MH_dev_329

Immunohistochemical analysis of carcinomatous and sarcomatous components in the uterine carcinosarcoma : a case report . Uterine carcinosarcoma ( malignant mixed Mullerian tumor ) is an uncommon female genital tract neoplasm characterized by an admixture of epithelial and stromal malignant cells . We report a case of 50 - year-old peri-menopausal woman diagnosed to have early-stage ( IB due to FIGO ) uterine carcinosarcoma of the homologous type with superficial ( 3mm ) myo-invasion . The patient showed no clinical symptoms of the disease and had no family history of female genital tract malignancies . Positive immunostaining for steroid receptors ( estrogen-alpha and progesterone receptors ) , cytokeratin , and P00533 REA was detected only in the carcinomatous area , whereas beta-catenin , BCL - 2 , P35354 REA , p16 ( INK 4a ) , P60484 REA , Q8IUH3 , and vimentin were immunoreactive in both components . P10275 REA , CD10 , desmin , HER - 2 / neu , and P04637 REA were found to be negative either in the carcinomatous or in the sarcomatous area . Tumor proliferative activity was higher in the carcinomatous ( 25 % ) than in the sarcomatous ( 2 % ) component . Based on these findings , immunohistochemical evaluation of multiple receptor status in the carcinomatous and sarcomatous areas of carcinosarcoma may provide a clue to the pathogenesis and hormonal receptor status of this uncommon uterine malignancy .

P10275 REA 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 SUB , 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 .

Immune responses to murine monoclonal antibody - DB04964 MEN correlate with prolonged survival of women with recurrent ovarian cancer . OBJECTIVE : We evaluated the therapeutic efficiency of the murine monoclonal antibody - DB04964 MEN in the treatment of patients with recurrent ovarian cancer . STUDY DESIGN : This was a retrospective study of immune responses and survival in 44 patients who were treated with technetium 99m - labeled monoclonal antibody - DB04964 MEN , a murine monoclonal antibody that is directed against the tumor-associated antigen Q8WXI7 . Most patients were pretreated heavily . Biologic activity was quantified by the assay of immune responses to the human anti-murine antibodies against the monoclonal antibody - DB04964 MEN variable region ( Ab ( 2 ) ) and antibodies that target the CA 125 antigen itself ( anti-CA 125 antibody ) . RESULTS : More than one half of patients ( 56.8 % ) survived for > 12 months after the first dose of monoclonal antibody DB04964 MEN ; 34.1 % of the patients survived > 24 months . To date , 6 of the 44 patients are alive , with survival times of 4 to 7.5 years after the start of the antibody treatment . More than 60 % of the evaluable patients met predefined criteria for robust , treatment-emergent human anti-murine antibodies and Ab ( 2 ) responses , and these responses were associated with improved survival rates . Median survival time increased approximately 3 - fold for human anti-murine antibody responders ( 22.6 months ) versus nonresponders ( 7.2 months ; P < . 0016 , log-rank test ) and 2 - fold for Ab ( 2 ) responders ( 18.3 months ) versus nonresponders ( 9.3 months ) . No serious drug-associated adverse events were reported . CONCLUSION : The associations between multiple types of immune response and improved clinical outcomes suggest that monoclonal antibody - DB04964 MEN should be further evaluated for potential use as an immunotherapy for Q8WXI7 - expressing malignancies .

