interacts_with DB08875?
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 is an oral multitargeted tyrosine kinase inhibitor that inhibits both MET and P35968 . 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 . DB08875 for the treatment of advanced medullary thyroid cancer . INTRODUCTION : Patients with advanced medullary thyroid cancer ( P04629 ) have poor prognoses and limited treatment options . Improved knowledge about molecular aberrations associated with P04629 and the availability of novel targeted tyrosine kinase inhibitors ( TKIs ) have led to new potential treatment modalities . DB08875 is an oral multitargeted TKI with activity against multiple receptors including P07949 , vascular endothelial growth factor receptor type 2 ( P35968 ) , and MET that has been evaluated in P04629 in the preclinical and clinical arenas . METHODS : This article reviews unmet clinical needs in advanced P04629 . The authors consider novel agents that have been studied in P04629 , with a focus on the investigational agent cabozantinib . Up-to-date clinical data of cabozantinib in P04629 are discussed . RESULTS : Recent clinical evaluation suggests that cabozantinib is the first agent to prolong progression-free survival in patients with progressive P04629 . These findings indicate that cabozantinib may be an effective therapy in advanced P04629 . No improvement in overall survival has been demonstrated but data are not mature . CONCLUSION : DB08875 may be an effective treatment option for patients with advanced P04629 and is worthy of further evaluation . P00797 inhibition reduces atherosclerotic plaque neovessel formation and regresses advanced atherosclerotic plaques . OBJECTIVE : The interaction between the renin-angiotensin system and toll-like receptors ( TLRs ) in the pathogenesis of advanced atherosclerotic plaques is not well understood . We studied the effects of the renin inhibitor aliskiren on the progression of advanced atherosclerotic plaque in apolipoprotein E-deficient ( ApoE(-/-) ) mice with a special focus on plaque neovessel formation . METHODS AND RESULTS : Four-wk-old ApoE(-/-) mice were fed a high-fat diet for 8 wks , and the mice were randomly assigned to one of three groups and administered a vehicle , hydralazine , or aliskiren for an additional 12 wks . DB09026 reduced the atherosclerotic plaque area and plaque neovessel density . It increased the plaque collagen and elastin contents , and reduced plasma angiotensin II levels and plaque macrophage infiltration and cathepsin S ( CatS ) protein . DB09026 also decreased the levels of AT1R , gp91phox , O60603 , monocyte chemotactic protein-1 , and CatS mRNAs in the aortic roots . DB01275 had no beneficial vascular effects , although its administration resulted in the same degree of blood pressure reduction as aliskiren . CatS deficiency mimicked the aliskiren-mediated vasculoprotective effect in the ApoE(-/-) mice , but aliskiren showed no further benefits in ApoE(-/-) CatS(-/-) mice . In vitro , O60603 silencing reduced CatS expression induced by angiotensin II . Moreover , aliskiren or the inhibition of CatS impaired the endothelial cell angiogenic action in vitro or/and ex vivo . CONCLUSION : P00797 inhibition appears to inhibit advanced plaque neovessel formation in ApoE(-/-) mice and to decrease the vascular inflammatory action and extracellular matrix degradation , partly by reducing AT1R/ O60603 -mediated CatS activation and activity , thus regressing advanced atherosclerosis . An absolute role of the PKC-dependent NF-kappaB activation for induction of P14780 in hepatocellular carcinoma cells . Matrix metalloproteinases ( MMPs ) play an important role in inflammation , tumor cell invasion , and metastasis . We found that phorbol-12-myristate-13-acetate ( PMA ) -stimulated invasion of the hepatocellular carcinoma ( HCC ) SNU-387 and SNU-398 cells and that PMA induced the secretion of P14780 in the cells , but did not induce the secretion of P08253 . The PMA-induced P14780 secretion was abolished by treatment of a pan-protein kinase C ( PKC ) inhibitor , GF109203X , and an inhibitor of NF-kappaB activation , sulfasalazine , and partly inhibited by treatment of inhibitors of P29323 pathway , PD98059 and U0126 . In addition , the PMA-stimulated activation of the P14780 promoter was completely inhibited by a mutation of the NF-kappaB site within the P14780 promoter , but not completely by mutations of two AP-1 sites . Moreover , the P14780 induction by P14210 and P01375 was also completely inhibited by GF109203X and sulfasalazine , but not by PD98059 and U0126 . These data demonstrate that the PKC-dependent NF-kappaB activation is absolute for P14780 induction and that the PKC-dependent P29323 activation devotes to increase the expression level of P14780 , in HCC cells . Exome-level comparison of primary well-differentiated neuroendocrine tumors and their cell lines . Neuroendocrine cancer cell lines are used to investigate therapeutic targets in neuroendocrine tumors ( NET ) and have been instrumental in the design of clinical trials targeting the PI3K/AKT/ P42345 pathways , P15692 inhibitors , and somatostatin analogues . It remains unknown , however , whether the genomic makeup of NET cell lines reflect that of primary NET since comprehensive unbiased genome sequencing has not been performed on the cell lines . Four bronchopulmonary NET ( BP-NET ) -NCI-H720 , NCI-H727 , NCI-H835 , and UMC11-and two pancreatic neuroendocrine tumors ( panNET ) -BON-1 and QGP1-were cultured . DNA was isolated , and exome sequencing was done . GATK and EXCAVATOR were used for bioinformatic analysis . We detected a total of 1,764 nonsynonymous single nucleotide variants at a rate of 8 per Mb in BP-NET and 4.3 per Mb in panNET cell lines , including 52 mutated COSMIC cancer genes in these cell lines , such as P04637 , P38398 , P06400 , P49815 , P46531 , Q09472 , GNAS , P35968 , Q15831 , and P25054 but not P46100 , Q9UER7 , nor O00255 . Our data suggest that mutation rate , the pattern of copy number variations , and the mutational spectra in the BP-NET cell lines are more similar to the changes observed in small cell lung cancer than those found in primary BP-NET . Likewise , mutation rate and pattern including the absence of mutations in P46100 / Q9UER7 , O00255 , and P25490 in the panNET cell lines BON1 and QGP1 suggest that these cell lines do not have the genetic signatures of a primary panNET . These results suggest that results from experiments with BP-NET and panNET cell lines need to be interpreted with caution . P00533 variant III mutations in lung tumorigenesis and sensitivity to tyrosine kinase inhibitors . The tyrosine kinase inhibitors gefitinib ( DB00317 ) and erlotinib ( Tarceva ) have shown anti-tumor activity in the treatment of non-small cell lung cancer ( NSCLC ) . Dramatic and durable responses have occurred in NSCLC tumors with mutations in the tyrosine kinase domain of the epidermal growth factor receptor ( P00533 ) . In contrast , these inhibitors have shown limited efficacy in glioblastoma , where a distinct P00533 mutation , the variant III ( vIII ) in-frame deletion of exons 2-7 , is commonly found . In this study , we determined that EGFRvIII mutation was present in 5 % ( 3/56 ) of analyzed human lung squamous cell carcinoma ( SCC ) but was not present in human lung adenocarcinoma ( 0/123 ) . We analyzed the role of the EGFRvIII mutation in lung tumorigenesis and its response to tyrosine kinase inhibition . Tissue-specific expression of EGFRvIII in the murine lung led to the development of NSCLC . Most importantly , these lung tumors depend on EGFRvIII expression for maintenance . Treatment with an irreversible P00533 inhibitor , HKI-272 , dramatically reduced the size of these EGFRvIII-driven murine tumors in 1 week . Similarly , Ba/ P13726 cells transformed with the EGFRvIII mutant were relatively resistant to gefitinib and erlotinib in vitro but proved sensitive to HKI-272 . These findings suggest a therapeutic strategy for cancers harboring the EGFRvIII mutation . Induction of high mobility group box 1 release from serotonin-stimulated human umbilical vein endothelial cells . High mobility group box 1 ( P09429 ) is a non-histone nuclear protein which is released from the nucleus of activated macrophages into the extracellular space in response to stimuli such as endotoxin or necrosis . The P09429 functions as a potent proinflammatory cytokine in the extracellular spaces . Recently , P09429 has been implicated in the progression of atherosclerosis . However , the association between P09429 and the development of atherosclerosis is poorly understood . Therefore , we examined whether serotonin ( 5-HT ) , a key factor involved in the development of atherosclerosis , induced P09429 release in human umbilical vein endothelial cells ( HUVECs ) . We found that 5-HT induced the release of P09429 but not of P27361 /2 and JNK from HUVECs via the 5-HT receptor ( P28222 ) /p38 mitogen-activated protein kinase ( MAPK ) signaling pathway . The p38MAPK inhibitor SB203580 and the P28222 antagonist GR55526 markedly inhibited P09429 release from 5-HT-stimulated HUVECs . The vascular endothelial growth factor ( P15692 ) derived from activated macrophages in atherosclerotic lesions also plays an important role in the progression of atherosclerosis . We found that P09429 induced P15692 production in macrophage-like RAW264.7 cells . P09429 induced the activation of p38MAPK , P27361 /2 and Akt . The P19957 -kinase inhibitor LY294002 significantly inhibited P15692 production in P09429 -stimulated macrophages , while other kinase inhibitors did not . These results suggest that P09429 release may contribute as a risk factor in the development and progression of atherosclerosis . P10275 rediscovered : the new biology and targeting the androgen receptor therapeutically . Discoveries over the past decade suggest that castration-resistant prostate cancer ( CRPC ) is sensitive , but not resistant to , further manipulation of the androgen-androgen receptor ( AR ) axis . Several new therapies that target this axis have demonstrated clinical activity . In this article , preclinical and clinical findings occurring in the field of AR-targeted therapies are reviewed . Reviews of scientific and clinical development are divided into those occurring prereceptor ( androgen production and conversion ) and at the level of the receptor ( AR aberrations and therapies targeting AR directly ) . Intracrine androgen production and AR amplification , among others , are among the principal aberrancies driving CRPC growth . Phase III data with abiraterone acetate and phase II data with DB08899 , along