MH_dev_146

Skeletal receptors for steroid-family regulating glycoprotein hormones : A multilevel , integrated physiological control system . Pituitary glycoprotein hormone receptors , including Q01718 REA , P16473 REA , and P23945 REA , occur in bone . Their skeletal expression reflects that central endocrine control is evolutionarily recent . DB01285 MEN receptors , in osteoblasts or the adrenal cortex , drive P15692 REA synthesis . P15692 REA is essential to maintain vasculature . In bone , DB01285 MEN suppression by glucocorticoids can cause osteonecrosis . DB00024 receptors occur on osteoblasts and osteoclasts , in both cases reducing activity . Thus , DB00024 directly reduces skeletal turnover , consistent with evolutionary adaptation to stress . DB00094 receptors accelerate bone resorption , whereas estrogen promotes bone formation , the forces usually balancing . With ovarian failure , low estrogen with high DB00094 causes rapid bone loss . The skeletal DB00094 effect in the menopause seems paradoxical , but it is a logical adaptation in lactation , where prolonged DB00094 elevation also occurs . In addition to receptors , there is some synthesis of pituitary glycoproteins at distributed sites ; this is not well studied , but it may further modify the paradigm of central endocrine regulation .

Elevated maternal cortisol early in pregnancy predicts third trimester levels of placental corticotropin releasing hormone ( P06850 REA ) : priming the placental clock . The purposes of this study were to determine the intervals when placental corticotrophic-releasing hormone ( P06850 REA ) was most responsive to maternal cortisol . A sample of 203 women each were evaluated at 15 , 19 , 25 and 31 weeks gestation and followed to term . Placental P06850 REA and maternal adrenocorticotropin hormone ( DB01285 MEN ) , B-endorphin and cortisol were determined from plasma . P06850 REA levels increased faster and were higher in women who delivered preterm compared with women who delivered at term ( P13726 REA , 603 = 5.73 , p < . 001 ) . Simple effects indicated that P06850 REA levels only at 31 weeks predicted preterm birth ( F1 , 201 = 5.53 , p = . 02 ) . Levels of cortisol were higher in women who delivered preterm at 15 weeks gestation ( F1 , 201 = 4.45 , p = . 03 ) with a similar trend at 19 weeks gestation . Hierarchical regression suggested that the influence on birth outcome of maternal cortisol early in pregnancy was mediated by its influence on placental P06850 REA at 31 weeks . Elevated cortisol at 15 weeks predicted the surge in placental P06850 REA at 31 weeks ( R = . 49 , d . f . = 1,199 , Fchange = 61.78 , p < . 0001 ) . Every unit of change in cortisol ( microg / dl ) at 15 weeks was associated with a 34 unit change of P06850 REA ( pg / ml ) at 31 weeks . These findings suggested that early detection of stress signals by the placenta stimulated the subsequent release of P06850 REA and resulted in increased risk for preterm delivery .

DB08875 SUB inhibits growth of androgen-sensitive and castration-resistant prostate cancer and affects bone remodeling . DB08875 SUB is an inhibitor of multiple receptor tyrosine kinases , including MET and P35968 REA . In a phase II clinical trial in advanced prostate cancer ( PCa ) , cabozantinib treatment improved bone scans in 68 % of evaluable patients . Our studies aimed to determine the expression of cabozantinib targets during PCa progression and to evaluate its efficacy in hormone-sensitive and castration-resistant PCa in preclinical models while delineating its effects on tumor and bone . Using immunohistochemistry and tissue microarrays containing normal prostate , primary PCa , and soft tissue and bone metastases , our data show that levels of MET , P-MET , and P35968 REA are increasing during PCa progression . Our data also show that the expression of cabozantinib targets are particularly pronounced in bone metastases . To evaluate cabozantinib efficacy on PCa growth in the bone environment and in soft tissues we used androgen-sensitive LuCaP 23.1 and castration-resistant C4 - 2B PCa tumors . In vivo , cabozantinib inhibited the growth of PCa in bone as well as growth of subcutaneous tumors . Furthermore , cabozantinib treatment attenuated the bone response to the tumor and resulted in increased normal bone volume . In summary , the expression pattern of cabozantinib targets in primary and castration-resistant metastatic PCa , and its efficacy in two different models of PCa suggest that this agent has a strong potential for the effective treatment of PCa at different stages of the disease .

Inhibition of the liver expression of arylalkylamine N-acetyltransferase increases the expression of angiogenic factors in cholangiocytes . BACKGROUND AND AIMS : Reduction of biliary serotonin N-acetyltransferase ( Q16613 REA ) expression and melatonin administration / secretion in cholangiocytes increases biliary proliferation and the expression of SR , P13569 REA and Cl ( - ) / HCO 3 ( - ) P04920 REA . The balance between biliary proliferation / damage is regulated by several autocrine neuroendocrine factors including vascular endothelial growth factor-A / C ( P15692 REA / C ) . VEGFs are secreted by several epithelia , where they modulate cell growth by autocrine and paracrine mechanisms . No data exists regarding the effect of Q16613 REA modulation on the expressions of VEGFs by cholangiocytes . METHODS : In this study , we evaluated the effect of local modulation of biliary Q16613 REA expression on the cholangiocytes synthesis of P15692 REA / C . RESULTS : The decrease in Q16613 REA expression and subsequent lower melatonin secretion by cholangiocytes was associated with increased expression of P15692 REA / C . Overexpression of Q16613 REA in cholangiocyte lines decreased the expression of P15692 REA / C . CONCLUSIONS : Modulation of melatonin synthesis may affect the expression of P15692 REA / C by cholangiocytes and may modulate the hepatic microvascularization through the regulation of P15692 REA / C expression regulating biliary functions .

Benzyl isothiocyanate suppresses pancreatic tumor angiogenesis and invasion by inhibiting HIF-α / P15692 REA / Rho-GTPases : pivotal role of P35610 REA - 3 . Our previous studies have shown that benzyl isothiocyanate ( BITC ) suppresses pancreatic tumor growth by inhibiting P35610 REA - 3 ; however , the exact mechanism of tumor growth suppression was not clear . Here we evaluated the effects and mechanism of BITC on pancreatic tumor angiogenesis . Our results reveal that BITC significantly inhibits neovasularization on rat aorta and Chicken-Chorioallantoic membrane . Furthermore , BITC blocks the migration and invasion of BxPC - 3 and PanC - 1 pancreatic cancer cells in a dose dependant manner . Moreover , secretion of P15692 REA and P08253 REA in normoxic and hypoxic BxPC - 3 and PanC - 1 cells was significantly suppressed by BITC . Both P15692 REA and P08253 REA play a critical role in angiogenesis and metastasis . Our results reveal that BITC significantly suppresses the phosphorylation of P35968 REA ( DB00135 - 1175 ) , and expression of HIF-α . Rho-GTPases , which are regulated by P15692 REA play a crucial role in pancreatic cancer progression . BITC treatment reduced the expression of RhoC whereas up-regulated the expression of tumor suppressor RhoB . P35610 REA - 3 over-expression or P05231 REA treatment significantly induced HIF - 1α and P15692 REA expression ; however , BITC substantially suppressed P35610 REA - 3 as well as P35610 REA - 3 - induced HIF - 1α and P15692 REA expression . Finally , in vivo tumor growth and matrigel-plug assay show reduced tumor growth and substantial reduction of hemoglobin content in the matrigel plugs and tumors of mice treated orally with 12 µmol BITC , indicating reduced tumor angiogenesis . Immunoblotting of BITC treated tumors show reduced expression of P35610 REA - 3 phosphorylation ( DB00135 - 705 ) , HIF-α , P35968 REA , P15692 REA , P08253 REA , CD31 and RhoC . Taken together , our results suggest that BITC suppresses pancreatic tumor growth by inhibiting tumor angiogenesis through P35610 REA - 3 - dependant pathway .

DB08875 SUB ( DB05153 ) , a novel MET and P35968 REA inhibitor , simultaneously suppresses metastasis , angiogenesis , and tumor growth . The signaling pathway of the receptor tyrosine kinase MET and its ligand hepatocyte growth factor ( P14210 REA ) is important for cell growth , survival , and motility and is functionally linked to the signaling pathway of P15692 REA , which is widely recognized as a key effector in angiogenesis and cancer progression . Dysregulation of the MET / P15692 REA axis is found in a number of human malignancies and has been associated with tumorigenesis . DB08875 SUB ( DB05153 ) is a small-molecule kinase inhibitor with potent activity toward MET and P15692 REA receptor 2 ( P35968 REA ) , as well as a number of other receptor tyrosine kinases that have also been implicated in tumor pathobiology , including P07949 REA , P10721 REA , P30530 REA , and P36888 REA . Treatment with cabozantinib inhibited MET and P35968 REA phosphorylation in vitro and in tumor models in vivo and led to significant reductions in cell invasion in vitro . In mouse models , cabozantinib dramatically altered tumor pathology , resulting in decreased tumor and endothelial cell proliferation coupled with increased apoptosis and dose-dependent inhibition of tumor growth in breast , lung , and glioma tumor models . Importantly , treatment with cabozantinib did not increase lung tumor burden in an experimental model of metastasis , which has been observed with inhibitors of P15692 REA signaling that do not target MET . Collectively , these data suggest that cabozantinib is a promising agent for inhibiting tumor angiogenesis and metastasis in cancers with dysregulated MET and VEGFR signaling .

Fluorescence energy transfer detection as a homogeneous DNA diagnostic method . A homogeneous DNA diagnostic assay based on template-directed primer extension detected by fluorescence resonance energy transfer , named template-directed dye-terminator incorporation ( P0CAT3 ) assay , has been developed for mutation detection and high throughput genome analysis . Here , we report the successful application of the P0CAT3 assay to detect mutations in the cystic fibrosis transmembrane conductance regulator ( P13569 REA ) gene , the human leukocyte antigen H ( HLA-H ) gene , and the receptor tyrosin kinase ( P07949 REA ) protooncogene that are associated with cystic fibrosis , hemochromatosis , and multiple endocrine neoplasia , type 2 , respectively . Starting with total human DNA , the samples are amplified by the PCR followed by enzymatic degradation of excess primers and deoxyribonucleoside triphosphates before the primer extension reaction is performed . All these standardized steps are performed in the same tube , and the fluorescence changes are monitored in real time , making it a useful clinical DNA diagnostic method .