A genetically defined model for human ovarian cancer . Disruptions of the p53 , retinoblastoma ( P06400 REA ) , and DB01367 signaling pathways and activation of human telomerase reverse transcriptase ( hTERT ) are common in human ovarian cancer ; however , their precise role in ovarian cancer development is not clear . We thus introduced the catalytic subunit of hTERT , the SV40 early genomic region , and the oncogenic alleles of human P01112 REA or P01116 REA into human ovarian surface epithelial cells and examined the phenotype and gene expression profile of those cells . Disruption of p53 and P06400 REA pathway by SV40 early genomic region and hTERT immortalized but did not transform the cells . Introduction of P01112 REA ( V12 ) or P01116 REA ( V12 ) into the immortalized cells , however , allowed them to form s . c . tumors after injection into immunocompromised mice . Peritoneal injection of the transformed cells produced undifferentiated carcinoma or malignant mixed Mullerian tumor and developed ascites ; the tumor cells are focally positive for Q8WXI7 and mesothelin . Gene expression profile analysis of transformed cells revealed elevated expression of several cytokines , including interleukin ( IL ) - 1beta , P05231 REA , and P10145 REA , that are up-regulated by the nuclear factor-kappaB pathway , which is known to contribute to the tumor growth of naturally ovarian cancer cells . Incubation with antibodies to IL - 1beta or P10145 REA led to apoptosis in the ras-transformed cells and ovarian cancer cells but not in immortalized cells that had not been transformed . Thus , the transformed human ovarian surface epithelial cells recapitulated many features of natural ovarian cancer including a subtype of ovarian cancer histology , formation of ascites , Q8WXI7 expression , and nuclear factor-kappaB-mediated cytokine activation . These cells provide a novel model system to study human ovarian cancer .

DB01283 MEN ( DB01283 MEN ) : a new selective P35354 REA inhibitor . DB01283 MEN , a new selective P35354 REA inhibitor , has been recently approved in England and Mexico for the treatment of acute and chronic pain . Although it is the fifth P35354 REA inhibitor to come to the market , it has a unique structure that could prove to be important in the adverse event profile . Double blind randomised trials have proved its efficacy in acute pain , dysmenorrhea , rheumatoid arthritis and osteoarthritis . Its gastrointestinal safety profile has been studied in multiple trials . The main clinical trail , therapeutic arthritis research and gastrointestinal event trial , has as primary end point : perforations , obstructions and bleeding and as secondary end points : cardiovascular , renal and hepatic safety profile . The results of this trial will probably change the way we look at selective P35354 REA inhibitors .

Role of the androgen receptor axis in prostate cancer . P10275 REA ( AR ) is expressed in nearly all prostate cancers , including treatment-refractory disease . The role of this receptor in the molecular endocrinology of prostate cancer has become increasingly clear in recent years . The AR is now known to participate in tumor progression through 3 mechanisms : expression ( activation and upregulation of receptor activity ) , point mutations , and ligand-independent activation . With regard to the latter mechanism , interleukin - 6 ( P05231 REA ) is among the most important nonsteroidal regulators of AR activity . In the absence of androgen , P05231 REA causes activation of AR that is approximately 50 % of the maximal activity induced by androgen . At low concentrations of androgen , P05231 REA and androgen synergistically activate AR . Nonsteroidal antiandrogens usually antagonize this activation , but they switch to an agonist effect in the presence of oncostatin M , an P05231 REA - related cytokine . The growth of parental LNCaP cells is initially inhibited by exposure to P05231 REA , but long-term treatment renders the cells resistant to such inhibition and confers a growth advantage . Both P05231 REA and oncostatin M stimulate AR activity , but only oncostatin M is associated with strong acquisition of the agonist properties of nonsteroidal antiandrogens . It is hoped that continuing research on AR expression and function in prostate cancer will pave the way for new therapeutic strategies .

The thienopyridine derivatives ( platelet adenosine diphosphate receptor antagonists ) , pharmacology and clinical developments . The thienopyridines , ticlopidine and clopidogrel , are antiplatelet drugs . They are prodrugs and are metabolised in the liver to active metabolites that are non-competitive antagonists of the platelet adenosine diphosphate receptor , Q9H244 REA . Inhibition of platelet aggregation by these drugs is delayed until 24-48 h after administration , with maximal inhibition achieved after 3-5 days . Recovery of platelet function after drug withdrawal is slow ( 7-14 days ) . DB00208 MEN and clopidogrel are effective in preventing atherothrombotic events in cardiovascular , cerebrovascular and peripheral vascular disease . Gastrointestinal side effects and skin rashes are common . However , neutropenia and thrombotic thrombocytopenic purpura are significant and sometimes fatal adverse effects of ticlopidine . DB00758 appears to offer several advantages over ticlopidine : a more rapid onset of action and a lower incidence of neutropenia and thrombotic thrombocytopenic purpura . A combination of clopidogrel and aspirin has become standard for antithrombotic therapy in cardiovascular disease . The anaesthetic considerations of patients taking the thienopyridine compounds are discussed .