with other similar therapies , confirm for the clinician that the scientific findings related to persistent AR signaling in a castrate milieu can be harnessed to produce significant clinical benefit for patients with the disease . Studies aimed at optimizing the timing of their use and exploring the mechanisms of resistance to these therapies are under way . The clinical success of therapies that directly target androgen synthesis as well as the most common aberrancies of the AR confirm that prostate cancer retains dependence on AR signaling , even in the castrate state . Dynamic genetic linkage of intermediate blood pressure phenotypes during postural adaptations in a founder population . Blood pressure ( BP ) is a dynamic phenotype that varies rapidly to adjust to changing environmental conditions . Standing upright is a recent evolutionary trait , and genetic factors that influence postural adaptations may contribute to BP variability . We studied the effect of posture on the genetics of BP and intermediate BP phenotypes . We included 384 sib-pairs in 64 sib-ships from families ascertained by early-onset hypertension and dyslipidemia . Blood pressure , three hemodynamic and seven neuroendocrine intermediate BP phenotypes were measured with subjects lying supine and standing upright . The effect of posture on estimates of heritability and genetic covariance was investigated in full pedigrees . Linkage was conducted on 196 candidate genes by sib-pair analyses , and empirical estimates of significance were obtained . A permutation algorithm was implemented to study the postural effect on linkage . ADRA1A , APO , CAST , Q9Y5Q5 , P34998 , P24530 , P09038 , GC , P17302 , Q92953 , P08254 , P01303 , P08235 , P26678 , P37173 , P25445 , and P34981 showed evidence of linkage with any phenotype in the supine position and not upon standing , whereas P15121 , P16671 , P25101 , P12259 , P14780 , PKD2 , P27169 , P37231 , Q9UBK2 , P17252 , and P07949 were specifically linked to standing phenotypes . Genetic profiling was undertaken to show genetic interactions among intermediate BP phenotypes and genes specific to each posture . When investigators perform genetic studies exclusively on a single posture , important genetic components of BP are missed . Supine and standing BPs have distinct genetic signatures . Standardized maneuvers influence the results of genetic investigations into BP , thus reflecting its dynamic regulation . DB08875 suppresses tumor growth and metastasis in hepatocellular carcinoma by a dual blockade of P35968 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 , 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 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 blocked the hepatocyte growth factor ( P14210 ) -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 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 . Response to DB08875 in patients with P07949 fusion-positive lung adenocarcinomas . The discovery of P07949 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 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 inhibitors in the treatment of P07949 fusion-positive tumors , clinical data on response are lacking . We report preliminary data for the first three patients treated with the P07949 inhibitor cabozantinib on a prospective phase II trial for patients with P07949 fusion-positive NSCLCs ( NCT01639508 ) . Confirmed partial responses were observed in 2 patients , including one harboring a novel Q9UPN9 - P07949 fusion . A third patient with a P33176 - P07949 fusion has had prolonged stable disease approaching 8 months ( 31 weeks ) . All three patients remain progression-free on treatment . Germline P07949 634 mutation positive MEN 2A-related C-cell hyperplasias have genetic features consistent with intraepithelial neoplasia . C-cell hyperplasias are normally multifocal in multiple endocrine neoplasia type 2A . We compared clonality , microsatellite pattern of tumor suppressor genes , and cellular kinetics of C-cell hyperplasia foci in each thyroid lobe . We selected 11 females from multiple endocrine neoplasia type 2A kindred treated with thyroidectomy due to hypercalcitoninemia . C-cell hyperplasia foci were microdissected for DNA extraction to analyze the methylation pattern of androgen receptor alleles and microsatellite regions ( P04637 , P06400 , P19544 , and P21359 ) . Consecutive sections were selected for MIB-1 , pRB1 , p53 , Mdm-2 , and p21WAF1 immunostaining , DNA content analysis , and in situ end labeling . Appropriate tissue controls were run . Only two patients had medullary thyroid carcinoma foci . Nine informative C-cell hyperplasia patients showed germline point mutation in P07949 , eight of them with the same androgen receptor allele preferentially methylated in both lobes . C-cell hyperplasia foci showed heterogeneous DNA deletions revealed by loss of heterozygosity of P04637 ( 12 of 20 ) , P06400 ( 6 of 14 ) , and P19544 ( 4 of 20 ) and hypodiploid G0/ P55008 cells ( 14 of 20 ) , low cellular turnover ( MIB-1 index 4.5 % , in situ end labeling index 0.03 % ) , and significantly high nuclear area to DNA index ratio . MEN 2A ( germline point mutation in P07949 codon 634 ) C-cell hyperplasias are monoclonal and genetically heterogeneous and show down-regulated apoptosis , findings consistent with an intraepithelial neoplasia . Concordant X-chromosome inactivation and interstitial gene deletions suggest clone expansions of precursors occurring at a point in embryonic development before divergence of each thyroid lobe and may represent a paradigm for other germline mutations . DB05039 inhibits tumor cell invasiveness and P14780 expression by suppressing IKK/NF-κB activation . The β2 adrenergic receptor ( P07550 ) is a G protein-coupled transmembrane receptor expressed in the human respiratory tract and widely recognized as a pharmacological target for treatments of asthma and chronic obstructive pulmonary disorder ( P48444 ) . Although a number of P07550 agonists have been developed for use in asthma therapy , indacaterol is the only ultra-long-acting inhaled β2-agonist ( LABA ) approved by the FDA for relieving the symptoms in P48444 patients . The precise molecular mechanism underlying the pharmacological effect of indacaterol , however , remains unclear . Here , we show that β-arrestin-2 mediates the internalization of P07550 following indacaterol treatment . Moreover , we demonstrate that indacaterol significantly inhibits tumor necrosis factor-α ( P01375 -α ) -induced NF-κB activity by reducing levels of both phosphorylated-IKK and -IκBα , thereby decreasing NF-κB nuclear translocation and the expression of P14780 , an NF-κB target gene . Subsequently , we show that indacaterol significantly inhibits P01375 -α/NF-κB-induced cell invasiveness and migration in a human cancer cell line . In conclusion , we propose that indacaterol may inhibit NF-κB activity in a β-arrestin2-dependent manner , preventing further lung damage and improving lung function in P48444 patients . P10275 YAC transgenic mice recapitulate SBMA motor neuronopathy and implicate VEGF164 in the motor neuron degeneration . X-linked spinal and bulbar muscular atrophy ( SBMA ) is an inherited neuromuscular disorder characterized by lower motor neuron degeneration . SBMA is caused by polyglutamine repeat expansions in the androgen receptor ( AR ) . To determine the basis of AR polyglutamine neurotoxicity , we introduced human AR yeast artificial chromosomes carrying either 20 or 100 CAGs into mouse embryonic stem cells . The AR100 transgenic mice developed a late-onset , gradually progressive neuromuscular phenotype accompanied by motor neuron degeneration , indicating striking recapitulation of the human disease . We then tested the hypothesis that polyglutamine-expanded AR interferes with CREB binding protein ( CBP ) -mediated transcription of vascular endothelial growth factor ( P15692 ) and observed altered CBP-AR binding and P15692 reduction in AR100 mice . We found that mutant AR-induced death of motor neuron-like cells could be rescued by P15692 . Our results suggest that SBMA motor neuronopathy involves altered expression of P15692 , consistent with a role for P15692 as a neurotrophic/survival factor in motor neuron disease . P00797 angiotensin system modulates P42345 pathway through AT2R in HIVAN . P42345 ( P42345 ) has been reported to contribute to the development of HIV-associated nephropathy ( HIVAN ) . We hypothesized that HIV may be activating renal tissue P42345 pathway through renin angiotensin system ( DB01367 ) via Angiotensin Receptor Type II receptor ( AT2R ) . Renal tissues of Vpr transgenic and Tg26 ( HIVAN ) mice displayed enhanced phosphorylation of P42345 and p70S6K . DB09026 , a renin inhibitor attenuated phosphorylation of both P42345 and p70S6K in renal tissues of HIVAN mice . Interestingly , Angiotensin Receptor Type I ( AT1R ) blockade did not modulate renal tissue phosphorylation of P42345 in HIVAN mice ; on the other hand , AT2R blockade attenuated renal tissue phosphorylation of P42345 in HIVAN mice . In vitro studies , both renin and Ang II displayed enhanced mouse tubular cell ( P04629 ) phosphorylation of p70S6K in a dose dependent manner . HIV/ P04629 also displayed enhanced phosphorylation of both P42345 and p70S6K ; interestingly this effect of HIV was further enhanced by losartan ( an AT1R blocker ) . On the other hand , AT2R blockade attenuated HIV-induced tubular cell phosphorylation of P42345 and p70S6K , whereas , AT2R agonist enhanced phosphorylation of P42345 and p70S6K . These findings indicate that HIV stimulates P42345 pathway in HIVAN through the activation of renin angiotensin system via AT2R . A transgenic platform for testing drugs intended for reversal of cardiac remodeling identifies a novel 11βHSD1 inhibitor rescuing hypertrophy independently of re-vascularization . RATIONALE : Rescuing adverse myocardial remodeling is an unmet clinical goal and , correspondingly , pharmacological means for its intended reversal are urgently needed . OBJECTIVES : To harness a newly-developed experimental model recapitulating progressive heart failure development for the discovery of new drugs capable of reversing adverse remodeling . METHODS AND RESULTS : A P15692 -based conditional transgenic system was employed in which an induced perfusion deficit and a resultant compromised cardiac function lead to progressive remodeling and eventually heart failure . Ability of candidate drugs administered at sequential remodeling stages to reverse hypertrophy , enlarged LV size and improve cardiac function was monitored . Arguing for clinical relevance of the experimental system , clinically-used drugs operating on the P00797 -Angiotensin- DB04630 -System ( RAAS ) , namely , the P12821 inhibitor Enalapril and the direct renin inhibitor Aliskerin fully reversed remodeling . Remodeling reversal by these drugs was not accompanied by neovascularization and reached a point-of-no-return . Similarly , the PPARγ agonist Pioglitazone was proven capable of reversing all aspects of cardiac remodeling without affecting the vasculature . Extending the arsenal of remodeling-reversing drugs to pathways other than RAAS , a specific inhibitor of 11β-hydroxy-steroid dehydrogenase type 1 ( 11β HSD1 ) , a key enzyme required for generating active glucocorticoids , fully rescued myocardial hypertrophy . This was associated with mitigating the hypertrophy-associated gene signature , including reversing the myosin heavy chain isoform switch but in a pattern distinguishable from that associated with neovascularization-induced reversal . CONCLUSIONS : A system was developed suitable for identifying novel remodeling-reversing drugs operating in different pathways and for gaining insights into their mechanisms of action , exemplified here by uncoupling their vascular affects . Moving beyond chemotherapy : novel cytostatic agents for malignant mesothelioma . It is now known that vascular endothelial growth factor ( P15692 ) and platelet derived growth factor ( PDGF ) are autocrine growth factors in malignant mesothelioma ; epidermal growth factor receptor ( P00533 ) is also highly overexpressed . Cytotoxic drugs that target these growth factors offer fresh potential for the treatment of mesothelioma . Clinical trials have recently been initiated to evaluate the anti-tumour activity of the P15692 inhibitors SU5416 , bevacizumab and thalidomide . ZD1839 ( DB00317 , AstraZeneca ) , an inhibitor of P00533 tyrosine kinase , is also being evaluated . Two clinical trials are planned to evaluate the two PDGF inhibitors Gleevec ( Imatinib mesylate , STI-571 , Novartis Pharmaceuticals ) and PTK787 ( Novartis Pharmaceuticals ) . Silencing alpha-fetoprotein inhibits P15692 and P08253 /9 production in human hepatocellular carcinoma cell . P02771 not only serves as a diagnostic marker for liver cancer , but also posses a variety of biological functions . However , the role of P02771 on tumor angiogenesis and cell invasion remains incompletely understood . In this study , we aimed to evaluate if P02771 can regulate the major angiogenic factors and matrix metalloproteinases in human liver cancer cells . P02771 silencing was achieved by Stealth RNAi . Expression of P02771 was examined by a full-automatic electrochemistry luminescence immunity analyzer . Expression of P15692 , P35968 , P14780 , and P08253 was examined by Western blot and immunocytochemistry . Apoptosis was detected by TUNEL assay . Angiogenesis was detected by in vitro angiogenesis assay kit . Silencing of P02771 led to an increased apoptosis , which was associated with a decreased expression of vascular endothelial growth factor , vascular endothelial growth factor receptor 2 , matrix metalloproteinases-2/9 . These results suggest that P02771 may play a regulatory role on angiogenesis and cell invasion during liver cancer development . The role of tumor suppressor dysregulation in prostate cancer progression . P10275 activity is essential for prostate cancer development and progression . While there are classically defined roles for the retinoblastoma ( P06400 ) and p53 tumor suppressor pathways in maintenance of cell cycle control and the DNA damage response , recent studies have demonstrated a direct role of these two pathways in regulating AR expression and function . While the role of Pten deregulation in prostate cancer has provided much insight in to the mechanisms underlying prostate cancer initiation and progression , emerging roles for P06400 and p53 are likely to further expand upon our understanding of tumor suppressor/nuclear receptor interaction . As disconnecting mitogenic signaling from AR-mediated gene transcription underlies the progression to castrate resistant prostate cancer ( CRPC ) , functional inactivation of these two tumor suppressor pathways represents one mechanism through which AR protein levels can be upregulated and AR-mediated gene transcription can become aberrant . Importantly , recent advances in small molecule inhibitor design and discovery have led to the identification of agents capable of targeting these two prominent pathways and restoring the function of deregulated wild-type P06400 and p53 protein . While such agents have undergone extensive study in many solid tumor types , the additional importance of P06400 and p53 in restraining transcription of the AR gene within the prostate provides impetus for examining how loss of these two tumor suppressor proteins can facilitate transition of prostate cancers to CRPC . As will be reviewed in this article , restoration of P06400 and p53 functions are not only important in regard to shortterm cell cycle regulation and response to genomic stresses , but likely have direct implications for deregulation of the AR locus . Sporadic fundic gland polyps : an immunohistochemical study of their antigenic profile . Fundic Gland Polyps ( FGPs ) are small sessile ( 2-5 mm ) , usually multiple polyps arising in the gastric , acid-secreting mucosa of disputed histogenesis . They have been described in a sporadic form , prevalently in middle aged females , or associated with familial adenomatosis coli-Gardner 's syndrome . We performed an immunohistochemical study on 24 sporadic FGPs , using monoclonal antibodies ( MAbs ) against differentiation markers , class II MHC antigens ( HLA-DR ) , oncofetal and proliferation antigens , aimed to characterize the antigenic profile of the polyps . A preliminary cytogenetic study on five polyps was also done , using an in situ culture method after collagenase treatment . Cytokeratins 8-18 ( P62158 5.2 MAb ) and 20 ( IT-Ks 20.8 MAb ) , Epithelial Membrane Antigen ( P15941 ) and Chromogranin A were normally expressed by FGPs . FGPs did not express HLA II DR . FGPs did not react with an anti- P06731 MAb ( F6 ) , but they were frequently positive ( 22/24 , 91.6 % ) with B72.3 MAb ( reacting with the cancer-associated mucin epitope sialyl-Tn ) . The PC10 MAb ( against P12004 or cyclin ) showed enhanced expression in the deep glandular-cystic compartment of FGPs ; the P12004 index of FGPs was significantly higher than in normal fundic mucosa . The cytogenetic study on the 5 cases analysed , revealed a normal karyotype . We have demonstrated that FGPs express in the paranuclear zone the sialyl-Tn epitope , a side-chain sugar normally masqued in adult gastric mucins , thus revealing an alteration in mucin synthesis ; FGPs ' higher proliferation index as compared with normal fundic mucosa supports the hypothesis of their hyperproliferative nature . Expression of vascular endothelial growth factor and its receptors in the central nervous system in amyotrophic lateral sclerosis . Vascular endothelial growth factor ( P15692 ) prolongs survival in the mutant P00441 transgenic mouse model of amyotrophic lateral sclerosis ( P35858 ) , whereas dysregulation of P15692 through deletion of its hypoxia-regulatory element causes motor neuron degeneration in mice . We investigated the expression of P15692 and its major agonist receptors in the normal central nervous system and in patients with P35858 . Immunohistochemistry demonstrated similar expression patterns of P15692 and P15692 receptor 2 ( P35968 ) in the spinal cord with finely punctate staining of the neuropil and strong expression in anterior horn cells ( AHCs ) . Granular staining on the surface of some AHCs , similar to that seen with synaptic markers , suggested synaptic labeling . P35968 staining was reduced in the neuropil of P35858 cases ( p=0.018 ) associated with a reduction of synaptophysin but not P60880 expression . A greater proportion of AHCs in P35858 cases showed low expression of P15692 ( p=0.006 ) and P35968 ( p=0.009 ) compared with controls . Expression of P15692 and P35968 was confirmed by Western blotting and quantitative reverse transcriptase-polymerase chain reaction ( QPCR ) . The similar expression patterns of P15692 and P35968 suggests autocrine/paracrine effects on spinal motor neurons , and the reduction in their expression seen in P35858 cases would support the hypothesis that , as in mouse models of the disease , reduced P15692 signaling may play a role in the pathogenesis of P35858 . ShRNA silencing glycogen synthase kinase-3 beta inhibits tumor growth and angiogenesis in pancreatic cancer . P49841 ( GSK-3β ) , a serine/threonine protein kinase , plays a vital role in the tumorigenesis of many cancers , but its role in pancreatic cancer remains unknown . In this study , we showed that GSK-3β was aberrantly activated in pancreatic cancer . GSK-3β knockdown resulted in arrested proliferation and increased apoptosis in pancreatic cancer cell lines . Expression of Bcl-2 and vascular endothelial growth factor ( P15692 ) decreased significantly in a GSK-3β knockdown group . In a xenograft tumor model , GSK-3β knockdown inhibited tumor growth and angiogenesis . Our study showed that GSK-3β may become a promising therapeutic target for human pancreatic cancer . Benign mixed tumor of the skin , hypercellular variant : a case report . A 71-year-old man presented with a slowly growing 2.0x2.0x1.0 cm scalp lesion that was surgically removed . Microscopic examination showed a well-circumscribed dermally located tumor composed of ductal elements lined by double to multiple cell layers of bland cuboidal inner cells and elongated spindled outer cells with areas showing cribriform and solid growth patterns . Some cells showed prominent cytoplasmic clearing . A few mitotic figures are noted ranging from 1-2 mitotic figure/10 hpf . There are also foci of squamous differentiation as well as occasional mature adipocytes . The background stroma was predominantly sclerotic with only small area of myxoid background ( confirmed by Hale 's colloidal iron ) . Immunohistochemical studies revealed positive immunoreactivity for P15941 , P06731 , CD117 , HWMK , LWMK , CK7 , P10275 and S100 in the ductal ( epithelial ) cells and positive immunereactivity for calponin , SMA , CK 5/6 and p63 in the myoepithelial component . No immunoreactivity for Brst-2 , ER , PR and CK20 was noted . MIB-1 showed mildly increased proliferrative index highlighting 5 % of the nuclei . The overall morphology and immunohistochemical profile are that of a benign cutanoues mixed tumor ( chondroid syringoma ) . Given the unusual striking celluarlity , we suggest to