Lowering of body core temperature by exposure to a cold environment and by a P08908 REA agonist : effects on physiological and psychological variables and blood serotonin levels . The present study was designed to compare the effects of a pharmacologically induced decrease in body core temperature to the effects observed with lowering of body temperature by exposure to a cold environment . Our special interest was the involvement of 5 - HT in thermoregulatory responses . Sixty healthy male volunteers were randomly assigned to one of the following conditions : exposure to normal ambient temperature ( 28 degrees C ) and placebo , exposure to cold ambient temperature ( 5 degrees C ) and placebo , or normal ambient temperature and 10 mg of the partial P08908 REA agonist ipsapirone . As indicators of physiological responses to lowering of body temperature , tympanic temperature , skin temperature , P15941 REA , metabolic rate , and heart rate were monitored and saliva cortisol levels and peripheral 5 - HT concentrations were determined . In addition , ratings on ambient temperature , thermal discomfort , and feelings of irritability were obtained . While lowering of body core temperature was associated with marked counterregulations ( decrease of skin temperature , increase in P15941 REA and metabolic rate ) and feelings of discomfort , this was not observed with ipsapirone . An increase in cortisol levels was primarily observed in the ipsapirone group and was not reflected by respective changes in whole blood or platelet 5 - HT indicating that brain and platelet 5 - HT are not related .

Inhibition of angiogenesis by vitamin D-binding protein : characterization of anti-endothelial activity of P02774 REA . Angiogenesis is a complex process involving coordinated steps of endothelial cell activation , proliferation , migration , tube formation and capillary sprouting with participation of intracellular signaling pathways . Regulation of angiogenesis carries tremendous potential for cancer therapy . Our earlier studies showed that vitamin D-binding protein-macrophage activating factor ( P02774 REA ) acts as a potent anti-angiogenic factor and inhibits tumor growth in vivo . The goal of this investigation was to understand the effect of P02774 REA on human endothelial cell ( O14777 REA ) and the mechanism of angiogenesis inhibition . P02774 REA inhibited human endothelial cell ( O14777 REA ) proliferation by inhibiting DNA synthesis ( IC ( 50 ) = 7.8 + / - 0.15 microg / ml ) . P02774 REA significantly induced S - and G0 / P55008 - phase arrest in O14777 REA in 72 h . P02774 REA potently blocked P15692 REA - induced migration , tube-formation of O14777 REA in a dose dependent manner . In addition , P02774 REA inhibited growth factor-induced microvessel sprouting in rat aortic ring assay . Moreover , P02774 REA inhibited P15692 REA signaling by decreasing P15692 REA - mediated phosphorylation of P35968 REA and P27361 REA / 2 , a downstream target of P15692 REA signaling cascade . However , Akt activation was not affected . These studies collectively demonstrate that P02774 REA inhibits angiogenesis by blocking critical steps such as O14777 REA proliferation , migration , tube formation and microvessel sprouting . P02774 REA exerts its effect by inhibiting VEGR - 2 and P27361 REA / 2 signaling cascades . Understanding the cellular and molecular mechanisms of anti-endothelial activity of P02774 REA will allow us to develop it as an angiogenesis targeting novel drug for tumor therapy .

[ Association of Castleman ' s disease and Hodgkin ' s disease . Eight cases and review of the literature ] . We have recorded 8 patients presenting a Hodgkin ' s disease associated with Castleman ' s disease . Four men and 4 women with a 44 years mean age ( 15-60 ) , presented as a solitary mass ( 2/7 ) or as a multicentric tumoral disease ( 5/7 ) . One of our patients was HIV . Histological studies showed typical features of Castleman ' s disease . Nodular sclerosing Hodgkin ' s disease with numerous lacunar cells were present in 3 cases , interfollicular Hodgkin ' s disease in 4 cases and nodular paragranuloma in one case . Hodgkins ' and Reed Sternberg cells were positive for CD15 ( 4/7 ) , P28908 REA ( 5/7 ) , P15941 REA ( 3/6 ) and Q9NR12 - 1 ( 4/5 ) . In situ hybridization on tissue sections demonstrate presence of EBV DNA in one case and EBER 1 - RNA in 2 of 4 cases . The difficulty in making the diagnosis of Hodgkin ' s disease the relation between both diseases , and the role of P05231 REA are discussed .

DB08875 SUB : a MET , P07949 REA , and P35968 REA tyrosine kinase inhibitor . DB08875 SUB is a receptor tyrosine kinase inhibitor with activity against MET , P35968 REA , P36888 REA , c - P10721 REA , and P07949 REA . Activity of cabozantinib toward a broad range of tumor models could be detected in several preclinical studies . Of note , cabozantinib decreases metastasis potential and tumor invasiveness when compared with placebo or agents that target VEGFR and have no activity against MET . Clinical phase I and II studies with cabozantinib have been conducted in various malignancies including medullary thyroid cancer ( P04629 REA ) , NSCLC , breast , ovarian , pancreatic , and prostate cancer . In P04629 REA , gain of function mutations of P07949 REA are central for tumorigenesis . Hereditary forms of P04629 REA ( MEN II ) are caused by germline mutations of P07949 REA , in sporadic P04629 REA in up to 50 % of cases P07949 REA mutations occur . Additionally , activating molecular changes in VEGFR and MET pathways have also been implicated in P04629 REA progression . Clinical responses with cabozantinib in P04629 REA could be observed in early clinical trials , and following confirmation of clinical benefit in a randomized phase III trial , cabozantinib gained FDA approval for first-line treatment of advanced P04629 REA in 2012 . In prostate cancer models , MET expression increases with androgen ablation and clinical progression of bone and lymph node metastasis . A phase II trial with cabozantinib also showed very promising response rates in patients with metastatic prostate cancer . Therefore , randomized phase III studies are currently ongoing to validate the efficacy of cabozantinib in heavily pretreated prostate cancer patients .

Alveolar hypoxia promotes murine lung tumor growth through a P35968 REA / P00533 REA - dependent mechanism . Patients with chronic obstructive pulmonary disease ( P48444 REA ) are at an increased risk for the development of lung cancer , the mechanisms for which are incompletely understood . We hypothesized that the hypoxic pulmonary microenvironment present in P48444 REA would augment lung carcinogenesis . Mice were subjected to chemical carcinogenesis protocols and placed in either hypoxia or normoxia . Mice exposed to chronic hypoxia developed tumors with increased volume compared with normoxic controls . Both lungs and tumors from hypoxic mice showed a preferential stabilization of HIF - 2α and increased expression of P15692 REA , P09038 REA , and their receptors as well as other survival , proliferation , and angiogenic signaling pathways regulated by HIF - 2α . We showed that tumors arising in hypoxic animals have increased sensitivity to P35968 REA / P00533 REA inhibition , as chemoprevention with vandetanib showed markedly increased activity in hypoxic mice . These studies showed that lung tumors arising in a hypoxic microenvironment express increased growth , angiogenic , and survival signaling that could contribute to the increased lung cancer risk in P48444 REA . Furthermore , the differential sensitivity of tumors arising in hypoxia to P35968 REA / P00533 REA inhibition suggests that the altered signaling present in tumors arising in hypoxic lung might be therapeutically exploited in patients with underlying P48444 REA .

Response to DB08875 SUB in patients with P07949 REA fusion-positive lung adenocarcinomas . The discovery of P07949 REA fusions in lung cancers has uncovered a new therapeutic target for patients whose tumors harbor these changes . In an unselected population of non-small cell lung carcinomas ( NSCLCs ) , P07949 REA fusions are present in 1 % to 2 % of cases . This incidence increases substantially , however , in never-smokers with lung adenocarcinomas that lack other known driver oncogenes . Although preclinical data provide experimental support for the use of P07949 REA inhibitors in the treatment of P07949 REA fusion-positive tumors , clinical data on response are lacking . We report preliminary data for the first three patients treated with the P07949 REA inhibitor cabozantinib on a prospective phase II trial for patients with P07949 REA fusion-positive NSCLCs ( NCT 01639508 ) . Confirmed partial responses were observed in 2 patients , including one harboring a novel Q9UPN9 - P07949 REA fusion . A third patient with a P33176 REA - P07949 REA fusion has had prolonged stable disease approaching 8 months ( 31 weeks ) . All three patients remain progression-free on treatment .

DB08875 SUB suppresses tumor growth and metastasis in hepatocellular carcinoma by a dual blockade of P35968 REA and MET . PURPOSE : MET signaling has been suggested a potential role in hepatocellular carcinoma ( HCC ) and associated with prometastasis during antiangiogenesis therapy . We investigated the potential association between MET expression and therapeutic response to sorafenib in patients with HCC . Antitumor effects of cabozantinib , a dual inhibitor of MET and P35968 REA , were examined in cultured HCC cells as well as in vivo models . EXPERIMENTAL DESIGN : Total MET and phosphorylated MET ( p-MET ) were measured in 29 resected HCC specimens , and correlated with response to sorafenib as postoperative adjuvant therapy . In the second set of experiments using cultured HCC cells , and mouse xenograft and metastatic models , effects of cabozantinib were examined . RESULTS : High level of p-MET in resected HCC specimens was associated with resistance to adjuvant sorafenib therapy . In cultured HCC cells that expressed p-MET , cabozantinib inhibited the activity of MET and its downstream effectors , leading to P55008 - phase arrest . DB08875 SUB inhibited tumor growth in p-MET-positive and p-MET-negative HCC by decreasing angiogenesis , inhibiting proliferation , and promoting apoptosis , but it exhibited more profound efficacy in p-MET-positive HCC xenografts . DB08875 SUB blocked the hepatocyte growth factor ( P14210 REA ) - stimulated MET pathway and inhibited the migration and invasion of the HCC cells . Notably , cabozantinib reduced the number of metastatic lesions in the lung and liver in the experimental metastatic mouse model . CONCLUSIONS : Patients with HCC with high level of p-MET are associated with resistance to adjuvant sorafenib treatment . The dual blockade of P35968 REA and MET by cabozantinib has significant antitumor activities in HCC , and the activation of MET in HCC may be a promising efficacy-predicting biomarker . Clin Cancer Res ; 20 ( 11 ) ; 2959-70 . © 2014 AACR .

DB08875 SUB for the treatment of advanced medullary thyroid cancer . INTRODUCTION : Patients with advanced medullary thyroid cancer ( P04629 REA ) have poor prognoses and limited treatment options . Improved knowledge about molecular aberrations associated with P04629 REA and the availability of novel targeted tyrosine kinase inhibitors ( TKIs ) have led to new potential treatment modalities . DB08875 SUB is an oral multitargeted TKI with activity against multiple receptors including P07949 REA , vascular endothelial growth factor receptor type 2 ( P35968 REA ) , and MET that has been evaluated in P04629 REA in the preclinical and clinical arenas . METHODS : This article reviews unmet clinical needs in advanced P04629 REA . The authors consider novel agents that have been studied in P04629 REA , with a focus on the investigational agent cabozantinib . Up-to-date clinical data of cabozantinib in P04629 REA are discussed . RESULTS : Recent clinical evaluation suggests that cabozantinib is the first agent to prolong progression-free survival in patients with progressive P04629 REA . These findings indicate that cabozantinib may be an effective therapy in advanced P04629 REA . No improvement in overall survival has been demonstrated but data are not mature . CONCLUSION : DB08875 SUB may be an effective treatment option for patients with advanced P04629 REA and is worthy of further evaluation .