Inhibition of tumor cell growth , invasion , and metastasis by EXEL - 2880 ( DB05030 MEN , GSK 1363089 ) , a novel inhibitor of P14210 REA and P15692 REA receptor tyrosine kinases . The DB00134 receptor tyrosine kinase and its ligand , hepatocyte growth factor ( P14210 REA ) , are overexpressed and / or activated in a wide variety of human malignancies . Vascular endothelial growth factor ( P15692 REA ) receptors are expressed on the surface of vascular endothelial cells and cooperate with DB00134 to induce tumor invasion and vascularization . EXEL - 2880 ( DB05030 MEN , GSK 1363089 ) is a small-molecule kinase inhibitor that targets members of the P14210 REA and P15692 REA receptor tyrosine kinase families , with additional inhibitory activity toward P10721 REA , Flt - 3 , platelet-derived growth factor receptor beta , and Tie - 2 . Binding of EXEL - 2880 to DB00134 and P15692 REA receptor 2 ( P35968 REA ) is characterized by a very slow off-rate , consistent with X-ray crystallographic data showing that the inhibitor is deeply bound in the DB00134 kinase active site cleft . EXEL - 2880 inhibits cellular P14210 REA - induced DB00134 phosphorylation and P15692 REA - induced extracellular signal-regulated kinase phosphorylation and prevents both P14210 REA - induced responses of tumor cells and P14210 REA / P15692 REA - induced responses of endothelial cells . In addition , EXEL - 2880 prevents anchorage-independent proliferation of tumor cells under both normoxic and hypoxic conditions . In vivo , these effects produce significant dose-dependent inhibition of tumor burden in an experimental model of lung metastasis . Collectively , these data indicate that EXEL - 2880 may prevent tumor growth through a direct effect on tumor cell proliferation and by inhibition of invasion and angiogenesis mediated by P14210 REA and P15692 REA receptors .

Mixed adenoneuroendocrine carcinomas of the gastrointestinal tract : targeted next-generation sequencing suggests a monoclonal origin of the two components . BACKGROUND : Mixed adenoneuroendocrine carcinomas ( MANECs ) of the gastrointestinal tract are rare neoplasms characterized by coexisting exocrine and neuroendocrine neoplastic components . MANECs ' histogenetic classification and molecular characterization remain unclear , significantly affecting the identification of innovative therapeutic options for these tumors . METHODS : The exocrine and neuroendocrine components of 6 gastrointestinal MANECs were microdissected and subjected to the simultaneous mutation assessment in selected regions of 54 cancer-associated genes using Ion Torrent semiconductor-based next-generation sequencing . Sanger sequencing and immunohistochemistry were used as validation of the mutational status . RESULTS : A total of 20 driver gene somatic mutations were observed among the 12 neoplastic components investigated . In 11 of 12 ( 91.7 % ) samples , at least one mutation was detected ; 7 samples ( 58.3 % ) were found to have multiple mutations . P04637 REA gene mutations were the most frequent genetic alterations observed in the series , occurring in 11/12 samples ( 91.7 % ) . Somatic mutations in other genes were detected at lower frequencies : Q13315 REA , P35222 REA , Q15303 REA , P52333 REA , P35968 REA , P01116 REA , P06400 REA . CONCLUSIONS : Five of the 6 MANECs presented an overlapping mutational profile in both components , suggesting a monoclonal origin of the two MANEC components .