subclassify this as a hyper-cellular variant . DB00203 inhibits calcineurin/ Q13469 -mediated cyclin A expression in pulmonary artery smooth muscle cells . AIMS : To examine whether calcineurin/NFAT signaling pathway leads to proliferation of pulmonary artery smooth muscle cells ( PASMCs ) by regulating cell cycle proteins and whether the phosphodiesterase-5 ( O76074 ) inhibitor sildenafil affects calcineurin/NFAT-induced cell proliferation . MAIN METHODS : A [(3)H]thymidine incorporation assay was used to examine DNA synthesis ( cell proliferation ) ; cyclin A and Q13469 expressions were determined by Western blot . P24941 ( P24941 ) activity was measured with an in vitro kinase activity assay , and calcineurin and NFAT activity were evaluated using a calcineurin assay kit and a luciferase activity assay , respectively . A chemical inhibitor or siRNA transfection was used to inhibit calcineurin/NFAT signaling pathway . KEY FINDINGS : Serotonin dose-dependently stimulated cyclin A expression in PASMCs . This effect was accompanied by dose-dependent increases in P24941 activity and the rate of DNA synthesis . At the same time , PASMCs treated with serotonin showed dose-dependent activation of calcineurin/NFAT signaling pathway . Inhibition of calcineurin activity by cyclosporine A or loss of Q13469 protein by siRNA transfection abolished serotonin-induced cyclin A expression and consequent P24941 activation and DNA synthesis . We further found that pretreatment of cells with sildenafil suppressed serotonin-triggered activation of calcineurin/ Q13469 signaling pathway and resultant cyclin A expression , P24941 activation and cell proliferation , while the presence of DT-3 [ a specific protein kinase G ( PKG ) peptide inhibitor ] reversed the effects of sildenafil on PASMCs . SIGNIFICANCE : Our study suggests that enhanced PKG activity suppresses calcineurin/ Q13469 cascade-mediated cyclin A expression , P24941 activation and PASMC proliferation to contribute to the overall effects of sildenafil in the treatment of pulmonary hypertension . DB08875 inhibits prostate cancer growth and prevents tumor-induced bone lesions . PURPOSE : DB08875 , an orally available multityrosine kinase inhibitor with activity against mesenchymal epithelial transition factor ( MET ) and P15692 receptor 2 ( P35968 ) , 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 . RESULTS : DB08875 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 directly inhibited prostate cancer cell viability and induced apoptosis in vitro and in vivo and inhibited cell invasion in vitro . DB08875 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 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 . Noncatalytic function of P27361 /2 can promote Raf/MEK/ P29323 -mediated growth arrest signaling . Kinase activity is known as the key biochemical property of MAPKs . Here , we report that P27361 /2 also utilizes its noncatalytic function to mediate certain signal transductions . Sustained activation of the Raf/MEK/ P29323 pathway induces growth arrest , accompanied by changes in cell cycle regulators ( decreased retinoblastoma phosphorylation , Q01094 down-regulation , and/or P38936 (CIP1) up-regulation ) and cell type-specific changes in morphology and expression of c-Myc or P07949 in the human tumor lines LNCaP , U251 , and TT . Ablation of P27361 /2 by RNA interference abrogated all these effects . However , active site-disabled P29323 mutants ( P27361 -K71R , P28482 -K52R , and P28482 -D147A ) , which competitively inhibit activation of endogenous P27361 /2 , could not block Raf/MEK-induced growth arrest as well as changes in the cell cycle regulators , although they effectively blocked phosphorylation of the P27361 /2 catalytic activity readouts , p90(RSK) and ELK1 , as well as the cell type-specific changes . Because this indicated a potential noncatalytic P27361 /2 function , we generated stable lines of the tumor cells in which both P27361 and P28482 were significantly knocked down , and we further investigated the possibility using rat-derived kinase-deficient P29323 mutants ( P28482 -K52R and P28482 -T183A/Y185F ) that were not targeted by human small hairpin RNA . Indeed , P28482 -K52R selectively restored Raf-induced growth inhibitory signaling in P27361 /2-depleted cells , as manifested by regained cellular ability to undergo growth arrest and to control the cell cycle regulators without affecting c-Myc and morphology . However , P28482 -T183A/Y185F was less effective , indicating the requirement of TEY site phosphorylation . Our study suggests that functions of P27361 /2 other than its " canonical " kinase activity are also involved in the pathway-mediated growth arrest signaling . Opposed effects of lithium on the MEK- P29323 pathway in neural cells : inhibition in astrocytes and stimulation in neurons by GSK3 independent mechanisms . DB01356 is widely used in the treatment of bipolar disorder , but despite its proven therapeutic efficacy , the molecular mechanisms of action are not fully understood . The present study was undertaken to explore lithium effects of the MEK/ P29323 cascade of protein kinases in astrocytes and neurons . In asynchronously proliferating rat cortical astrocytes , lithium decreased time- and dose-dependently the phosphorylation of MEK and P29323 , with 1 mM concentrations achieving 60 and 50 % inhibition of P29323 and MEK , respectively , after a 7-day exposure . DB01356 also inhibited [3H]thymidine incorporation into DNA and induced a G2/M cell cycle arrest . In serum-deprived , quiescent astrocytes , pre-exposure to lithium resulted in the inhibition of cell cycle re-entry as stimulated by the mitogen endothelin-1 : under this experimental setting , lithium did not affect the rapid , peak phosphorylation of MEK taking place after 3-5 min , but was effective in inhibiting the long-term , sustained phosphorylation of MEK . DB01356 inhibition of the astrocyte MEK/ P29323 pathway was independent of inositol depletion . Further , compound SB216763 inhibited Tau phosphorylation at Ser396 and stabilized cytosolic beta-catenin , consistent with the inhibition of glycogen synthase kinase-3 beta ( P49841 ) , but failed to reproduce lithium effects on MEK and P29323 phosphorylation and cell cycle arrest . In cerebellar granule neurons , millimolar concentrations of lithium enhanced MEK and P29323 phosphorylation in a concentration-dependent manner , again through an inositol and P49841 independent mechanism . These opposing effects in astrocytes and neurons make lithium treatment a promising strategy to favour neural repair and reduce reactive gliosis after traumatic injury . A dose-ranging study of cabozantinib in men with castration-resistant prostate cancer and bone metastases . BACKGROUND : DB08875 is an oral MET/ P35968 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 40 mg daily was associated with a high rate of bone scan response . DB08875 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 . DB00203 induces angiogenic response in human coronary arteriolar endothelial cells through the expression of thioredoxin , hemeoxygenase and vascular endothelial growth factor . This study was undertaken to investigate the effect of phosphodiesterase-5 ( O76074 ) inhibitor , sildenafil , on angiogenic response in human coronary arteriolar endothelial cells ( HCAEC ) . The cells exposed to sildenafil ( 1-20 microM ) demonstrated significantly accelerated tubular morphogenesis with the induction of thioredoxin-1 ( P10599 -1 ) , hemeoxygenase-1 ( P09601 ) and P15692 . DB00203 induced P15692 and angiopoietin specific receptors such as P35968 , Tie-1 and Tie-2 . This angiogenic response was repressed by tinprotoporphyrin IX ( SnPP ) , an inhibitor of P09601 enzyme activity . DB00203 below 1 muM has no angiogenic effect as evidenced by reduced tuborogenesis . DB00203 along with SnPP inhibited both P15692 and Q15389 ( Ang-1 ) protein expression . Therefore our results demonstrated for the first time that sildenafil is a very potent pro-angiogenic factor . In-vitro antiproliferative activities and kinase inhibitory potencies of meridianin derivatives . Marine alkaloid meridianin G derivatives , substituted on the pyrimidine ring by aryl groups , were evaluated for their kinase inhibitory potencies and their in-vitro antiproliferative activities . The derivatives were tested toward a panel of nine protein kinases ( P35968 , IGF-1R , c- DB00134 , P07949 , c-Src , c-Abl , PKA , P24941 /cyclin A , and HER-1 ) and their in-vitro antiproliferative activities were evaluated toward a human fibroblast primary culture and two human solid cancer cell lines ( MCF-7 and PA 1 ) . Despite weak kinase inhibitory potencies , high in-vitro antiproliferative activities were found for compounds 5 , 7 , 12 , and 14 , which do not interfere with the PA 1 cell cycle and may be considered as direct cytolysis or apoptosis inducers . [ Functional characteristics of calcium-sensitive adenylyl cyclase of ciliate Tetrahymena pyriformis ] . DB01373 -sensitive forms of adenylyl cyclase ( AC ) were revealed in most vertebrates and invertebrates and also in some unicellular organisms , in particular ciliates . We have shown for the first time that calcium cations influence the AC activity of ciliate Tetrahymena pyriformis . These cations at the concentrations of 0.2-20 microM stimulated the enzyme activity , and maximum of catalytic effect was observed at 2 microM Ca2+ . DB01373 cations at a concentrations of 100 microM or higher inhibited the AC activity . P62158 antagonists W-5 and W-7 at the concentrations of 20-100 microM inhibited the catalytic effect induced by 5 microM Ca2+ and blocked the effect at higher concentrations of Ca2+ . DB00477 , another calmodulin antagonist , reduced Ca2+-stimulated AC activity only at the concentrations of 200-1000 microM . AC stimulating effects of serotonin , P01133 and DB02527 increased in the presence of 5 microM Ca2+ . AC stimulating effects of P01133 , DB02527 and insulin decreased in the presence of 100 microM Ca2+ , and AC stimulating effect of DB02527 decreased also in the presence of calmodulin antagonists ( 1 mM ) . At the same time , stimulating effect of D-glucose in the presence of Ca2+ and calmodulin antagonists did not change essentially . The data obtained speak in favor of the presence of calcium-sensitive forms of AC in ciliate T. pyriformis which mediate enzyme stimulation by P01133 , DB02527 , insulin , and serotonin . 