DB08875 SUB overcomes crizotinib resistance in P08922 fusion-positive cancer . PURPOSE : P08922 rearrangement leads to constitutive P08922 activation with potent transforming activity . In an ongoing phase I trial , the Q9UM73 tyrosine kinase inhibitor ( TKI ) crizotinib shows remarkable initial responses in patients with non-small cell lung cancer ( NSCLC ) harboring P08922 fusions ; however , cancers eventually develop crizotinib resistance due to acquired mutations such as G2032R in P08922 . Thus , understanding the crizotinib-resistance mechanisms in P08922 - rearranged NSCLC and identification of therapeutic strategies to overcome the resistance are required . EXPERIMENTAL DESIGN : The sensitivity of P04233 REA - P08922 - transformed Ba / P13726 REA cells to multiple Q9UM73 inhibitors was examined . Acquired P08922 inhibitor-resistant mutations in P04233 REA - P08922 fusion were screened by N-ethyl-N-nitrosourea mutagenesis with Ba / P13726 REA cells . To overcome the resistance mutation , we performed high-throughput drug screening with small-molecular inhibitors and anticancer drugs used in clinical practice or being currently tested in clinical trials . The effect of the identified drug was assessed in the P04233 REA - P08922 - mutant Ba / P13726 REA cells and crizotinib-resistant patient-derived cancer cells ( MGH 047 ) harboring G2032R - mutated P04233 REA - P08922 . RESULTS : We identified multiple novel crizotinib-resistance mutations in the P08922 kinase domain , including the G2032R mutation . As the result of high-throughput drug screening , we found that the cMET / P07949 REA / VEGFR inhibitor cabozantinib ( DB05153 ) effectively inhibited the survival of P04233 REA - P08922 wild-type ( WT ) and resistant mutants harboring Ba / P13726 REA and MGH 047 cells . Furthermore , cabozantinib could overcome all the resistance by all newly identified secondary mutations . CONCLUSIONS : We developed a comprehensive model of acquired resistance to P08922 inhibitors in NSCLC with P08922 rearrangement and identified cabozantinib as a therapeutic strategy to overcome the resistance .

Aripiprazole : pharmacodynamics of a dopamine partial agonist for the treatment of schizophrenia . Aripiprazole is the first approved atypical antipsychotic with a mechanism of action that exerts a partial agonism with high affinity at DB00988 MEN D2 - and Serotonin - P08908 REA - receptors as well as an antagonism at Serotonin - 5 - Q13049 REA - receptors . Aripiprazole provides good clinical effectiveness and a favorable profile of safety and tolerability . The special pharmacodynamics of aripiprazole are described herein .

P14174 REA deficiency in chronic obstructive pulmonary disease . The pathogenesis of chronic obstructive pulmonary disease ( P48444 REA ) remains poorly understood . Cellular senescence and apoptosis contribute to the development of P48444 REA ; however , crucial regulators of these underlying mechanisms remain unknown . P14174 REA ( MIF ) is a pleiotropic cytokine that antagonizes both apoptosis and premature senescence and may be important in the pathogenesis of P48444 REA . This study examines the role of MIF in the pathogenesis of P48444 REA . Mice deficient in MIF ( Mif ( - / - ) ) or the MIF receptor P04233 REA ( Cd74 ( - / - ) ) and wild-type ( WT ) controls were aged for 6 mo . Both Mif ( - / - ) and Cd74 ( - / - ) mice developed spontaneous emphysema by 6 mo of age compared with WT mice as measured by lung volume and chord length . This was associated with activation of the senescent pathway markers p53 / 21 and p16 . Following exposure to cigarette smoke , Mif ( - / - ) mice were more susceptible to the development of P48444 REA and apoptosis compared with WT mice . MIF plasma concentrations were measured in a cohort of 224 human participants . Within a subgroup of older current and former smokers ( n = 72 ) , MIF concentrations were significantly lower in those with P48444 REA [ 8.8 , 95 % CI ( 6.7- 11.0 ) ] compared with those who did not exhibit P48444 REA [ 12.7 ng / ml , 95 % CI ( 10.6- 14.8 ) ] . Our results suggest that both MIF and the MIF receptor P04233 REA are required for maintenance of normal alveolar structure in mice and that decreases in MIF are associated with P48444 REA in human subjects .

Levels of surfactant proteins A and D and P15941 REA are elevated in the induced sputum of chronic obstructive pulmonary disease patients : a sequential sputum analysis . BACKGROUND : Recent clinical studies have suggested that serum surfactant protein ( SP ) A , P35247 REA and P15941 REA ( P15941 REA ) are potential biomarkers for interstitial lung diseases . Serum levels of SP-A and P35247 REA have also been found to be elevated in chronic obstructive pulmonary disease ( P48444 REA ) , but their significance has not been evaluated or compared in induced sputum samples obtained directly from the airways . OBJECTIVE : A sequential sputum analysis was conducted to assess the value of SP-A , P35247 REA and P15941 REA levels in P48444 REA . METHODS : The study material consisted of induced sputum samples from 61 subjects , 28 with P48444 REA and 33 with prolonged cough ( cough lasting > 3 weeks and normal spirometry ) . Sputum was collected in 3 fractions ( 3 periods of 5 min each ) . Sputum levels of these proteins were measured , and receiver operating characteristic curve analysis was carried out to evaluate the sensitivity , specificity and area under the curve ( AUC ) for each fraction . RESULTS : The levels of SP-A , P35247 REA and P15941 REA were higher in patients with P48444 REA than in those with prolonged cough in each of the fractions . Sputum levels of these proteins correlated inversely with obstruction and positively with ageing , smoking history , sputum macrophages and eosinophils . Sputum fractionation had a relatively minor effect on the levels and AUC of these proteins . CONCLUSION : Sequential sputum analysis from 3 consecutive fractions indicated a significant difference in the levels of SP-A , P35247 REA and P15941 REA between P48444 REA and prolonged cough . However , sputum fractionation itself had a relatively minor effect on the levels of these proteins .

DB08875 SUB and prostate cancer : inhibiting seed and disrupting soil ? Treatment with cabozantinib , an inhibitor of MET and P35968 REA signaling , has demonstrated clinical benefit in early trials in men with metastatic prostate cancer . Preclinical evidence suggests that cabozantinib can kill cancer cell seeds while disrupting angiogenesis and stromal cells in the metastatic soil .

Cross-talk between PKA-Cβ and p65 mediates synergistic induction of Q07343 REA by roflumilast and NTHi . Phosphodiesterase 4B ( Q07343 REA ) plays a key role in regulating inflammation . DB01656 MEN , a phosphodiesterase ( PDE ) 4 - selective inhibitor , has recently been approved for treating severe chronic obstructive pulmonary disease ( P48444 REA ) patients with exacerbation . However , there is also clinical evidence suggesting the development of tachyphylaxis or tolerance on repeated dosing of roflumilast and the possible contribution of Q07343 REA up-regulation , which could be counterproductive for suppressing inflammation . Thus , understanding how Q07343 REA is up-regulated in the context of the complex pathogenesis and medications of P48444 REA may help improve the efficacy and possibly ameliorate the tolerance of roflumilast . Here we show that roflumilast synergizes with nontypeable Haemophilus influenzae ( NTHi ) , a major bacterial cause of P48444 REA exacerbation , to up-regulate PDE 4B2 expression in human airway epithelial cells in vitro and in vivo . Up-regulated PDE 4B2 contributes to the induction of certain important chemokines in both enzymatic activity-dependent and activity-independent manners . We also found that protein kinase A catalytic subunit β ( PKA-Cβ ) and nuclear factor-κB ( NF-κB ) p65 subunit were required for the synergistic induction of PDE 4B2 . PKA-Cβ phosphorylates p65 in a DB02527 - dependent manner . Moreover , Ser 276 of p65 is critical for mediating the PKA-Cβ-induced p65 phosphorylation and the synergistic induction of PDE 4B2 . Collectively , our data unveil a previously unidentified mechanism underlying synergistic up-regulation of PDE 4B2 via a cross-talk between PKA-Cβ and p65 and may help develop new therapeutic strategies to improve the efficacy of DB05876 inhibitor .

P02649 REA does not predict poor outcome 1 year after ischemic stroke . OBJECTIVES : The apolipoprotein E gene ( P02649 REA ) polymorphism may influence outcome in various forms of brain injury . The association between P02649 REA genotype and long-term ischemic stroke ( IS ) outcome is controversial . We have examined the effect of stroke risk factors , clinical status at admission and P02649 REA genotype on survival and dependency 1 year after IS . METHODS : We investigated 496 consecutively subjects with IS . Information concerning risk factors and clinical data were collected prospectively . Functional dependency was estimated with modified Rankin scale ( mRS ) and defined as a score of 3-5 . Each patient was offered a I year follow-up evaluation . P02649 REA genotyping was performed by the polymerase chain reaction-restriction fragment length polymorphism ( PCR-RFLP ) method . Multivariate regression models were used to analyse predictors of death and poor outcome ( death or dependency ) within 1 year after the stroke . RESULTS : The distribution ofAPOE genotypes was 69 % with genotype E3 / E3 , 18 % with genotype P13726 REA / E4 , 12 % with genotype E2 / 13 and 1 % with genotype F2 / 14 . At year 1 , 169 patients ( 38 % ) had died and 78 of the survivors ( 28 % ) were functionally dependent . The best predictors of death at year 1 were : age over 70 years , congestive heart failure , atrial fibrillation , disturbed consciousness and severe hand paresis . Poor outcome was independently predicted by : age over 70 years , congestive heart failure , pre-stroke mRS > or = 3 , marked disturbance of consciousness and severe hand paresis . CONCLUSION : We did not find any impact of P02649 REA genotype on mortality or poor outcome 1 year after IS .