DB00624 stimulates proliferation and inhibits interleukin - 6 production of normal and hereditary gingival fibromatosis fibroblasts . Hereditary gingival fibromatosis ( P14210 REA ) is a rare oral condition characterized by a slow and progressive enlargement of the gingiva , involving both the maxilla and mandible . In vitro , P14210 REA fibroblasts demonstrate a proliferative index significantly higher than fibroblasts from normal gingiva ( NG ) . The objective of this study was to determine the effect of dihydrotestosterone on the proliferation of gingival fibroblasts derived from patients with P14210 REA ( n = 4 ) and from four healthy individuals . Additionally , we analyzed the effect of dihydrotestosterone on interleukin - 6 ( P05231 REA ) production and determined the expression levels of androgen receptors in NG and P14210 REA fibroblasts . Gingival fibroblasts from NG and P14210 REA were incubated with increasing concentrations of dihydrotestosterone with or without androgen blockers , and cultured for 24 h , and the proliferation index was determined by automated cell counter . P05231 REA production , in this system , was quantified using a " capture " enzyme-linked immunosorbent assay ( ELISA ) . Semi-quantitative reverse transcriptase-polymerase chain reaction ( RT-PCR ) was performed to measure the mRNA expression of androgen receptors . The results indicated that dihydrotestosterone simultaneously downregulates the production of P05231 REA and upregulates the cell proliferation . DB01216 and cyprosterone acetate , two anti-androgens , partially reversed these effects . P10275 REA mRNA expression was identified in both NG and P14210 REA fibroblasts ; however , the levels in NG were higher than those observed in P14210 REA . These results show that testosterone coordinates the proliferation and production of P05231 REA of normal and P14210 REA fibroblasts .

Identification of novel genetic alterations in samples of malignant glioma patients . Glioblastoma is the most frequent and malignant human brain tumor . High level of genomic instability detected in glioma cells implies that numerous genetic alterations accumulate during glioma pathogenesis . We investigated alterations in AP-PCR DNA profiles of 30 glioma patients , and detected specific changes in 11 genes not previously associated with this disease : Q86UP9 , Q13326 , Q13639 REA , P05556 REA , P31327 REA , P07225 REA , P55259 REA , Q9UJ96 , Q08499 REA , Q8N743 , and Q14642 REA . Further correlations revealed that 8 genes might play important role in pathogenesis of glial tumors , while changes in P55259 REA , Q9UJ96 and Q8N743 should be considered as passenger mutations , consequence of high level of genomic instability . Identified genes have a significant role in signal transduction or cell adhesion , which are important processes for cancer development and progression . According to our results , Q86UP9 might be characteristic of primary glioblastoma , Q13326 , Q13639 REA , P05556 REA , P31327 REA , P07225 REA and Q14642 REA were detected predominantly in anaplastic astrocytoma , suggesting their role in progression of secondary glioblastoma , while alterations of Q08499 REA seem to have important role in development of both glioblastoma subtypes . Some of the identified genes showed significant association with p53 , p16 , and P00533 REA , but there was no significant correlation between loss of P60484 REA and any of identified genes . In conclusion our study revealed genetic alterations that were not previously associated with glioma pathogenesis and could be potentially used as molecular markers of different glioblastoma subtypes .

Monoclonal antibodies targeting P01584 REA reduce biomarkers of atherosclerosis in vitro and inhibit atherosclerotic plaque formation in P02649 REA - deficient mice . OBJECTIVE : Atherosclerosis is a condition that is increasingly contributing to worldwide mortality through complications such as stroke and myocardial infarction . IL - 1β plays multiple direct , local roles in the formation and stability of the atheroma by eliciting the production of additional cytokines and proteolytic enzymes from macrophages , endothelial cells ( EC ) and smooth muscle cells ( SMC ) . We therefore tested whether an anti-IL - 1β antibody , DB06062 MEN , might inhibit the secretion of pro-atherogenic cytokines from macrophages in vitro and affect a positive outcome in the P02649 REA - deficient mouse ( ApoE ( - / - ) ) model of atherosclerosis in vivo . METHODS AND RESULTS : In an in vitro co-culture model , DB06062 MEN inhibited macrophage-induced secretion of key atherogenic cytokines from EC and SMC , including P05231 REA , P10145 REA , P13500 REA and TNFα . The release of degradative enzymes , such as the matrix metalloproteinases P08254 REA and P14780 REA , was also decreased by DB06062 MEN . In addition , DB06062 MEN inhibited the secretion of P13232 REA from EC and P05112 REA from SMC , cytokines not previously reported to be driven by IL - 1β in this context . In vivo , XMA 052 MG1K , a chimeric murine version of DB06062 MEN , inhibited the formation of atherosclerotic lesions in the ApoE ( - / - ) model at all three doses tested . This effect was comparable to that reported for complete genetic ablation of IL - 1β or IL - 1R1 on an ApoE ( - / - ) background and was associated with decreases in plasma non-HDL / HDL cholesterol ratio and plaque lipid content and macrophage infiltration . CONCLUSIONS : These results demonstrate for the first time that an antibody targeting IL - 1β can inhibit the progression of atherosclerosis in vivo , highlighting the importance of this key cytokine in cardiovascular disease .