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 ( rearranged during transfection ) , P35968 ( vascular endothelial growth factor receptor 2 ) and MET ( mesenchymal-epithelial transition factor ) , which make attractive targets for drug development . DB08875 is an orally bioavailable tyrosine kinase inhibitor which blocks MET , VEGRF2 and P07949 , 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 . Gene transfer of glial cell-derived neurotrophic factor and cardiotrophin-1 protects PC12 cells from injury : involvement of the phosphatidylinositol 3-kinase and mitogen-activated protein kinase kinase pathways . Gene therapy for neurodegenerative diseases may utilize the expression of neurotrophic factors because of their potential to promote survival and regeneration of injured neuronal cells . Increasing numbers of these factors are being considered for gene transfer , but their specificity and efficacy in neuroprotection are greatly variable . The major aims of this study were to carry out gene transfer of various neurotrophic factors and investigate their mechanisms of action as well as their protective effects on the viability of rat pheochromocytoma ( PC12 ) cells . We used glutamate , S-nitroso-N-acetyl-DL-penicillamine ( P60880 ) , and staurosporine to induce excitatory damage , oxidative stress , and apoptosis , respectively , because these mechanisms are thought to participate in various disease processes leading to degeneration of cells . We utilized adenovirus vectors for efficient gene transfer of trophic factors ( glial-cell derived neurotrophic factor [ P39905 ] and cardiotrophin-1 [ Q16619 ] ) or calbindin-D28k . We found that P39905 and Q16619 gene transfers were equally effective in saving PC12 cells from injury , but calbindin expression did not show any beneficial effects . P39905 gene transfer was much more efficient in protecting PC12 cells from damage than direct P39905 administration . The protection by P39905 expression against staurosporine was mediated through both phosphatidylinositol 3-kinase ( PI3K ) and mitogen-activated protein kinase kinase ( MAPK kinase ; MEK ) pathways , but only the MEK pathway was involved in the protection against P60880 . In contrast , the protective effect of P39905 against glutamate toxicity was independent of these P07949 -dependent signal transduction pathways . A recombinant single-chain P13232 /HGFbeta hybrid cytokine induces juxtacrine interactions of the P13232 and P14210 ( c- DB00134 ) receptors and stimulates the proliferation of CFU- P28222 , CLPs , and pre-pro-B cells . A novel recombinant interleukin-7/hepatocyte growth factor beta-chain ( P13232 /HGFbeta ) hybrid cytokine was constructed as a single chain ( sc ) composed of P13232 and HGFbeta connected by a flexible linker . Unlike recombinant ( r ) P13232 , which stimulated pro-B cells and pre-B cells only , scIL-7/HGFbeta stimulated the proliferation of pre-pro-B cells , common lymphoid progenitors ( CLPs ) , and colony-forming unit ( CFU ) - P28222 in cultures of P13232 -/- mouse BM cells . When injected in vivo , 3- to 4-fold more splenic B-lineage cells appeared in recipients of bone marrow ( BM ) cells from the scIL-7/HGFbeta-stimulated cultures than from rIL-7-stimulated cultures . Moreover , on a per-cell basis , scIL-7/HGFbeta culture-generated cells produced 16- to 20-fold more BM and splenic B-lineage cells than did normal BM cells . Antibody blocking , receptor phosphorylation , and confocal microscopy demonstrated that scIL-7/HGFbeta signals though both the P13232 and P14210 ( c- DB00134 ) receptors , which form IL-7R/c- DB00134 complexes on the surface of CLPs and pre-pro-B cells . In addition , the IL-7Ralpha chain , gammac chain , and c- DB00134 were coisolated from purified CLPs and pre-pro-B cells on scIL-7/HGFbeta affinity gels , indicating that they are major components of the P13232 /HGFbeta receptor . Hence , the present results demonstrate that the P13232 /HGFbeta hybrid cytokine efficiently and selectively stimulates the most primitive B-lineage precursors in BM by inducing juxtacrine interactions between the P13232 and c- DB00134 receptors . Multiple antigenic polypeptide composed of heparanase B‑cell epitopes shrinks human hepatocellular carcinoma in mice . The purpose of this study was to evaluate the anti‑growth effect of the self‑designed multiple antigenic polypeptide ( Q96HU1 ) vaccine comprising B‑cell epitopes of heparanase ( Q9Y251 ) on HCC97‑H hepatocellular carcinoma ( HCC ) in mice . The polyclonal antibodies against the B‑cell epitopes of Q9Y251 were prepared by immunizing rabbits with freshly synthesized Q96HU1 vaccine . HCC‑bearing models were constructed on BALB/c nude mice . Anti‑ Q96HU1 antibodies were administrered to the models to assess the effects on Q9Y251 activity , HCC growth , the expression of P15692 / P09038 and the value of micro‑vessel density ( P53602 ) . The anti‑ Q96HU1 antibodies were harvested , purified and identified . These antibodies were able to specifically bind with the dominant epitopes of the precursor protein and large subunit monomer of Q9Y251 , decrease Q9Y251 activity , suppress the expressions of P15692 and P09038 , reduce the P53602 , and markedly shrink the HCC volume . Based on these findings , Q96HU1 vaccine based on the B‑cell epitopes of Q9Y251 seemed to provide theoretical evidence for further study of the synthesized Q9Y251 Q96HU1 vaccine in the treatment of HCC . Role of O60674 - P40763 in O60603 -mediated tissue factor expression . P13726 ( TF ) is a core protein with an essential function in the coagulation cascade that maintains the homeostasis of the blood vessels . TF not only participates in neointima formation , but also causes the development of atherosclerosis . This study investigated the mechanism regulating TF expression in macrophages using Pam3 CSK4 , a O60603 ligand . Pam3 CSK4 induced TF expression in two types of macrophages ( Raw264.7 and BMDM ) , but not in O60603 KO mice derived BMDM . Pam3 CSK4 induced TF expression was inhibited by pretreatment with pan-JAK inhibitor or O60674 inhibitor AG490 . O60674 knock-down by siRNA inhibited Pam3 CSK4 induced TF expression . Pam3 CSK4 stimulated P40763 phosphorylation ( S727 ) , while P40763 knock-down by siRNA reduced Pam3 CSK4 induced TF expression . These results suggest that Pam3 CSK4 induced TF expression is regulated by the O60674 - P40763 signaling pathway . Pam3 CSK4 , unlike increased TF expression , significantly decreased P41220 expression , while P41220 overexpression decreased Pam3 CSK4 induced TF expression . Inhibition of TF by P41220 WT did not occur in mutants with flawed Q99697 domains . We also investigated the correlation between P41220 and P40763 phosphorylation . P41220 knock-down elevated Pam3 CSK4 induced P40763 phosphorylation , but P41220 overexpression had the opposite effect on P40763 phosphorylation . These results suggest that , while Pam3 CSK4 induced TF expression is regulated by O60674 - P40763 signaling , P41220 is a negative regulator targeted to P40763 . DB01356 inhibits glycogen synthase kinase-3 activity and mimics wingless signalling in intact cells . BACKGROUND : Exposing eukaryotic cells to lithium ions ( Li+ ) during development has marked effects on cell fate and organization . The phenotypic consequences of Li+ treatment on Xenopus embryos and sporulating Dictyostelium are similar to the effects of inhibition or disruption , respectively , of a highly conserved protein serine/threonine kinase , glycogen synthase kinase-3 ( GSK-3 ) . In Drosophila , the GSK-3 homologue is encoded by zw3sgg , a segment-polarity gene involved in embryogenesis that acts downstream of wg . In higher eukaryotes , GSK-3 has been implicated in signal transduction pathways downstream of phosphoinositide 3-kinase and mitogen-activated protein kinases . RESULTS : We investigated the effect of Li+ on the activity of the GSK-3 family . At physiological doses , Li+ inhibits the activity of human P49841 and Drosophila Zw3Sgg , but has no effect on other protein kinases . The effect of Li+ on GSK-3 is reversible in vitro . Treatment of cells with Li+ inhibits GSK-3-dependent phosphorylation of the microtubule-associated protein Tau . Li+ treatment of Drosophila S2 cells and rat PC12 cells induces accumulation of cytoplasmic Armadillo/beta-catenin , demonstrating that Li+ can mimic Wingless signalling in intact cells , consistent with its inhibition of GSK-3 . CONCLUSIONS : Li+ acts as a specific inhibitor of the GSK-3 family of protein kinases in vitro and in intact cells , and mimics Wingless signalling . This reveals a possible molecular mechanism of Li+ action on development and differentiation . Human platelet antigen genotype is associated with progression of fibrosis in chronic hepatitis C . Although progression of fibrosis in the chronic hepatitis C depends on environmental , viral , and host factors , genetic polymorphisms have been associated recently with this progression , including the expression of integrins , adhesion proteins . Some integrins expressed on the platelet membrane show polymorphic antigenic determinants called human platelet antigens ( Q9Y251 ) , where the major ones are Q9Y251 -1 , -3 , -5 . The association between HCV infection and Q9Y251 -5b has been demonstrated . Similarly , the Q9Y251 profile could determine if Q9Y251 is related to progression of fibrosis . The goal of this study was to evaluate the association between the frequencies of Q9Y251 -1 , -3 , and -5 and degree of fibrosis in HCV-infected patients . Genomic DNA from 143 HCV-infected patients was used as the source for Q9Y251 genotyping by PCR-SSP or PCR-RFLP . Progression of fibrosis was evaluated using the METAVIR scoring system , and the patients were grouped according to degree of fibrosis into P55008 ( n = 81 , with F1 , portal fibrosis without septa or F2 , few septa ) and G2 ( n = 62 , with P13726 , numerous septa , or F4 , cirrhosis ) . Statistical analysis was performed using the proportional odds model . The genotypic frequency of Q9Y251 -1a/1b was significantly higher in the patients in G2 . To evaluate the influence of the time of infection to the development of fibrosis and its effect on the genetic factor Q9Y251 -1 , 96 patients from 143 studied were evaluated considering the time of HCV infection , and these results suggest that the Q9Y251 -1a/1b genotype promotes the development of fibrosis in HCV infection with time . DB08875 ( DB05153 ) , a novel MET and P35968 inhibitor , simultaneously suppresses metastasis , angiogenesis , and tumor growth . The signaling pathway of the receptor tyrosine kinase MET and its ligand hepatocyte growth factor ( P14210 ) is important for cell growth , survival , and motility and is functionally linked to the signaling pathway of P15692 , which is widely recognized as a key effector in angiogenesis and cancer progression . Dysregulation of the MET/ P15692 axis is found in a number of human malignancies and has been associated with tumorigenesis . DB08875 ( DB05153 ) is a small-molecule kinase inhibitor with potent activity toward MET and P15692 receptor 2 ( P35968 ) , as well as a number of other receptor tyrosine kinases that have also been implicated in tumor pathobiology , including P07949 , P10721 , P30530 , and P36888 . Treatment with cabozantinib inhibited MET and P35968 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 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 . DB08875 ( DB05153 ) for the treatment of locally advanced or metastatic progressive medullary thyroid cancer . DB08875 ( DB05153 ) is an oral multiple receptor tyrosine kinase inhibitor manufactured by Exelixis Inc. , CA , USA . It mainly inhibits three tyrosine kinase receptors : MET , P35968 and P07949 . 