Genomic landscape of non-small cell lung cancer in smokers and never-smokers . We report the results of whole-genome and transcriptome sequencing of tumor and adjacent normal tissue samples from 17 patients with non-small cell lung carcinoma ( NSCLC ) . We identified 3,726 point mutations and more than 90 indels in the coding sequence , with an average mutation frequency more than 10 - fold higher in smokers than in never-smokers . Novel alterations in genes involved in chromatin modification and DNA repair pathways were identified , along with Q9UI36 , P13569 REA , P78509 REA , Q2M3G0 REA , and P14210 REA . Deep digital sequencing revealed diverse clonality patterns in both never-smokers and smokers . All validated EFGR and P01116 REA mutations were present in the founder clones , suggesting possible roles in cancer initiation . Analysis revealed 14 fusions , including P08922 and Q9UM73 , as well as novel metabolic enzymes . Cell-cycle and JAK - P35610 REA pathways are significantly altered in lung cancer , along with perturbations in 54 genes that are potentially targetable with currently available drugs .

DB08875 SUB : a review of its use in patients with medullary thyroid cancer . DB08875 SUB ( Cometriq ( ® ) ) is an orally administered small molecule inhibitor of multiple tyrosine kinase receptors , including those involved in the pathogenesis of medullary thyroid cancer ( P04629 REA ) [ i . e . rearranged during transfection ( P07949 REA ) , MET and vascular endothelial growth factor receptor ( VEGFR ) - 2 ] . DB08875 SUB is indicated for the treatment of adults with progressive , unresectable locally advanced ( in the EU ) or metastatic ( in the EU and USA ) P04629 REA . Compared with placebo , cabozantinib significantly prolonged progression-free survival , reflecting a 72 % reduction in the risk of disease progression or death , in patients with unresectable , locally advanced or metastatic P04629 REA participating in a multinational , phase III study . A significantly higher proportion of patients receiving cabozantinib than those receiving placebo achieved an objective response or disease stabilization ( i . e . a complete or partial response , or stable disease ) . The overall survival benefit with cabozantinib is as yet unclear , with no significant benefit observed in two interim analyses ( one prespecified , and one unplanned and conducted at the request of the US FDA ) . The tolerability profile of oral cabozantinib is typical for a small molecule targeting the VEGFR and other tyrosine kinase-mediated pathways , with adverse events associated with the inhibition of the P15692 REA pathway ( e . g . gastrointestinal perforation , haemorrhage , hypertension and venous thrombosis ) reported in the phase III study . Treatment-emergent adverse events were generally managed with supportive therapy , dose reductions and / or dose interruptions . Although final overall survival data are awaited , current evidence suggests cabozantinib to be a valuable treatment option for adults with progressive , unresectable locally advanced or metastatic P04629 REA .

DB08820 MEN potentiation of multiple P13569 REA channels with gating mutations . BACKGROUND : The investigational P13569 REA potentiator ivacaftor ( VX - 770 ) increased P13569 REA channel activity and improved lung function in subjects with CF who have the G551D P13569 REA gating mutation . The aim of this in vitro study was to determine whether ivacaftor potentiates mutant P13569 REA with gating defects caused by other P13569 REA gating mutations . METHODS : The effects of ivacaftor on P13569 REA channel open probability and chloride transport were tested in electrophysiological studies using Fischer rat thyroid ( P17948 REA ) cells expressing different P13569 REA gating mutations . RESULTS : DB08820 MENMAX DB08820 MEN potentiated multiple mutant P13569 REA forms with defects in P13569 REA channel gating . These included the G551D , G178R , S549N , S549R , G551S , G970R , G1244E , S1251N , S1255P and G1349D P13569 REA gating mutations . CONCLUSION : These in vitro data suggest that ivacaftor has a similar effect on all P13569 REA forms with gating defects and support investigation of the potential clinical benefit of ivacaftor in CF patients who have P13569 REA gating mutations beyond G551D .

Phosphodiesterase - 4 influences the PKA phosphorylation status and membrane translocation of G-protein receptor kinase 2 ( P25098 REA ) in P29320 REA - 293beta2 cells and cardiac myocytes . Membrane-recruitment of P25098 REA ( G-protein receptor kinase 2 ) provides a fundamental step in the desensitization process controlling GPCRs ( G-protein-coupled receptors ) , such as the beta 2AR ( beta 2 - adrenergic receptor ) . In the present paper , we show that challenge of P29320 REA - 293beta2 [ human embryonic kidney cells stably overexpressing the FLAG-tagged beta 2AR - GFP ( green fluorescent protein ) ] cells with the beta-adrenoceptor agonist , isoprenaline , causes P25098 REA to become phosphorylated by PKA ( DB02527 - dependent protein kinase ) . This action is facilitated when DB02527 - specific DB05876 ( phosphodiesterase - 4 ) activity is selectively inactivated , either chemically with rolipram or by siRNA ( small interfering RNA ) - mediated knockdown of Q07343 REA and Q08499 REA . DB05876 - selective inhibition by rolipram facilitates the isoprenaline-induced membrane translocation of P25098 REA , phosphorylation of the beta 2AR by P25098 REA , membrane translocation of beta-arrestin and internalization of beta 2ARs . DB05876 - selective inhibition also enhances the ability of isoprenaline to trigger the PKA phosphorylation of P25098 REA in cardiac myocytes . In the absence of isoprenaline , rolipram-induced inhibition of DB05876 activity in P29320 REA - 293beta2 cells acts to stimulate PKA phosphorylation of P25098 REA , with consequential effects on P25098 REA membrane recruitment and P25098 REA - mediated phosphorylation of the beta 2AR . We propose that a key role for DB05876 enzymes is : ( i ) to gate the action of PKA on P25098 REA , influencing the rate of P25098 REA phosphorylation of the beta 2AR and consequential recruitment of beta-arrestin subsequent to beta-adrenoceptor agonist challenge , and ( ii ) to protect P25098 REA from inappropriate membrane recruitment in unstimulated cells through its phosphorylation by PKA in response to fluctuations in basal levels of DB02527 .

Case of multiple endocrine neoplasia 2B with probable ectopic adrenocorticotropic hormone-secreting liver metastasis from medullary thyroid carcinoma . A 31 year old woman was diagnosed with multiple endocrine neoplasia ( MEN ) 2B at 10 years old . Dark pigmentation gradually developed on her skin and her serum adrenocorticotropic hormone ( DB01285 MEN ) was high , suggesting concurrent ectopic DB01285 MEN syndrome ( EAS ) . P06850 REA ( P06850 REA ) loading test ruled out Cushing ' s disease and supported the diagnosis of EAS . Multiple low attenuation mass in the liver was observed in a computed tomography ( CT ) scan , and was suspected as ectopic DB01285 MEN - secreting metastatic tumor from medullary thyroid carcinoma ( P04629 REA ) . DB01285 MEN production by P04629 REA is relatively rare , particularly in patients with MEN ; patients with ectopic DB01285 MEN - secreting liver metastatic tumor from P04629 REA in MEN 2B have never been reported previously .

Cytoplasmic and nuclear estrogen binding capacity in the rat uterus during treatment with danazol and testosterone . DB01406 MEN , testosterone and dihydrotestosterone ( DB02901 ) were tested as competitors for estrogen receptors on immature rat uterus cytosol . No competitive binding could be demonstrated for any of these steroids . After that , prepubertal Wistar rats were exposed to danazol , testosterone or propylene glycol ( control ) for 3 days or 17 days . After the appropriate exposure to medication , the animals were killed . Both danazol and testosterone appeared to be uterotropic after 3 days of treatment , although the increase in the uterine weight was significant only in the danazol-treated group ( p less than 0.05 ) . This effect was lost after 17 days of treatment . P03372 REA binding assays were done on the cytosolic and nuclear fractions of the homogenized uterine tissue of each group . The estrogen binding capacity of cytosols was increased in both the danazol ( p less than 0.05 ) and the testosterone ( p less than 0.01 ) groups after 3 days of treatment . A parallel increase was found in the nuclear fraction of both groups . After 17 days of treatment , the comparison between the 3 groups showed no differences in the cytosolic or nuclear estrogen binding capacity . The information provided by this study suggests that some effects of danazol may be due to an androgenic action and that may be associated to increases in the free fraction of testosterone .

Levels of angiopoietins 1 and 2 in induced sputum supernatant in patients with P48444 REA . Pathological features of chronic obstructive pulmonary disease ( P48444 REA ) include lung vascular remodeling and angiogenesis . Q15389 REA ( Ang - 1 ) , is an essential mediator of angiogenesis by establishing vascular integrity , whereas angiopoietin - 2 ( Ang - 2 ) acts as its natural inhibitor . We determined the levels of angiopoietins in sputum supernatants of patients with P48444 REA and investigated their possible association with mediators and cells involved in the inflammatory and remodeling process . Fifty-nine patients with P48444 REA , 25 healthy smokers and 20 healthy non-smokers were studied . All subjects underwent lung function tests , sputum induction for cell count identification and Ang - 1 , Ang - 2 , P15692 REA , TGF-β 1 , P08253 REA , LTB 4 , P10145 REA , albumin measurement in sputum supernatants . Airway vascular permeability ( AVP ) index was also assessed . Ang - 2 levels were significantly higher in patients with P48444 REA compared to healthy smokers and healthy non-smokers [ median , interquartile ranges pg / ml , 267 ( 147-367 ) vs . 112 ( 67-171 ) and 98 ( 95-107 ) , respectively ; p < 0.001 ] . Regression analysis showed a significant association between Ang - 2 levels and AVP index , P15692 REA , P10145 REA and P08253 REA levels in P48444 REA , the strongest being with P15692 REA . Our results indicate that induced sputum Ang - 2 levels are higher in P48444 REA compared to healthy smokers and healthy non-smokers . Moreover , Ang - 2 is associated with AVP , P10145 REA , P08253 REA , and P15692 REA , indicating a possible role for Ang - 2 in the pathogenesis of the disease .

[ Cell cycle analysis of endometrial cancer cells in vitro treated with growth factor and steroid hormone ] . The aim of this study was to overtake the mechanism of the control system in endometrial cancer cell line in vitro . Ishikawa cell ( IK cell ) and O14777 REA - 1 cell ( O14777 REA cell ) derived from endometrial cancers were cultured with serum free medium ( SFM - 101 ) . IK cell possessed P03372 REA ( ER ) , P06401 REA ( PR ) , Epidermal growth factor ( P01133 REA ) and its receptor ( P00533 REA ) . O14777 REA cell had PR , P01133 REA , and P00533 REA , however O14777 REA cell did not keep ER . P01133 REA stimulated the growth of IK cell , but the growth of O14777 REA cell was not stimulated by P01133 REA . S phase cells were increased by P01133 REA in IK cell , but were not increased by P01133 REA in O14777 REA cell . The growth of IK cell was stimulated significantly by P01133 REA and Estradiol - 17 beta ( E2 ) + P01133 REA than control . However , E2 + P01133 REA did not stimulate the growth of IK cell than P01133 REA significantly . DB01406 MEN ( D ) and D + P01133 REA inhibited the growth of IK cell significantly than control . S phase cells were decreased by the treatment of D and D + P01133 REA . From our results , P01133 REA stimulated the growth of ER positive endometrial cancer cell , but P01133 REA did not stimulate ER negative endometrial cancer cell . E2 + P01133 REA and P01133 REA stimulated the growth of IK cell as a same . However , D inhibited the growth of IK cell that was stimulated by P01133 REA .