Q9UEF7 gene deficiency causes salt-sensitive hypertension via monocyte chemotactic protein - 1 / CC chemokine receptor 2 - mediated inflammation . Q9UEF7 ( KL ) is a newly discovered aging suppressor gene . In mice , the KL gene extends the lifespan when overexpressed and shortens the lifespan when disrupted . This study investigated if KL deficiency affects BP and salt sensitivity using KL mutant heterozygous ( + / - ) mice and wild-type ( WT ) mice ( 9 weeks of age , 16 mice per group ) . Notably , systolic BP in KL ( + / - ) mice began to increase at the age of 15 weeks , reached a peak level at the age of 17 weeks , and remained elevated thereafter , whereas systolic BP remained consistent in WT mice . High salt ( HS ) intake further increased BP in KL ( + / - ) mice but did not affect BP in WT mice . Blockade of CC chemokine receptor 2 ( P41597 REA ) , involved in monocyte chemotaxis , by a specific P41597 REA antagonist ( DB05130 MEN ) abolished the HS-induced increase in BP in KL ( + / - ) mice . Furthermore , HS loading substantially increased the expression of monocyte chemotactic protein - 1 and the infiltration of macrophages and T cells in kidneys in KL ( + / - ) mice , and treatment with DB05130 MEN abolished these effects . Treatment of KL ( + / - ) mice with DB05130 MEN also attenuated the increased renal expressions of serum glucocorticoid-regulated kinase 1 , thiazide-sensitive NaCl cotransporter , and DB00171 synthase β along with the renal structural damage and functional impairment induced by HS loading . In conclusion , KL deficiency caused salt-sensitive hypertension and renal damage by P41597 REA - mediated inflammation .

Intraprotein electron transfer in a two-domain construct of neuronal nitric oxide synthase : the output state in nitric oxide formation . Intersubunit intraprotein electron transfer ( IET ) from flavin mononucleotide ( Q68DA7 ) to heme is essential in nitric oxide ( NO ) synthesis by NO synthase ( NOS ) . Previous crystal structures and functional studies primarily concerned an enzyme conformation , which serves as the input state for reduction of Q68DA7 by electrons from NADPH and flavin adenine dinucleotide ( DB03147 MEN ) in the reductase domain . To favor the formation of the output state for the subsequent IET from Q68DA7 to heme in the oxygenase domain , a novel truncated two-domain oxyFMN construct of rat neuronal NOS ( P29475 REA ) , in which only the Q68DA7 and heme domains were present , was designed and expressed . The kinetics of IET between the Q68DA7 and heme domains in the P29475 REA oxyFMN construct in the presence and absence of added calmodulin ( P62158 ) were directly determined using laser flash photolysis of CO dissociation in comparative studies on partially reduced oxyFMN and single-domain heme oxygenase constructs . The IET rate constant in the presence of P62158 ( 262 s ( - ) ( 1 ) ) was increased approximately 10 - fold compared to that in the absence of P62158 ( 22 s ( - ) ( 1 ) ) . The effect of P62158 on interdomain interactions was further evidenced by electron paramagnetic resonance ( EPR ) spectra . This work provides the first direct evidence of the P62158 control of electron transfer ( ET ) between Q68DA7 and heme domains through facilitation of the Q68DA7 / heme interactions in the output state . Therefore , P62158 controls IET between heme and Q68DA7 domains by a conformational gated mechanism . This is essential in coupling ET in the reductase domain in NOS with NO synthesis in the oxygenase domain .

