly higher in olanzapine group than control group. Body temperature and the level of uncoupling protein 2 were also comparable between the olanzapine-treated and control groups. We found that the treatment increased BrdU-incorporating cell numbers in the hypothalamus, while the same regimen with haloperidol or control had little effect on cellular proliferation. Double-labeling immunohistochemistry revealed that the majority of the BrdU-positive cells were also Olig2- or APC-positive, indicating that oligodendrocyte-lineage cells were generated in response to olanzapine treatment. Enhancement of hypothalamic cellular proliferation after intracerebroventricular infusion of cytosine arabinoside coincided with elevated food intake and weight gain. These findings suggest a possible link between gliogenesis in the hypothalamus and weight gain following olanzapine treatment.
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PMID:Olanzapine increases cell mitotic activity and oligodendrocyte-lineage cells in the hypothalamus. 2064 74


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