Cortagine infused into the medial prefrontal cortex attenuates predator-induced defensive behaviors and Fos protein production in selective nuclei of the amygdala in male CD1 mice . P06850 REA ( CRF ) plays an essential role in coordinating the autonomic , endocrine and behavioral responses to stressors . In this study , we investigated the role of CRF within the medial prefrontal cortex ( mPFC ) in modulating unconditioned defensive behaviors , by examining the effects of microinfusing cortagine a selective type - 1 CRF receptor ( CRF 1 ) agonist , or acidic-astressin a preferential CRF 1 antagonist , into the mPFC in male CD - 1 mice exposed to a live predator ( rat exposure test - - P07949 REA ) . Cortagine microinfusions significantly reduced several indices of defense , including avoidance and freezing , suggesting a specific role for CRF 1 within the infralimbic and prelimbic regions of the mPFC in modulating unconditioned behavioral responsivity to a predator . In contrast , microinfusions of acidic-astressin failed to alter defensive behaviors during predator exposure in the P07949 REA . Cortagine microinfusions also reduced Fos protein production in the medial , central and basomedial , but not basolateral subnuclei of the amygdala in mice exposed to the rat predatory threat stimulus . These results suggest that CRF 1 activation within the mPFC attenuates predator-induced unconditioned anxiety-like defensive behaviors , likely via inhibition of specific amygdalar nuclei . Furthermore , the present findings suggest that the mPFC represents a unique neural region whereby activation of CRF 1 produces behavioral effects that contrast with those elicited following systemic administration of CRF 1 agonists .

A phase I study of cabozantinib ( DB05153 ) in patients with differentiated thyroid cancer . BACKGROUND : DB08875 SUB targets tyrosine kinases including MET , vascular endothelial growth factor ( P15692 REA ) receptor 2 , and rearranged during transfection ( P07949 REA ) . Differentiated thyroid cancer ( DTC ) is a tumor type that may be sensitive to cabozantinib . Therefore , we evaluated cabozantinib in a cohort of heavily pretreated patients with metastatic DTC . METHODS : This single-arm open-label phase I trial assessed the safety , tolerability , and antitumor activity of cabozantinib in DTC patients taking part in a drug-drug interaction study . Adult patients with histologically confirmed metastatic or surgically unresectable DTC ( including papillary , follicular , or Hürthle cell ) were enrolled . Patients received daily oral dosing of 140 mg cabozantinib . Safety was assessed by evaluation of adverse events ( AEs ) , vital signs , electrocardiograms , laboratory tests , and concomitant medications . Tumor response by magnetic resonance imaging or computed tomography scan was investigator assessed using Response Evaluation Criteria In Solid Tumors ( RECIST ) v1 . 0 . RESULTS : The study enrolled 15 patients who had failed standard radioactive iodine therapy . Patients had received a median of two prior systemic agents , and 11 patients ( 73 % ) had previously received at least one P15692 REA pathway inhibiting therapy . Common AEs included diarrhea , nausea , fatigue , and decreased appetite . Partial response was reported in eight patients ( 53 % ) . Median progression-free survival and median overall survival were not reached . CONCLUSIONS : DB08875 SUB demonstrates a safety profile similar to other multitargeted VEGFR inhibitors in advanced DTC patients . The antitumor activity observed in this study warrants further investigation of cabozantinib in patients with advanced DTC .

Combining resonance energy transfer methods reveals a complex between the alpha 2A - adrenergic receptor , Galphai 1beta1gamma2 , and P25098 REA . Traditionally , G-protein-coupled receptor ( GPCR ) interactions with their G proteins and regulatory proteins , GPCR kinases ( GRKs ) and arrestins , are described as sequential events involving rapid assemblies / disassemblies . To directly monitor the dynamics of these interactions in living cells , we combined two spectrally resolved bioluminescence and one fluorescence resonance energy transfer ( P07949 REA ) methods . The P07949 REA combination analysis revealed that stimulation of the α ( 2A ) - adrenergic receptor ( α ( 2A ) AR ) leads to the recruitment of P25098 REA at a receptor still associated with the Gα ( i1 ) β ( 1 ) γ ( 2 ) complex . The interaction kinetics of GRKs with Gγ ( 2 ) ( 2.8 ± 0.4 s ) and α ( 2A ) AR ( 5.2 ± 0.5 s ) were similar to that of the receptor-promoted change in P07949 REA between Gα ( i1 ) and Gγ ( 2 ) ( 5.2 ± 1.2 s ) , and persisted until the translocation of βarrestin 2 to the receptor , indicating that P25098 REA remains associated to the receptor / G-protein complex for longer periods than anticipated . Moreover , P25098 REA or a kinase-deficient P25098 REA mutant , but not P34947 REA , potentiated the receptor-promoted changes in P07949 REA between Gα ( i1 ) and Gγ ( 2 ) and abrogated the α ( 2A ) AR-stimulated calcium response , suggesting that the recruitment of P25098 REA to the complex contributes to the structural rearrangement and functional regulation of the signaling unit , independently of the kinase activity . P07949 REA combination analysis revealed unanticipated dynamics in GPCR signaling and will be applicable to many biological systems .

DB08875 SUB inhibits prostate cancer growth and prevents tumor-induced bone lesions . PURPOSE : DB08875 SUB , an orally available multityrosine kinase inhibitor with activity against mesenchymal epithelial transition factor ( MET ) and P15692 REA receptor 2 ( P35968 REA ) , induces resolution of bone scan lesions in men with castration-resistant prostate cancer bone metastases . The purpose of this study was to determine whether cabozantinib elicited a direct antitumor effect , an indirect effect through modulating bone , or both . EXPERIMENTAL DESIGN : Using human prostate cancer xenograft studies in mice , we determined the impact of cabozantinib on tumor growth in soft tissue and bone . In vitro studies with cabozantinib were performed using ( i ) prostate cancer cell lines to evaluate its impact on cell growth , invasive ability , and MET and ( ii ) osteoblast cell lines to evaluate its impact on viability and differentiation and P35968 REA . RESULTS : DB08875 SUB inhibited progression of multiple prostate cancer cell lines ( Ace - 1 , C4 - 2B , and LuCaP 35 ) in bone metastatic and soft tissue murine models of prostate cancer , except for PC - 3 prostate cancer cells in which it inhibited only subcutaneous growth . DB08875 SUB directly inhibited prostate cancer cell viability and induced apoptosis in vitro and in vivo and inhibited cell invasion in vitro . DB08875 SUB had a dose-dependent biphasic effect on osteoblast activity and inhibitory effect on osteoclast production in vitro that was reflected in vivo . It blocked MET and P35968 REA phosphorylation in prostate cancer cells and osteoblast-like cells , respectively . CONCLUSION : These data indicate that cabozantinib has direct antitumor activity , and that its ability to modulate osteoblast activity may contribute to its antitumor efficacy .

Analysis of breast cancer related gene expression using natural splines and the Cox proportional hazard model to identify prognostic associations . Many studies correlating gene expression data to clinical parameters assume a linear increase or decrease of the clinical parameter under investigation with the expression of a gene . We have studied genes encoding important breast cancer-related proteins using a model for survival-type data that is based on natural splines and the Cox proportional hazard model , thereby removing the linearity assumption . Expression data of 16 genes were studied in relation to metastasis-free probability in a cohort of 295 consecutive breast cancer patients treated at The Netherlands Cancer Institute . The independent predictive power for disease outcome of the 16 individual genes was tested in a multivariable model with known clinical and pathological risk factors . There is a linear relationship between increasing expression and a higher or lower hazard for distant metastasis for P03372 REA , Q15303 REA , P15692 REA , O96020 REA , Q15910 REA , and Q96NZ9 ; for P04626 REA , P21860 REA , P24385 REA , P24864 REA , O75530 REA , P61073 REA , P32248 REA , P48061 REA , and P05121 REA there is no clear increase or decrease ; and for P00533 REA there seems to be a non-linear relation . Multivariable analysis showed that the 70 - gene prognosis profile outperforms all the other variables in the model ( hazard-rate 5.4 , 95 % CI 2.5- 11.7 ; P = 0.000018 ) . P00533 REA - expression seems to have a non-linear relation with disease outcome , indicating that lower but also higher expression of P00533 REA are associated with worse outcome compared to intermediate expression levels ; the other genes show no or a linear relation .

Vascular endothelial growth factor signaling is required for the behavioral actions of antidepressant treatment : pharmacological and cellular characterization . This study extends earlier work on the role of vascular endothelial growth factor ( P15692 REA ) in the actions of antidepressant treatment in two key areas . First , by determining the requirement for P15692 REA in the actions of a 5 - HT selective reuptake inhibitor ( SSRI ) , fluoxetine in behavioral models of depression / antidepressant response ; and second , by examining the role of the P08908 REA receptor subtype in the regulation of P15692 REA , and the cellular localization of antidepressant regulation of P15692 REA expression . The results show that pharmacological inhibition of P15692 REA receptor signaling blocks the behavioral actions of fluoxetine in rats subjected to chronic unpredictable stress . Infusions of SU5416 or SU1498 , two structurally dissimilar inhibitors of P15692 REA - Flk - 1 receptor signaling , block the antidepressant effects of fluoxetine on sucrose preference , immobility in the forced swim test , and latency to feed in the novelty suppressed feeding paradigm . We also show that activation of P08908 REA receptors is sufficient to induce P15692 REA expression and that a P08908 REA antagonist blocks both the increase in P15692 REA and behavioral effects induced by fluoxetine . Finally , double labeling studies show that chronic fluoxetine administration increases P15692 REA expression in both neurons and endothelial cells in the hippocampus . Taken together these studies show that P15692 REA is necessary for the behavioral effects of the SSRI fluoxetine , as well as norepinephrine selective reuptake inhibitor , and that these effects may be mediated by P08908 REA receptors located on neurons and endothelial cells .