Novel treatments with small molecules in psoriatic arthritis . Current treatment options for patients with active psoriatic arthritis ( PsA ) include synthetic disease-modifying antirheumatic drugs and biologic agents . Propelled by increased understanding of immunopathogenesis of PsA , new therapeutic agents targeting different biologic pathways have been evaluated . This article discusses novel small-molecule , orally available treatments that are currently in clinical development for the treatment of psoriasis and PsA . This includes the phosphodiesterase 4 inhibitor apremilast and Janus kinase ( JAK ) inhibitors . Apremilast has demonstrated significant improvements in patients with moderate to severe psoriasis and PsA in phase II and III clinical trials and has recently been approved for the treatment of PsA . DB08895 MENMAX DB08895 MEN , an oral inhibitor of P52333 REA , P23458 REA , and , to a lesser degree , O60674 REA , approved for the treatment of rheumatoid arthritis in several countries , has demonstrated positive results in psoriasis in phase II studies . Studies in PsA are ongoing . With these new developments , treatment options will continue to improve in the future .

DB02546 and bortezomib synergistically cause ubiquitinated protein accumulation in prostate cancer cells . PURPOSE : Protein ubiquitination is a novel strategy used to treat malignancies . We investigated whether the histone deacetylase inhibitor vorinostat ( Cayman Chemical , Ann Arbor , Michigan ) and the proteasome inhibitor bortezomib ( LC Laboratories , Woburn , Massachusetts ) would synergistically cause the accumulation of ubiquitinated proteins in prostate cancer cells . MATERIALS AND METHODS : LNCaP , PC - 3 and DU 145 cells ( ATCC ™ ) were treated with vorinostat and / or bortezomib . Cell viability and induction of apoptosis were assessed . In vivo efficacy was evaluated in a murine subcutaneous tumor model using PC - 3 cells . The influence of androgen receptor expression on bortezomib efficacy was examined using RNA interference . Changes in the expression of ubiquitinated proteins , cell cycle associated proteins and acetylated histone were evaluated . RESULTS : P10275 REA expression seemed to decrease bortezomib activity . PC - 3 and DU 145 cells were more susceptible to bortezomib than LNCaP cells and the silencing of androgen receptor expression in LNCaP cells enhanced bortezomib activity . DB02546 and bortezomib synergistically induced apoptosis , inhibited prostate cancer cell growth and suppressed tumor growth in a murine xenograft model . The combination decreased cyclin D1 and cyclin-dependent kinase 4 expression , and increased P38936 REA expression . The combination synergistically caused the accumulation of ubiquitinated proteins and histone acetylation . This histone acetylation was a consequence of the accumulation of ubiquitinated proteins . CONCLUSIONS : DB02546 and bortezomib inhibit the growth of prostate cancer cells synergistically by causing ubiquitinated proteins to accumulate in cells . The current study provides a framework for testing the combination in patients with advanced prostate cancer .