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 is now evaluating its approval in Europe . DB08875 : a MET , P07949 , and P35968 tyrosine kinase inhibitor . DB08875 is a receptor tyrosine kinase inhibitor with activity against MET , P35968 , P36888 , c- P10721 , and P07949 . 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 ) , NSCLC , breast , ovarian , pancreatic , and prostate cancer . In P04629 , gain of function mutations of P07949 are central for tumorigenesis . Hereditary forms of P04629 ( MEN II ) are caused by germline mutations of P07949 , in sporadic P04629 in up to 50 % of cases P07949 mutations occur . Additionally , activating molecular changes in VEGFR and MET pathways have also been implicated in P04629 progression . Clinical responses with cabozantinib in P04629 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 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 . DB08875 and prostate cancer : inhibiting seed and disrupting soil ? Treatment with cabozantinib , an inhibitor of MET and P35968 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 . [ The role of matrix metalloproteinases and their inhibitors in pathogenesis of pancreatic pseudocysts ] . The investigation was conducted in 47 patients , operated on for pancreatic pseudocysts ( PP ) . Activity of matrix metalloproteinases ( P14780 ) and content of their tissue inhibitor ( P16035 ) were determined in the blood serum for estimation of inflammatory factors , hypoxia severity and state of the pancreatic tissue reconstruction . High activity of P14780 and P16035 in presence of PP types I and II was noted in patients , what , probably , is caused by compensation reaction , directed towards inhibition of the collagen system destruction ( predominantly of collagen type IV ) and prevention of further reconstruction of pancreatic connective tissue . While progressing of pancreatic fibrosis the P14780 activity and the P16035 level have lowered in comparison with these indices while its absence . In PP type III the P14780 activity was by 83.6 % higher , than in a control group , but , by 51.4 and 35.1 % lower , than in PP types I and IV . In all the patients endothelial dysfunction with endothelial injury was observed , witnessed by significant rising of the P15692 content in the blood serum . It have created favorable conditions for pancreatic tissue remodeling while parenchymal defect have been constituted by tissue , owing lower level of organization , including a cicatricial one . In cases of cellular repeated affection more activation of pancreatic stellate cells and enhancement of production of extracellular matrix component were noted . A phase I study of cabozantinib ( DB05153 ) in patients with differentiated thyroid cancer . BACKGROUND : DB08875 targets tyrosine kinases including MET , vascular endothelial growth factor ( P15692 ) receptor 2 , and rearranged during transfection ( P07949 ) . 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 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 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 . Raddeanin A , a triterpenoid saponin isolated from Anemone raddeana , suppresses the angiogenesis and growth of human colorectal tumor by inhibiting P35968 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 -induced phosphorylation of P35968 and its downstream protein kinases including PLCγ1 , O60674 , Q05397 , Src , and Akt . Molecular docking simulation indicated that RA formed hydrogen bonds and hydrophobic interactions within the DB00171 binding pocket of P35968 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 . Nongenomic , glucocorticoid receptor-mediated regulation of serotonin transporter cell surface expression in embryonic stem cell derived serotonergic neurons . Depressive disorders have been linked to the combined dysregulation of the hypothalamus-pituitary-adrenal ( Q9Y251 ) -axis and the serotonergic system . The Q9Y251 -axis and serotonergic ( 5-HT ) neurons exert reciprocal regulatory actions . It has been reported that glucocorticoid-glucocorticoid receptor ( GR ) signaling influences serotonin transporter ( 5-HTT ) transcription but data also points to the fact that 5-HTT expression is regulated nongenomically via redistribution of 5-HTT from the cell surface into intracellular compartments . In order to analyze the acute effects of glucocorticoids on 5-HTT cell surface localization we differentiated serotonergic neurons from mouse embryonic stem ( ES ) cells derived from the C57BL/6N blastocysts . These postmitotic 5-HT neurons express all relevant serotonergic markers following the application of a growth factor-based differentiation protocol . Increasing concentrations of the GR agonist dexamethasone ( DB00514 ) resulted in enhanced , dose-dependent 5-HTT cell surface localization in the presence of the protein synthesis inhibitor cycloheximide already 1h after incubation . Inhibition of GR function by the specific GR-antagonist mifepristone abolished the increase in 5-HTT cell surface localization . Hence , our data account for a nongenomic upregulation of 5-HTT cell surface expression by glucocorticoid-GR interaction which likely constitutes a rapid physiological response to increased levels of glucocorticoids as seen during stress . Taken together , we provide a cellular model to analyze and dissect glucocorticoid- P31645 interactions on a molecular level that corresponds to in vivo animal models using C57BL/6N mice . 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 ( 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 ( CRF1 ) agonist , or acidic-astressin a preferential CRF1 antagonist , into the mPFC in male CD-1 mice exposed to a live predator ( rat exposure test -- P07949 ) . Cortagine microinfusions significantly reduced several indices of defense , including avoidance and freezing , suggesting a specific role for CRF1 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 . 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 CRF1 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 CRF1 produces behavioral effects that contrast with those elicited following systemic administration of CRF1 agonists . The C-type lectin Q99685 expressed by dendritic cells detects glycan changes on P15941 in colon carcinoma . The epithelial mucin P15941 is a high molecular weight membrane glycoprotein frequently overexpressed and aberrantly glycosylated in adenocarcinoma . Mucins normally contain high amounts of O-linked carbohydrate structures that may influence immune reactions to this antigen . During malignant transformation , certain glyco-epitopes of P15941 , such as Tn-antigen , TF-antigen and their sialylated forms become exposed . The role of these glycan structures in tumor biology is unknown , but their presence is known to correlate with poor prognosis in several adenocarcinomas . We analyzed the potency of P15941 containing Tn-antigens ( P15941 -Tn ) to target C-type lectins that function as carbohydrate recognition and uptake molecules on dendritic cells ( DC ) . We identified the macrophage galactose type C-type lectin ( Q99685 ) , expressed by both DC and macrophages , as the receptor for recognition and binding of P15941 -Tn . To validate the occurrence of Q99685 - P15941 interactions in situ , we studied the binding of Q99685 to P15941 in primary colon carcinoma tissue . Isolation of P15941 out of colon carcinoma tissue showed strong binding activity to Q99685 . Interestingly , Q99685 binding to P15941 was highly correlated to binding by the lectin Helix pomatia agglutinin ( Q9Y251 ) , which is associated with poor prognosis in colorectal cancer . The detection of Q99685 positive cells in situ at the tumor site together with the modified glycosylation status of P15941 to target Q99685 on DC suggests that Q99685 positive antigen presenting cells may play a role in tumor progression . Q9Y251 and vascular endothelial growth factor expression in the progression of oral mucosal melanoma . Oral mucosal melanoma is an aggressive neoplasm with poor prognosis . Q9Y251 is an endo-beta-d-glucuronidase , which cleaves heparan sulphate chains . The vascular endothelial growth factor ( P15692 ) is the most potent angiogenic mitogen and interaction with its receptor ( VEGFR ) has been associated with angiogenesis . We investigated the expression of these molecules in the progression of oral mucosal melanoma . Immunohistochemistry was carried out in 15 oral melanotic macules and 19 oral melanomas using heparanase , P15692 , P35968 , P28906 and Ki-67 . Microvessel density was determined and subjected to statistical analysis . Q9Y251 and P35968 were not expressed in the oral melanotic macule . Atypical melanocytes and melanoma cells expressed heparanase , P15692 and P35968 . An intense expression was noted in the early invasive phase , which marks the crucial transition from in situ to the invasive phase . In the invasive component , heparanase was intense but selective in the invasive fronts and at the periphery of nests unlike the extensive expression of P15692 and P35968 . However , hot spots were only observed at the periphery of the nests . In conclusion , melanoma cells expressed heparanase , P15692 and P35968 . The coexpression of these molecules in atypical melanocytes and melanoma cells suggests their function in cell migration and invasion . Moreover , the intense expression in the crucial transition from in situ to the invasive phase suggests their role in the progression of the tumor . The role of P15692 and P35968 in angiogenesis was evident only at the periphery of the nests in the invasive components . DB08875 inhibits growth of androgen-sensitive and castration-resistant prostate cancer and affects bone remodeling . DB08875 is an inhibitor of multiple receptor tyrosine kinases , including MET and P35968 . 