Serotonin P08908 REA receptor binding potential declines with age as measured by [ 11C ] WAY - 100635 and PET . Positron emission tomography ( PET ) and [ 11C ] WAY - 100635 were used to examine the effect of age on serotonin - 1A ( P08908 REA ) receptor binding potential ( BP ) in 19 healthy subjects . Regions of interest ( ROI ) were drawn on the co-registered magnetic resonance imaging ( Q9BWK5 ) in orbitofrontal ( OFC ) , dorsolateral prefrontal ( DLPFC ) , anterior cingulate ( ACC ) , lateral ( LTC ) , and mediotemporal ( P04629 REA ) , parietal , occipital and cerebellar cortex , and the raphe nuclei . BP values were calculated using a simplified reference tissue method . In addition , a voxelwise analysis was performed using SPM 99 . Voxelwise analysis revealed a significant global decrease of 5 - HT ( 1A ) BP with age ( set level < . 001 ) . ROI analysis revealed significant age-related 5 - HT ( 1A ) BP decreases in DLPFC ( r = -0.56 ) , ACC ( r = -0.44 ) , OFC ( r = -0.42 ) , LTC ( r = -0.40 ) , parietal ( r = -0.65 ) , and occipital cortex ( r = -0.43 ) , but not in P04629 REA or raphe nuclei . Overall , cortical 5 - HT ( 1A ) BP declined by approximately 10 % per decade , except for the P04629 REA , where we did not find a significant age effect . Hence , careful age matching may be recommended for future studies using PET and [ 11C ] WAY - 100635 to examine P08908 REA receptors .

Profile of cabozantinib and its potential in the treatment of advanced medullary thyroid cancer . Medullary thyroid cancer is an uncommon malignancy for which until recently little effective treatment existed . It is often characterized by mutation and overexpression of the receptor tyrosine kinases P07949 REA ( rearranged during transfection ) , P35968 REA ( vascular endothelial growth factor receptor 2 ) and MET ( mesenchymal-epithelial transition factor ) , which make attractive targets for drug development . DB08875 SUB is an orally bioavailable tyrosine kinase inhibitor which blocks MET , VEGRF 2 and P07949 REA , and has shown considerable activity in medullary thyroid cancer in a Phase III trial , including in heavily pretreated patients . Its novel combination of vascular endothelial growth factor and MET inhibition is believed to address the MET escape pathway , which is thought to be the cause of nonsustained tumor responses resulting from inhibition of vascular endothelial growth factor alone .

A dose-ranging study of cabozantinib in men with castration-resistant prostate cancer and bone metastases . BACKGROUND : DB08875 SUB is an oral MET / P35968 REA inhibitor . A recent phase II study of cabozantinib ( 100 mg daily ) showed improved bone scans in subjects with metastatic castration-resistant prostate cancer ( mCRPC ) , but adverse events ( AE ) caused frequent dose reductions . This study was designed to determine the efficacy and tolerability of cabozantinib at lower starting doses . EXPERIMENTAL DESIGN : An adaptive design was used to determine the lowest active daily dose among 60 , 40 , and 20 mg . The primary endpoint was week 6 bone scan response , defined as ≥ 30 % decrease in bone scan lesion area . The secondary endpoint was change in circulating tumor cells ( CTC ) . RESULTS : Among 11 evaluable subjects enrolled at 40 mg , there were 9 partial responses ( PR ) , 1 complete response , and 1 stable disease ( SD ) . Of 10 subjects subsequently enrolled at 20 mg , there were 1 PR , 5 SDs , and 4 with progressive disease . Among 13 subjects enrolled on the 40 mg expansion cohort , there were 6 PRs and 7 SDs . No subjects required dose reduction or treatment interruption at 6 or 12 weeks ; 3 subjects at dose level 0 discontinued due to AEs by 12 weeks . At 40 mg , median treatment duration was 27 weeks . 58 % of subjects with ≥ 5 CTCs / 7.5 mL at baseline converted to < 5 . CONCLUSIONS : DB08875 SUB 40 mg daily was associated with a high rate of bone scan response . DB08875 SUB 40 mg daily was associated with better tolerability than previously reported for cabozantinib 100 mg daily . These observations informed the design of phase III studies of cabozantinib in mCRPC .

Biological and immunological studies of bovine hypothalamic DB05394 . P06850 REA B ( CRF-B ) is a peptide ( s ) isolated from bovine hypothalamic extracts by Sephadex G - 100 chromatography on the basis of its ability to stimulate secretion of adrenocorticotropin ( DB01285 MEN ) in vitro and in vivo . It is similar in molecular size to the 41 - residue ovine CRF ( oCRF ) or rat CRF ( rCRF ) recently elucidated and appears to be their bovine counterpart . Immunoreactivity of CRF-B was examined in homologous radioimmunoassays ( RIAs ) for oCRF or rCRF , using several anti-oCRF and anti-rCRF antibodies . CRF-B cross-reacted well with anti-oCRF antibodies but poorly with anti-rCRF antibodies . Purification of CRF-B with preparative isoelectric focusing yielded four CRF peaks , B - 1 ( pH 4.7 ) , B - 2 ( pH 5.5 ) , B - 3 ( pH 6.3 ) , and B - 4 ( pH 7.0 ) , which accounted for 16 , 30 , 46 , and 8 % of the total immunoreactivity , respectively . CRF B - 2 , B - 3 , and B - 4 showed both immunological activity and biological activity in vitro ( cell culture assay ) and in vivo ( Arimura assay ) , whereas CRF B - 1 showed only immunoreactivity . Their relative bioactivity / immunoreactivity ratios were 0 ( B - 1 ) , 1 ( B - 2 ) , 1 ( B - 3 ) , and 3 ( B - 4 ) . All of these CRF-B subtypes exhibited RIA displacement curves parallel to that for the oCRF standard and coeluted with oCRF on Sephadex G - 100 chromatography , which suggests that their molecular modifications are relatively minor .

Genetic factors influencing outcome from neurotrauma . PURPOSE OF REVIEW : Clinical outcome after neurotrauma is considerably variable and can only partly be explained by known prognostic factors . There is converging evidence from genetic research that a number of genetic variants may contribute to this variability . This review provides recent data from human studies , published in the previous year , on genetic factors influencing outcome after neurotrauma . The bibliographic databases MEDLINE , EMBASE and PsycINFO were searched to identify relevant studies . RECENT FINDINGS : Genetic susceptibility to various aspects of clinical outcome after neurotrauma was reported in recent clinical studies . Genetic loci investigated include polymorphisms in P02649 REA , P21397 REA , P23560 REA , NOS 3 , P05231 REA , P12036 , P31645 REA , P21964 REA , P48454 REA and Q8IX03 genes . The importance of these findings and future directions are discussed . SUMMARY : Recent genetic studies have revealed emerging aspects and extended the existing knowledge regarding the pathogenesis of neurotrauma and the genetic influence on phenotypic diversity . A better understanding of the underlying biological pathways and molecular mechanisms of an individual ' s response to neurotrauma may hold the promise of novel treatment strategies and improved clinical outcome .

Genetic basis of delay discounting in frequent gamblers : examination of a priori candidates and exploration of a panel of dopamine-related loci . INTRODUCTION : Delay discounting is a behavioral economic index of impulsivity that reflects preferences for small immediate rewards relative to larger delayed rewards . It has been consistently linked to pathological gambling and other forms of addictive behavior , and has been proposed to be a behavioral characteristic that may link genetic variation and risk of developing addictive disorders ( i . e . , an endophenotype ) . Studies to date have revealed significant associations with polymorphisms associated with dopamine neurotransmission . The current study examined associations between delay discounting and both previously linked variants and a novel panel of dopamine-related variants in a sample of frequent gamblers . METHODS : Participants were 175 weekly gamblers of European ancestry who completed the Monetary Choice Questionnaire to assess delay discounting preferences and provided a DNA via saliva . RESULTS : In a priori tests , two loci previously associated with delayed reward discounting ( rs1800497 and rs4680 ) were not replicated , however , the long form of P21917 REA VNTR was significantly associated with lower discounting of delayed rewards . Exploratory analysis of the dopamine-related panel revealed 11 additional significant associations in genes associated with dopamine synthesis , breakdown , reuptake , and receptor function ( P35462 REA , Q01959 REA , DDC , P09172 REA , and Q05940 REA ) . An aggregate genetic risk score from the nominally significant loci accounted for 17 % of the variance in discounting . Mediational analyses largely supported the presence of indirect effects between the associated loci , delay discounting , and pathological gambling severity . CONCLUSIONS : These findings do not replicate previously reported associations but identify several novel candidates and provide preliminary support for a systems biology approach to understand the genetic basis of delay discounting .

P14210 REA improves viability after H2O2 - induced toxicity in bile duct epithelial cells . Intracellular defence mechanisms against oxidative stress may play an important role in the progression of liver diseases , including cholangiopathies . The multifunctional anti-apoptotic hepatocyte growth factor ( P14210 REA ) has been suggested to have antioxidant functions . The effect of P14210 REA upon cell viability , the generation of ROS , the expression of genes that play a role in ROS defence , and the activation of caspase - 3 were measured in bile duct epithelial ( BDE ) cells in the presence or absence of H ( 2 ) O ( 2 ) . P14210 REA reduced H ( 2 ) O ( 2 ) - induced loss of viability , diminished H ( 2 ) O ( 2 ) - mediated ROS generation and abrogated H ( 2 ) O ( 2 ) - triggered changes in DB00143 / GSSG ratio . Furthermore , P14210 REA increased the gene-expression of gamma-glutamylcysteine synthetase ( P48506 REA ) and glutathione reductase ( P00390 REA ) , while no effect was seen upon the gene-expression of superoxide dismutase 1 ( P00441 REA ) , catalase ( CAT ) , glutathione peroxidase ( P07203 REA ) , and glutathione synthetase ( P00390 REA ) . Finally , P14210 REA diminished the proteolytical activation of the key mediator of apoptosis ( caspase - 3 ) after H ( 2 ) O ( 2 ) exposure . Together , P14210 REA may improve viability in bile duct epithelia cells after H ( 2 ) O ( 2 ) induced toxicity by proliferation , strengthening the intrinsic antioxidant defences , and / or by an attenuation of apoptosis . These in vitro results support the evaluation of P14210 REA as antioxidative factor in hepatobiliary pathologies .

[ Moclobemide ( DB01171 MEN ) , the first P21397 REA - inhibitor : really something new ? ] .