Altered transcriptional regulators in response to serum in immortalized lymphocytes from Alzheimer ' s disease patients . Cell cycle disturbances may precede neuronal death in Alzheimer ' s disease ( AD ) . We described alterations , in lymphocytes from AD patients , on the activity of two transcription factors , E2F and NF-kappaB , involved in cell proliferation and survival regulation , demonstrating that cell cycle dysfunction also occurs in peripheral cells . The analysis of E2F - DNA binding activity revealed lower signal intensity of protein-DNA complexes in AD cells , which correlated with increased phosphorylation of retinoblastoma ( P06400 REA ) related proteins and enhanced proliferation . The calmodulin ( P62158 ) antagonist calmidazolium ( DB01489 ) abrogated the increased activity of AD cells by partially dephosphorylating P06400 REA and Q08999 REA . The NF-kappaB-DNA binding activity increased as cell progress through the cell cycle . The reduced NF-kappaB activation observed in AD cells appears not to be related to the increased phosphorylation of the P06400 REA family proteins nor with the enhanced proliferative activity of AD cells , but seems to protect them from death induced by the loss of trophic support . Ca2 + / P62158 antagonists rescue NF-kappaB-DNA binding activity and sensitize AD cells to serum withdrawal . These observations suggest that disruption of Ca2 + / P62158 signaling pathway could be linked mechanistically to its pro cell survival actions , promoting enhanced proliferation or decreased cell death depending on the presence of growth-stimulatory signals .

The role of tumor suppressor dysregulation in prostate cancer progression . P10275 REA activity is essential for prostate cancer development and progression . While there are classically defined roles for the retinoblastoma ( P06400 REA ) 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 REA 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 REA and p53 protein . While such agents have undergone extensive study in many solid tumor types , the additional importance of P06400 REA 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 REA 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 .

The in vitro pharmacological profile of DB05655 MEN , a selective 5 - HT ( 4 ) receptor agonist with high intrinsic activity . The in vitro pharmacological profile of DB05655 MEN , a novel , selective 5 - HT ( 4 ) receptor agonist , was compared to that of clinically efficacious gastroprokinetic 5 - HT ( 4 ) receptor agonists . DB05655 MEN produced an elevation of cyclic adenosine monophosphate in human embryonic kidney 293 cells expressing the human recombinant 5 - HT ( 4 ( c ) ) ( h5 - HT ( 4 ( c ) ) ) receptor ( pEC ( 50 ) = 8.3 ) and 5 - HT ( 4 ) receptor-mediated relaxation of the rat esophagus ( pEC ( 50 ) = 7.9 ) and contraction of the guinea pig colon ( pEC ( 50 ) = 7.9 ) . In all in vitro assays , DB05655 MEN was a high intrinsic activity agonist , unlike tegaserod , mosapride , and cisapride which , in the majority of test systems , had lower intrinsic activity . DB05655 MEN had high affinity ( pK ( i ) = 7.7 ) and selectivity ( > or = 25 - fold ) for h5 - HT ( 4 ( c ) ) receptors over other biogenic amine receptors . DB05655 MEN was > 500 - fold selective over other 5 - HT receptors ( including h5 - HT ( 2B ) and h5 - HT ( 3A ) ) and , at 3 microM , had no effect on human ether-à-go-go-related gene K + channels . In conclusion , DB05655 MEN is a selective 5 - HT ( 4 ) receptor agonist in vitro . The high intrinsic activity and preferential binding of DB05655 MEN to Q13639 REA over other 5 - HT receptors may result in an improved clinical profile for the treatment of gastrointestinal disorders of reduced motility .

P10275 REA - induced tumor suppressor , B2CW77 , inhibits breast cancer growth and transcriptionally activates p53 / p73 - mediated apoptosis in breast carcinomas . P10275 REA ( AR ) expression by immunohistochemistry correlates with better prognosis and survival among breast cancer patients . We and others have shown that AR inhibits proliferation and induces apoptosis in breast cancer cells . However , the mechanism of AR ' s anti-tumor effect in breast cancer is still not fully understood . Our recent study indicates that AR upregulates expression of tumor suppressor gene P60484 REA by promoter activation in breast cancer . B2CW77 , encoding B2CW77 protein , is a newly identified gene , which shares a bidirectional promoter with P60484 REA and is transcribed in the opposite direction . So far , the function of B2CW77 has never been studied in tumorigenesis . Here , we define B2CW77 as a tumor suppressor in breast carcinomas , which inhibits tumor growth and invasiveness . After analyzing 188 normal breast and 1247 malignant breast cancer tissues , we observed the loss of B2CW77 in multiple breast cancer subtypes and this decreased B2CW77 expression associates with tumor progression and increasing histological grade in invasive carcinomas . We characterize B2CW77 , for the first time , as a transcription factor , directly promoting the expression of P04637 REA and O15350 REA , with consequent elevated apoptosis and cell cycle arrest in breast cancer cells . We demonstrate , in vitro and in murine xenograph models , that both B2CW77 and P60484 REA are AR-target genes , mediating androgen-induced growth inhibition and apoptosis in breast cancer cells . Our observations suggest that B2CW77 might be used as a potential prognostic marker and novel therapy target for breast carcinomas .