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 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 . Small in-frame deletion in the epidermal growth factor receptor as a target for DB05294 . DB05294 is an inhibitor of vascular endothelial growth factor receptor-2 ( P35968 / P35968 ) tyrosine kinase , with additional activity against epidermal growth factor receptor ( P00533 ) tyrosine kinase . DB05294 inhibits angiogenesis and growth of a wide range of tumor models in vivo . Gefitinib ( " DB00317 " ) is a selective P00533 tyrosine kinase inhibitor that blocks signal transduction pathways implicated in cancer cell proliferation . Here , the ability of gefitinib and DB05294 to inhibit tumor cell proliferation was examined directly in eight cancer cell lines in vitro , and a strong correlation was noted between the IC(50) values of gefitinib and DB05294 ( r = 0.79 ) . No correlation was observed between the sensitivity to DB05294 and the level of P00533 or VEGFR expression . The NSCLC cell line PC-9 was seen to be hypersensitive to gefitinib and DB05294 , and a small ( 15-bp ) in-frame deletion of an DB00171 -binding site ( exon 19 ) in the P00533 was detected ( delE746-A750-type deletion ) . To clarify the involvement of the deletional mutation of P00533 in the cellular sensitivity to DB05294 , we examined the effect of this agent on HEK293 stable transfectants expressing deletional P00533 that designed as the same deletion site observed in PC-9 cells ( 293-pDelta15 ) . These cells exhibited a 60-fold higher sensitivity to DB05294 compared with transfectants expressing wild-type P00533 . DB05294 inhibited the phosphorylation of the mutant P00533 by 10-fold compared with cells with wild-type P00533 . In conclusion , the findings suggested that a small in-frame deletion in the P00533 increased the cellular sensitivity to DB05294 . Feasibility of using molecular docking-based virtual screening for searching dual target kinase inhibitors . Multitarget agents have been extensively explored for solving limited efficacies , poor safety , and resistant profiles of an individual target . Theoretical approaches for searching and designing multitarget agents are critically useful . Here , the performance of molecular docking to search dual-target inhibitors for four kinase pairs ( P24941 - P49841 , P00533 -Src , Lck-Src , and Lck- P35968 ) was assessed . First , the representative structures for each kinase target were chosen by structural clustering of available crystal structures . Next , the performance of molecular docking to distinguish inhibitors from noninhibitors for each individual kinase target was evaluated . The results show that molecular docking-based virtual screening illustrates good capability to find known inhibitors for individual targets , but the prediction accuracy is structurally dependent . Finally , the performance of molecular docking to identify the dual-target kinase inhibitors for four kinase pairs was evaluated . The analyses show that molecular docking successfully filters out most noninhibitors and achieves promising performance for identifying dual-kinase inhibitors for P24941 - P49841 and Lck- P35968 . But a high false-positive rate leads to low enrichment of true dual-target inhibitors in the final list . This study suggests that molecular docking serves as a useful tool in searching inhibitors against dual or even multiple kinase targets , but integration with other virtual screening tools is necessary for achieving better predictions . P00797 inhibition with aliskiren . 1. Initial attempts to inhibit renin in humans have faced numerous difficulties . Molecular modelling and X-ray crystallography of the active site of renin have led to the development of new orally active renin inhibitors , such as aliskiren . 2 . DB09026 has a low bioavailability ( between 2.6 and 5.0 % ) compensated by its high potency to inhibit renin ( IC50 : 0.6 nmol/L ) and a long plasma half-life ( 23-36 h ) , which makes it suitable for once-daily dosing . 3 . The once-daily administration of aliskiren to hypertensive patients lowers BP as strongly as standard doses of established angiotensin II type 1 ( AT1 ) receptor blockers ( losartan , valsartan , irbesartan ) , hydrochlorothiazide , angiotensin converting enzyme inhibitors ( ramipril and lisinopril ) or long acting calcium channel blockers ( amlodipine ) . In combination therapy , aliskiren further decreases blood pressure when combined with either hydrochlorothiazide , amlodipine , irbesartan or ramipril . 4 . The biochemical consequences of renin inhibition differ from those of angiotensin I-converting enzyme ( P12821 ) inhibition and Ang II antagonism , particularly in terms of angiotensin profiles and interactions with the bradykinin-nitric oxide-cyclic guanosine monophosphate pathway and possibly the (pro)renin receptor . 5 . Blockade of the renin angiotensin system ( DB01367 ) with P12821 inhibitors , AT1 receptor blockers or a combination of these drugs has become one of the most successful therapeutic approaches in medicine . However , it remains unclear how to optimize DB01367 blockade to maximize cardiovascular and renal benefits . In this context , renin inhibition to render the DB01367 fully quiescent is a new possibility requiring further study . Synaptic and photoreceptor components in retinal pigment epithelial cell transplanted retinas of Royal College of Surgeons dystrophic rats . Plexiform layer synaptic and photoreceptor cell components were investigated in retinas of Royal College of Surgeons ( RCS ) dystrophic rats transplanted with normal retinal pigment epithelial ( Q96AT9 ) cells by immunocytochemistry using previously characterized monoclonal antibodies . In retinas of normal adult rats and Q96AT9 -cell transplanted retinas of 4 month-old RCS rats , HNK-1 , a marker for a carbohydrate of the neural cell adhesion molecule ( N- P62158 ) , was detected immunocytochemically in the inner and outer plexiform layers and ganglion cell bodies and their axons . HNK-1 was also detected in the inner plexiform layer of nontreated retinas of 4 month-old RCS rats , but was reduced to scattered patches in the outer plexiform layer . In addition , immunoreactivity for the SVP-38 antibody recognizing synaptophysin was found in both plexiform layers of normal adult rat retinas and Q96AT9 -transplanted retinas of 4 month-old RCS rats . Furthermore , photoreceptor cell bodies and their inner and outer segments were immunostained for the opsin monoclonal antibody P07949 -P1 in retinas of normal adult rats and Q96AT9 -cell transplanted retinas of 4 month-old RCS rats . However , in nontreated retinas of 4-month-old RCS rats , only immunostained debris material was detected . These results strongly suggest that normal Q96AT9 transplants not only rescue photoreceptor cells in RCS rats , but also maintain an essential functional capacity , in this case , synaptic components in the plexiform layers . DB08875 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 - P08922 -transformed Ba/ P13726 cells to multiple Q9UM73 inhibitors was examined . Acquired P08922 inhibitor-resistant mutations in P04233 - P08922 fusion were screened by N-ethyl-N-nitrosourea mutagenesis with Ba/ P13726 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 - P08922 -mutant Ba/ P13726 cells and crizotinib-resistant patient-derived cancer cells ( MGH047 ) harboring G2032R-mutated P04233 - 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 /VEGFR inhibitor cabozantinib ( DB05153 ) effectively inhibited the survival of P04233 - P08922 wild-type ( WT ) and resistant mutants harboring Ba/ P13726 and MGH047 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 . Implantation of P15692 transfected preadipocytes improves vascularization of fibrin implants on the cylinder chorioallantoic membrane ( P62158 ) model . The successful substitution or augmentation of soft tissues by implantation of three dimensional cell constructs , consisting of human preadipocytes and fibrin glue as a carrier matrix , requires a rapid and homogeneous vascularization of the whole implant in order to provide a sufficient blood supply of centrally situated cells . Previous investigations have shown that under in vivo conditions primary human preadipocytes induce vascularization of fibrin matrices by secretion of several growth factors , such as P15692 and P09038 . The current study investigates whether vascularization of implants can be improved by transplantation of preadipocytes following transfection with a P15692 -vector . Transfection was performed by electroporation with an pCMX-GFP and pCMX-VEGF165 vector . Transfection efficiency ( GFP expression ) and P15692 expression were determined in vitro by FACS analysis and P15692 immunoassay , respectively . In vivo investigations to determine the vascularization of the implants were performed on the cylinder chorioallantoic membrane ( P62158 ) . Four million P15692 transfected cells were transferred within a fibrin matrix onto the P62158 on the 7(th) day of incubation and after 8 days the vascularization of the implant was histologically examined and evaluated by means of a computer-assisted image analysis program . Transfection of preadipocytes with the GFP vector by electroporation yielded transfection efficiencies between 12 % and 41 % of surviving cells . Results of the P15692 immunoassay demonstrated that P15692 expression was significantly higher following transfection . Investigations on the P62158 outlined a significantly higher rate of vascularization in the transfected vs. control population . Our investigations demonstrate that primary human preadipocytes can be successfully transfected by electroporation with a P15692 vector . The enhanced P15692 expression on transfected cells results in an increase of vascularization of the cell constructs on the P62158 . Novel withanolides target medullary thyroid cancer through inhibition of both P07949 phosphorylation and the mammalian target of rapamycin pathway . BACKGROUND : Despite development of current targeted therapies for medullary thyroid cancer ( P04629 ) , long-term survival remains unchanged . Recently isolated novel withanolide compounds from Solanaceae physalis are highly potent against MTCs . We hypothesize that these withanolides uniquely inhibit P07949 phosphorylation and the mammalian target of rapamycin ( P42345 ) pathway in P04629 cells as a mechanism of antiproliferation and apoptosis . METHODS : P04629 cells were treated with novel withanolides and P04629 -targeted drugs . In vitro studies assessed cell viability and proliferation ( MTS ; trypan blue assays ) , apoptosis ( flow