Multiplex protein signature for the detection of bladder cancer in voided urine samples . PURPOSE : Accurate urine assays for bladder cancer detection would benefit patients and health care systems . Through extensive genomic and proteomic profiling of urine components we previously identified a panel of 8 biomarkers that can facilitate the detection of bladder cancer in voided urine samples . In this study we confirmed this diagnostic molecular signature in a diverse multicenter cohort . MATERIALS AND METHODS : We performed a case-control , phase II study in which we analyzed voided urine from 102 subjects with bladder cancer and 206 with varying urological disorders . The urinary concentration of 8 biomarkers ( P10145 REA , P14780 REA and 10 , P05121 REA , P15692 REA , P03950 REA , Q16790 REA and P02649 REA ) was assessed by enzyme-linked immunosorbent assay . Diagnostic performance of the panel of tested biomarkers was evaluated using ROCs and descriptive statistical values , eg sensitivity and specificity . RESULTS : Seven of the 8 urine biomarkers were increased in subjects with bladder cancer relative to those without bladder cancer . The 7 biomarkers were assessed in a new model , which had an AUROC of 0.88 ( 95 % CI 0.84- 0.93 ) , and 74 % sensitivity and 90 % specificity . In contrast , the sensitivity of voided urine cytology and the UroVysion ® cytogenetic test in this cohort was 39 % and 54 % , respectively . Study limitations include analysis performed on banked urine samples and the lack of voided urine cytology and cytogenetic test data on controls . CONCLUSIONS : The study provides further evidence that the reported panel of diagnostic biomarkers can reliably achieve the noninvasive detection of bladder cancer with higher sensitivity than currently available urine based assays .

Managing the underlying cause of cystic fibrosis : a future role for potentiators and correctors . Cystic fibrosis ( CF ) , a severe genetic disease , is caused by mutations that alter the structure and function of P13569 REA , a plasma membrane channel permeable to chloride and bicarbonate . Defective anion transport in CF irreversibly damages the lungs , pancreas , liver , and other organs . CF mutations cause loss of P13569 REA function in multiple ways . In particular , class 3 mutations such as p . Gly 551Asp strongly decrease the time spent by P13569 REA in the open state ( gating defect ) . Instead , class 2 mutations impair the maturation of P13569 REA protein and its transport from the endoplasmic reticulum to the plasma membrane ( trafficking defect ) . The deletion of phenylalanine 508 ( p . Phe 508del ) , the most frequent mutation among CF patients ( 70-90 % ) , destabilizes the P13569 REA protein , thus causing both a trafficking and a gating defect . These two defects can be overcome with drug-like molecules generically called correctors and potentiators , respectively . The potentiator Kalydeco ™ ( also known as DB08820 MEN or VX - 770 ) , developed by Vertex Pharmaceuticals , has been recently approved by the US FDA and the European Medicines Agency ( P15941 REA ) for the treatment of CF patients carrying at least one P13569 REA allele with the p . Gly 551Asp mutation ( 2-5 % of all patients ) . In contrast , the corrector VX - 809 , which significantly improves p . Phe 508del - P13569 REA trafficking in vitro , is still under study in clinical trials . Because of multiple defects caused by the p . Phe 508del mutation , it is probable that rescue of the mutant protein will require combined treatment with correctors having different mechanisms of action . This review evaluates the status of experimental and clinical research in pharmacotherapy for the CF basic defect .

DB09280 - DB08820 MEN in Patients with Cystic Fibrosis Homozygous for Phe 508del P13569 REA .

P56817 REA levels by P02649 REA genotype in non-demented and Alzheimer ' s post-mortem brains . The P02649 REA genotype is a known susceptibility factor for Alzheimer ' s disease ( AD ) . It is apparent that the presence of the P02649 REA ε40 allele increases the risk for developing AD , lowers the age of onset in AD , and may influence the pathological burden seen in AD . In this study , we asked whether P56817 REA levels differ by P02649 REA genotype in the AD and non-demented ( ND ) brain . We isolated mid-frontal cortex ( MFC ) and mid-temporal cortex ( P04629 REA ) from post-mortem ND and AD subjects that were P02649 REA ε3 / 3 , ε3 / 4 , ε4 / 4 carriers . All AD subjects met NINDS-ADRDA and NIA-Reagan criteria for a diagnosis of AD . The MFC and P04629 REA were homogenized and the lysates underwent ELISA and Western blotting for P56817 REA . The ELISA revealed that total P56817 REA levels were lower in the MFC of AD compared to ND subjects . Furthermore , in P02649 REA ε4 carriers P56817 REA levels were lower than ε3 / 3 carriers in the ND frontal cortex . No difference in P56817 REA levels was observed in AD MFC and in ND and AD P04629 REA tissues . The ELISA results were confirmed by Western blotting . Our data suggest that brain BACEl levels may be influenced by the apolipoprotein E genotype before the onset of AD , providing an alternative explanation for the lower amyloid beta 42 levels in P04141 REA in ND and AD subjects .

DB01037 MEN transdermal system : in the treatment of major depressive disorder . The monamine oxidase ( MAO ) inhibitor selegiline is selective for P27338 REA at the low oral dosages used in the treatment of Parkinson ' s disease . However , P21397 REA is also inhibited at the high oral dosages needed to effectively treat depression ( not an approved indication ) , necessitating a tyramine-restricted diet . The selegiline transdermal system was designed to deliver antidepressant drug concentrations to the CNS , without substantially impairing small intestine P21397 REA activity . At the target dose of 6 mg / 24 hours , tyramine dietary restrictions are not needed . Short-term treatment with fixed ( 6 mg / 24 hours ) or flexible ( 6 , 9 or 12 mg / 24 hours ) doses of selegiline transdermal system was superior to placebo on most measures of antidepressant activity in 6 - or 8 - week , randomised , double-blind , multicentre studies in adult outpatients with major depressive disorder ( MDD ) . Likewise , long-term treatment with a fixed dose of selegiline transdermal system 6 mg / 24 hours was superior to placebo as maintenance therapy in a 52 - week , randomised , double-blind , multicentre , relapse-prevention trial in patients with MDD . DB01037 MEN transdermal system therapy was generally well tolerated in placebo-controlled studies ; application site reactions , mostly of mild to moderate severity , were the most commonly reported adverse events . The incidence of sexual adverse effects and weight gain was low and similar to that with placebo .

Liver regeneration induced by a designer human P05231 REA / sIL - 6R fusion protein reverses severe hepatocellular injury . The cytokine P05231 REA plays a significant role in liver regeneration in conjunction with additional growth factors ( P14210 REA , P01375 REA , and TGF-alpha ) . Many P05231 REA effects depend on a naturally occurring soluble P05231 REA receptor ( sIL - 6R ) . Here , the chimeric protein hyper - P05231 REA , constructed from the human P05231 REA protein fused to a truncated form of its receptor , was found to have superagonistic P05231 REA properties , and as such , enhanced liver cell regeneration . Hyper - P05231 REA reversed the state of hepatotoxicity and enhanced the survival rates of rats suffering from fulminant hepatic failure after D-galactosamine administration . The hyper - P05231 REA protein has a significant potential for use in the treatment of severe human liver diseases .

Serum hepcidin levels and reticulocyte hemoglobin concentrations as indicators of the iron status of peritoneal dialysis patients . P8 1172 is the key mediator of renal anemia , and reliable measurement of serum hepcidin levels has been made possible by the ProteinChip system . We therefore investigated the iron status and serum hepcidin levels of peritoneal dialysis ( PD ) patients who had not received frequent doses of an erythrocytosis-stimulating agent ( Q14254 REA ) and had not received iron therapy . In addition to the usual iron parameters , the iron status of erythrocytes can be determined by measuring reticulocyte hemoglobin ( P07949 REA - He ) . The mean serum hepcidin level of the PD patients ( n = 52 ) was 80.7 ng / mL . Their serum hepcidin levels were significantly positively correlated with their serum ferritin levels and transferrin saturation ( TSAT ) levels , but no correlations were found between their serum hepcidin levels and P07949 REA - He levels , thereby suggesting that hepcidin has no effect on the iron dynamics of reticulocytes . Since low serum levels of CRP and P05231 REA , biomarkers of inflammation , were not correlated with the serum hepcidin levels , there is likely to be a threshold for induction of hepcidin expression by inflammation .

Stable expression of a neuronal dopaminergic progenitor phenotype in cell lines derived from human amniotic fluid cells . Cells from human amniotic fluid derived from the fetus are considered a source of multipotent cells . Their properties have not been fully exploited , partially because unlike other embryonic sources such as embryonic stem ( ES ) cells , cell lines from amniocentesis samples have not been generated . We have established and characterized the properties of eight individual cell lines . Flow cytometry using several cell surface markers showed that all cell lines generated consisted of homogeneous populations that lack HLAII antigenicity . Using a combination of immunocytochemistry , Western blotting , and RT-PCR , we found weak expression of Oct 4 and nestin and strong expression of tubulin-betaIII , P11137 , and tau . Specific markers for cholinergic , ( nor ) adrenergic , and GABAergic neurons or glia were weakly expressed or absent , whereas expression of factors implicated in early induction of dopaminergic neurons , TGF-beta 3 and beta-catenin were present . Further analysis showed strong expression of EN - 1 , c - P07949 REA , PTX 3 , and P43354 REA essential for induction and survival of midbrain dopaminergic neurons , TH , P20711 REA , and Q05940 REA components of dopamine synthesis and secretion , and syntaxin 1A and P60880 REA necessary for neurotransmitter exocytosis . This phenotype was retained throughout passages and up to the current passage 36 . Expression of neuronal and dopaminergic markers in individual AF cell lines was comparable to expression in neurons induced from ES cells and in IMR - 32 and SH-SY 5Y neuroblastomas . Our data show that cell lines can be derived from subcultures of amniocentesis , and are primarily composed of a population of progenitors with a phenotype similar to that of committed mesencephalic dopaminergic neurons .

Ca2 + - calmodulin and janus kinase 2 are required for activation of sodium-proton exchange by the Gi-coupled 5 - hydroxytryptamine 1a receptor . The type 1 sodium-proton exchanger ( P19634 REA ) is expressed ubiquitously and regulates key cellular functions , including mitogenesis , cell volume , and intracellular pH . Despite its importance , the signaling pathways that regulate P19634 REA remain incompletely defined . In this work , we present evidence that stimulation of the 5 - hydroxytryptamine 1A ( P08908 REA ) receptor results in the formation of a signaling complex that includes activated O60674 REA ( Jak 2 ) , Ca2 + / calmodulin ( P62158 ) , and P19634 REA , and which involves tyrosine phosphorylation of P62158 . The signaling pathway also involves rapid agonist-induced association of P62158 and P19634 REA as assessed by coimmunoprecipitation studies and by bioluminescence resonance energy transfer studies in living cells . We propose that P19634 REA is activated through this pathway : P08908 REA receptor --> G ( i2 ) alpha and / or G ( i3 ) alpha --> Jak 2 activation --> tyrosine phosphorylation of P62158 --> increased binding of P62158 to P19634 REA --> induction of a conformational change in P19634 REA that unmasks an obscured proton-sensing and / or proton-transporting region of P19634 REA --> activation of P19634 REA . The G ( i / o ) - coupled P08908 REA receptor now joins a handful of Gq-coupled receptors and hypertonic shock as upstream activators of this emerging pathway . In the course of this work , we have presented clear evidence that P62158 can be activated through tyrosine phosphorylation in the absence of a significant role for elevated intracellular Ca2 + . We have also shown for the first time that the association of P62158 with P19634 REA in living cells is a dynamic process .