Gq-mediated Akt translocation to the membrane : a novel PIP 3 - independent mechanism in platelets . Akt is an important signaling molecule regulating platelet aggregation . Akt is phosphorylated after translocation to the membrane through Gi signaling pathways by a phosphatidylinositol -3,4 , 5 - trisphosphate ( PIP 3 ) - dependent mechanism . However , Akt is more robustly phosphorylated by thrombin compared with adenosine 5 ' - diphosphate in platelets . This study investigated the mechanisms of Akt translocation as a possible explanation for this difference . Stimulation of washed human platelets with protease-activated receptor agonists caused translocation of Akt to the membrane rapidly , whereas phosphorylation occurred later . The translocation of Akt was abolished in the presence of a Gq-selective inhibitor or in Gq-deficient murine platelets , indicating that Akt translocation is regulated downstream of Gq pathways . Interestingly , phosphatidylinositol 3 - kinase ( PI3K ) inhibitors or Q9H244 REA antagonist abolished Akt phosphorylation without affecting Akt translocation to the membrane , suggesting that Akt translocation occurs through a PI3K / PIP 3 / Gi-independent mechanism . An Akt scaffolding protein , P38936 REA - activated kinase ( PAK ) , translocates to the membrane after stimulation with protease-activated receptor agonists in a Gq-dependent manner , with the kinetics of translocation similar to that of Akt . Coimmunoprecipitation studies showed constitutive association of PAK and Akt , suggesting a possible role of PAK in Akt translocation . These results show , for the first time , an important role of the Gq pathway in mediating Akt translocation to the membrane in a novel Gi / PI3K / PIP 3 - independent mechanism .

O15520 REA and Q9NSA1 as regulators in adipocyte development and metabolism . The FGF family comprises twenty-two evolutionarily related members with diverse functions in development , metabolism , and neuronal activities . O15520 REA and Q9NSA1 play unique roles in adipocyte development and metabolism , respectively . O15520 REA mediates biological responses by activating FGF receptor 2b ( FGFR 2b ) with heparin / heparan sulfate in a paracrine manner . In contrast , Q9NSA1 mediates biological responses by activating FGFRs with β Q9UEF7 in cultured cells . However , Q9NSA1 acts in an autocrine manner via a β Q9UEF7 - independent signaling pathway in mice . Fgf 10 knockout mice die shortly after birth . Preadipocyte proliferation and adipogenesis are greatly impaired in Fgf 10 knockout mouse embryos . O15520 REA stimulates preadipocyte proliferation through the Ras / MAPK pathway followed by the cyclin D2 - dependent phosphorylation of Q08999 REA . O15520 REA also stimulates adipogenesis by inducing the expression of P06400 REA through the Ras / MAPK pathway . P06400 REA binds C / EBPα . The P06400 REA - C / EBPα complex induces adipogenesis . Fgf 21 is abundantly expressed in the liver . Hepatic Fgf 21 expression is markedly induced in mice by fasting . Q9NSA1 exerts pharmacological effects on glucose and lipid metabolism in hepatocytes and adipocytes . However , the phenotypes of Fgf 21 knockout mice , which are apparently normal and fertile , indicate Q9NSA1 not to be a physiological regulator for hepatic functions . Hepatic Q9NSA1 inhibits lipolysis in adipocytes , and so is a negative regulator of lipolysis during fasting . Q9NSA1 may be a " thrifty factor " . Serum Q9NSA1 levels are increased in patients with metabolic diseases related with obesity , indicating potential roles of Q9NSA1 in adipocyte metabolism .