cytometry with P08758 /PI staining ; confirmed by Western blot analysis ) , long-term cytotoxic effects ( clonogenic assay ) , and suppression of key regulatory proteins such as P07949 , Akt , and P42345 ( by Western blot analysis ) . RESULTS : The novel withanolides potently reduced P04629 cell viability ( half maximal inhibitory concentration [ IC(50) ] , 270-2,850 nmol/L ; 250-1,380 nmol/L for vandetanib ; 360-1,640 nmol/L for cabozantinib ) with induction of apoptosis at < 1,000 nmol/L of drug . Unique from other targeted therapies , withanolides suppressed P07949 and Akt phosphorylation and protein expression ( in a concentration- and time-dependent manner ) as well as P42345 activity and translational activity of Q13541 and protein synthesis mediated by p70S6kinase activation at IC(50) concentrations . CONCLUSION : Novel withanolides from Physalis selectively and potently inhibit P04629 cells in vitro . Unlike other P04629 -targeted therapies , these compounds uniquely inhibit both P07949 kinase activity and the Akt/ P42345 prosurvival pathway . Further translational studies are warranted to evaluate their clinical potential . P10145 and P14902 expression by human gingival fibroblasts via TLRs . Human gingival fibroblasts ( HGFs ) , a predominant cell type in tooth-supporting structure , are presently recognized for their active role in the innate immune response . They produce a variety of inflammatory cytokines in response to microbial components such as LPS from the key periodontal pathogen , Porphyromonas gingivalis . In this study , we demonstrated that HGFs expressed mRNA of TLRs 1 , 2 , 3 , 4 , 5 , 6 , and 9 , but not TLRs 7 , 8 , and 10 . Stimulation of HGFs with highly purified O60603 ligand ( P. gingivalis LPS ) , O15455 ligand ( poly(I:C) ) , O00206 ligand ( Escherichia coli LPS ) , and O60602 ligand ( Salmonella typhimurium flagellin ) led to expression of P10145 and P14902 . A potent TLR 9 ligand , CpG oligodeoxynucleotide 2006 had no effect , although HGFs showed a detectable Q9NR96 mRNA expression . No significant enhancement on P10145 or P14902 expression was observed when HGFs were stimulated with various combinations of TLR ligands . Surprisingly , the Q9NR96 ligand CpG oligodeoxynucleotide 2006 was able to specifically inhibit poly(I:C)-induced P10145 and P14902 expression . P01375 enhanced TLR ligand-induced P10145 production in HGFs , whereas P01579 enhanced TLR ligand-induced P14902 expression . P14210 production of P14902 in response to P. gingivalis LPS , P01579 , or the two in combination inhibited T cell proliferation in MLRs . The observed T cell inhibition could be reversed by addition of either 1-methyl-dl-tryptophan or l-tryptophan . Our results suggest an important role of HGFs not only in orchestrating the innate immune response , but also in dampening potentially harmful hyperactive inflammation in periodontal tissue . [ Serotonin transporter gene and stress reactivity in unipolar depression. Role of the Q9Y251 system as endophenotype of the P31645 gene ] . BACKGROUND : A length polymorphism in the promoter region of the serotonin transporter gene ( 5-HTTLPR ) is associated with both depression and hypothalamic-pituitary-adrenal ( Q9Y251 ) system activity . A dysregulation of the Q9Y251 system is considered to be a candidate endophenotype of depression . The objective of the present study was an investigation of a possible gene-endophenotype-interaction between 5-HTTLPR and Q9Y251 system activity in a sample of inpatients with major depression . MATERIALS AND METHODS : A total of 237 inpatients with major depression were genotyped for 5-HTTLPR and participated in a combined dexamethasone-corticotropin-releasing hormone test ( DB00514 - P06850 test ) as well as using the Hamilton score ( Hamilton rating scale for depression ) to determine the severity of the psychopathology . RESULTS : Patients with the ss-genotype showed a significantly higher Q9Y251 -system activity in comparison to patients with the lI-genotype , but no association between 5-HTTLPR and the severity of psychopathology could be detected . CONCLUSIONS : The results of the current study demonstrate an influence of 5-HTTLPR on dysregulation of the Q9Y251 system in patients with major depression and support the hypothesis that 5-HTTLPR- and Q9Y251 -system-interaction constitutes an important component in the pathogenesis of depression . Q9Y251 -mediated loss of nuclear syndecan-1 enhances histone acetyltransferase ( O60235 ) activity to promote expression of genes that drive an aggressive tumor phenotype . Q9Y251 acts as a master regulator of the aggressive tumor phenotype in part by enhancing expression of proteins known to drive tumor progression ( e.g. P15692 , P14780 , hepatocyte growth factor ( P14210 ) , and O14788 ) . However , the mechanism whereby this enzyme regulates gene expression remains unknown . We previously reported that elevation of heparanase levels in myeloma cells causes a dramatic reduction in the amount of syndecan-1 in the nucleus . Because syndecan-1 has heparan sulfate chains and because exogenous heparan sulfate has been shown to inhibit the activity of histone acetyltransferase ( O60235 ) enzymes in vitro , we hypothesized that the reduction in nuclear syndecan-1 in cells expressing high levels of heparanase would result in increased O60235 activity leading to stimulation of protein transcription . We found that myeloma cells or tumors expressing high levels of heparanase and low levels of nuclear syndecan-1 had significantly higher levels of O60235 activity when compared with cells or tumors expressing low levels of heparanase . High levels of O60235 activity in heparanase-high cells were blocked by SST0001 , an inhibitor of heparanase . Restoration of high syndecan-1 levels in heparanase-high cells diminished nuclear O60235 activity , establishing syndecan-1 as a potent inhibitor of O60235 . Exposure of heparanase-high cells to anacardic acid , an inhibitor of O60235 activity , significantly suppressed their expression of P15692 and P14780 , two genes known to be up-regulated following elevation of heparanase . These results reveal a novel mechanistic pathway driven by heparanase expression , which leads to decreased nuclear syndecan-1 , increased O60235 activity , and up-regulation of transcription of multiple genes that drive an aggressive tumor phenotype . P10275 expression in C-cells and in medullary thyroid carcinoma . Recent studies have shown a higher incidence of C-cell hyperplasia ( CCH ) in men compared with women in postmortem thyroid tissues . We postulated that the expression of androgen receptor ( AR ) protein may , in part , explain the differences . To test this hypothesis , we examined thyroid tissue from 27 consecutive autopsy cases for the presence of CCH ( defined as > 50 C-cells/x100 magnification in three fields ) and for AR expression in autopsy cases and in 43 medullary thyroid carcinomas ( MTCs ) from patients with sporadic and familial disease as well as two multiple endocrine neoplasia type 2A patients with only CCH . CCH was present in 8 of 20 males ( 40 % ) and in 1 of 7 females ( 14 % ) at autopsy . AR protein was detected in most surgically resected thyroids with P04629 and CCH ( 80 % ) , but in only 25 % of autopsy thyroids , probably reflecting postmortem degradation of the receptor protein . Reverse transcriptase polymerase chain reaction confirmed the presence of AR mRNA in P04629 and in papillary thyroid carcinomas . These results support the observation that CCH is more common in postmortem thyroids of males and suggest that the presence of AR with higher circulating levels of androgens may contribute to the higher incidence of CCH in men . DB08875 : a review of its use in patients with medullary thyroid cancer . DB08875 ( Cometriq(®) ) is an orally administered small molecule inhibitor of multiple tyrosine kinase receptors , including those involved in the pathogenesis of medullary thyroid cancer ( P04629 ) [ i.e. rearranged during transfection ( P07949 ) , MET and vascular endothelial growth factor receptor ( VEGFR ) -2 ] . DB08875 is indicated for the treatment of adults with progressive , unresectable locally advanced ( in the EU ) or metastatic ( in the EU and USA ) P04629 . 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 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 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 . Adjuvant effects of formalin-inactivated HSV through activation of dendritic cells and inactivation of myeloid-derived suppressor cells in cancer immunotherapy . Use of adequate adjuvant is necessary for induction of effective antitumor immune responses . To develop an effective adjuvant for cancer immunotherapy , we selected formalin-inactivated (f)-HSV as an adjuvant component , and analyzed the mechanisms underlying its adjuvant effects . First , we found that f-HSV can induce the tumor antigen-specific CTLs by enhancing antigen cross-presentation by dendritic cells ( DCs ) , mainly through O60603 , but not Q9NR96 . Next , f-HSV was also found to prevent the accumulation of myeloid-derived suppressor cells ( MDSCs ) . We demonstrated that the expansion of MDSCs in the blood and spleen during tumor progression required B cells producing the inflammatory angiogenesis factors , vascular endothelial growth factor ( P15692 ) -A and neuropilin-1 ( NRP-1 ) , a co-receptor for P15692 receptor-2 ( P35968 ) . Interestingly , the transmembrane-type NRP-1 on B cells changed to soluble-type NRP-1 ( sNRP-1 ) by f-HSV treatment . We further showed that the sNRP-1 and P15692 secreted from B cells by f-HSV treatment could abrogate the immunosuppressive ability of MDSCs . These results suggest that f-HSV can enhance antitumor immune responses as an adjuvant , not only through activation of DCs , but also inactivation of MDSCs via B cells . No significant association between genetic variants in 7 candidate genes and response to methylphenidate treatment in adult patients with ADHD . Results from pharmacogenetic investigations of methylphenidate ( DB00422 ) response in patients with ADHD are still inconsistent , especially among adults . This study investigates the role of genetic variants ( P31645 , P28222 , Q8IWU9 , P09172 , P21917 , P21964 , and P60880 ) in the response to DB00422 in a sample of 164 adults . Genes were chosen owing to previous evidence for an influence in ADHD susceptibility . No significant differences in allele or genotype frequencies between DB00422 responders and nonresponders were detected . In conclusion , our findings do not support an effect of these genes in the pharmacogenetics of DB00422 among adults with ADHD .