Targeting MET and vascular endothelial growth factor receptor signaling in castration-resistant prostate cancer . Effective management of bone metastases in men with castration-resistant prostate cancer ( CRPC ) remains an important unmet medical need . MET and vascular endothelial growth factor receptor ( VEGFR ) are rational targets for intervention in CRPC . Clinical trials involving agents that inhibit one but not both pathways have reported modest activity and no improvement in overall survival . DB08875 SUB is an oral multitargeted tyrosine kinase inhibitor that inhibits both MET and P35968 REA . A phase II randomized discontinuation study involving subjects with CRPC demonstrated that cabozantinib therapy is associated with improvement in bone scans , bone turnover markers , and pain response , but with significant adverse events leading to dose reduction and treatment discontinuation . Lower doses of cabozantinib retain high levels of activity with less toxicity . Ongoing phase III clinical trials will define the role of cabozantinib in CRPC . We summarize the rationale for targeting MET and VEGFR pathways in CRPC and the clinical data available to date .

P06850 REA family of peptides regulates intestinal angiogenesis . BACKGROUND & AIMS : The corticotrophin-releasing hormone ( P06850 REA ) family of peptides modulates intestinal inflammation and the P06850 REA receptor 2 ( Q13324 REA ) suppresses postnatal angiogenesis in mice . We investigated the functions of P34998 REA and Q13324 REA signaling during intestinal inflammation and angiogenesis . METHODS : The activities of P34998 REA and Q13324 REA were disrupted by genetic deletion in mice or with selective antagonists . A combination of in vivo , ex vivo , and in vitro measures of angiogenesis were used to determine their activity . P34998 REA ( - / - ) mice and Q13324 REA ( - / - ) mice with dextran sodium sulfate-induced colitis were analyzed in comparison with wild-type littermates ( controls ) . RESULTS : Colitis was significantly reduced in mice in which P34998 REA activity was disrupted by genetic deletion or with an antagonist , determined by analyses of survival rate , weight loss , histological scores , and cytokine production . Inflammation was exacerbated in mice in which Q13324 REA activity was inhibited by genetic deletion or with an antagonist , compared with controls . The inflamed intestines of P34998 REA ( - / - ) mice had reduced microvascular density and expression of vascular endothelial growth factor ( P15692 REA ) - A , whereas the intestines of Q13324 REA ( - / - ) mice had increased angiogenesis and P15692 REA levels . An antagonist of P35968 REA activity alleviated colitis in Q13324 REA ( - / - ) mice . Ex vivo aortic vessel outgrowth was reduced when P34998 REA was deficient but increased when Q13324 REA was deficient . The P34998 REA preferred agonist P06850 REA stimulated tube formation , proliferation , and migration of cultured intestinal microvascular endothelial cells by phosphorylating Akt , whereas the specific Q13324 REA agonist Q969E3 REA had opposite effects . CONCLUSION : P34998 REA promotes intestinal inflammation , as well as endogenous and inflammatory angiogenesis whereas Q13324 REA inhibits these activities .

Raddeanin A , a triterpenoid saponin isolated from Anemone raddeana , suppresses the angiogenesis and growth of human colorectal tumor by inhibiting P35968 REA signaling . Raddeanin A ( RA ) is an active triterpenoid saponin from a traditional Chinese medicinal herb , Anemone raddeana Regel . It was previously reported that RA possessed attractive antitumor activity through inhibiting proliferation and inducing apoptosis of multiple cancer cells . However , whether RA can inhibit angiogenesis , an essential step in cancer development , remains unknown . In this study , we found that RA could significantly inhibit human umbilical vein endothelial cell ( HUVEC ) proliferation , motility , migration , and tube formation . RA also dramatically reduced angiogenesis in chick embryo chorioallantoic membrane ( P62158 ) , restrained the trunk angiogenesis in zebrafish , and suppressed angiogenesis and growth of human HCT - 15 colorectal cancer xenograft in mice . Western blot assay showed that RA suppressed P15692 REA - induced phosphorylation of P35968 REA and its downstream protein kinases including PLCγ 1 , O60674 REA , Q05397 REA , Src , and Akt . Molecular docking simulation indicated that RA formed hydrogen bonds and hydrophobic interactions within the DB00171 binding pocket of P35968 REA kinase domain . Our study firstly provides the evidence that RA has high antiangiogenic potency and explores its molecular basis , demonstrating that RA is a potential agent or lead candidate for antiangiogenic cancer therapy .

[ DB00988 MEN - beta-hydroxylaseaktivität im Plasma von Dialysepatienten ( author ' s transl ) ] . Plasma dopamin-b-hydroxylase ( P09172 REA ) was studied in 70 healthy control persons and in 37 hemodialysed patients . Basal P09172 REA in controls corresponded to 50.0 + / - 29.3 IU . There was was no significant difference between males ( 53.9 + / 1 33.8 IU ) and females ( 47.4 + / - 25 IU ) ; no correlation could be found between age and plasma P09172 REA . In hemodialysed patients basal P09172 REA levels were significantly ( p less than 0.01 ) decreased ( 32.5 % / - 17.6 IU ) , suggesting lowered sympathetic activity and / or abnormalities in release , distribution space , or metabolism of P09172 REA . During hemodialysis plasma P09172 REA activity rose during ultrafiltration . This finding indicates a directionally appropriate sympathetic reflex response to volume depletion in dialysed patients .

Worksite-based behavioral treatment of mild hypertension . Two behaviorally-oriented , nonpharmacological treatments - rational-emotive therapy / assertiveness training ( P07949 REA / AT ) and anxiety management training ( AMT ) - and one control treatment - hypertension education counseling ( O14777 REA ) - were compared in reducing blood pressures of 22 white-collar mold hypertensives in a worksite setting . Results showed significant reductions by posttreatment in diastolic pressures of participants in the two behavioral treatment conditions , but no significant differential treatment effect across groups . Systolic pressure reductions by postreatment were significant only in the P07949 REA / AT training condition . Reductions were generally maintained at an either-week follow-up .

Angiogenic factors reconstitute hematopoiesis by recruiting stem cells from bone marrow microenvironment . The mechanism by which angiogenic factors recruit bone marrow ( BM ) - derived quiescent endothelial and hematopoietic stem cells ( HSCs ) is not known . Here , we report that functional vascular endothelial growth factor receptor - 1 ( P17948 REA , Flt - 1 ) is expressed on a subpopulation of human P28906 REA ( + ) and mouse Lin-Sca - 1 ( + ) c-Kit ( + ) BM-repopulating stem cells , conveying signals for recruitment of HSCs and reconstitution of hematopoiesis . Inhibition of P17948 REA signaling , but not P35968 REA ( Flk - 1 , P35968 REA ) , blocked P19526 REA cell cycling , differentiation and hematopoietic recovery after BM suppression , resulting in the demise of the treated mice . Plasma elevation of placental growth factor ( P49763 REA ) , which signals through P17948 REA , but not P35968 REA , restored hematopoiesis during the early and late phases following BM suppression . The mechanism whereby P49763 REA enhanced early phases of BM recovery was mediated directly through rapid chemotaxis of readily available P17948 REA ( + ) BM-repopulating and progenitor cells . The late phase of hematopoietic recovery was driven by P49763 REA - induced upregulation of matrix metalloproteinase - 9 ( P14780 REA ) in the BM , mediating the release of soluble Kit-ligand ( sKitL ) . sKitL increased proliferation and motility of HSCs and progenitor cells , thereby augmenting hematopoietic recovery . P49763 REA promotes recruitment of P17948 REA ( + ) HSCs from a quiescent to a proliferative microenvironment within the BM , favoring differentiation , mobilization , and reconstitution of hematopoiesis .

Expression profile of genes associated with the dopamine pathway in vitiligo skin biopsies and blood sera . BACKGROUND : Dopamine has been proven to be toxic for melanocytes . In vitiligo patients the level of dopamine is increased and the functioning of several enzymes participating in the dopamine pathway is changed . METHODS : With the use of quantitative real-time polymerase chain reaction and ELISA the expression of genes connected to the dopamine pathway ( PAH , P61457 REA , TH , DDC , P09172 REA , PNMT , P07203 REA , P21397 REA , P27338 REA , P21964 REA , P21728 REA - P21918 REA , P54219 REA and Q05940 REA ) was observed in vitiligo patients ' and control subjects ' skin and blood . RESULTS : The mRNA expression of P07203 REA , DDC , P21397 REA , P21728 REA and P21918 REA differs in vitiligo skin and the protein level of DDC , P21397 REA , P27338 REA , P21728 REA and P21918 REA is changed in vitiligo patients ' skin and / or blood sera . CONCLUSIONS : The dopamine pathway probably influences melanogenesis directly or through the melanocortin pathway . We provide new data about changes of expression profile of the dopamine-synthesizing enzyme DDC , the dopamine-degrading enzymes P21397 REA and P27338 REA and the D1 - like family dopamine receptors in vitiligo skin and blood sera .

DB08875 SUB ( DB05153 ) for the treatment of locally advanced or metastatic progressive medullary thyroid cancer . DB08875 SUB ( DB05153 ) is an oral multiple receptor tyrosine kinase inhibitor manufactured by Exelixis Inc . , CA , USA . It mainly inhibits three tyrosine kinase receptors : MET , P35968 REA and P07949 REA . In both preclinical and clinical studies it has been shown to inhibit tumor angiogenesis , invasiveness and metastases . The most frequent side effects are fatigue , diarrhea , decreased appetite , nausea , weight loss and palmar-plantar erythrodysesthesia . A Phase III clinical trial ( EXAM study ) of DB05153 versus placebo in advanced and progressive medullary thyroid cancer showed a 28 versus 0 % overall response rate and a progression-free survival of 11.2 versus 4.0 months ( hazard ratio : 0.28 ; 95 % CI : 0.19- 0.40 ; p < 0.0001 ) in patients treated with cabozantinib and placebo , respectively . The drug has been approved by the US FDA for the treatment of advanced / progressive metastatic medullary thyroid cancer in the USA . The P15941 REA is now evaluating its approval in Europe .