MH_dev_198

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

HIV - 1 pathogenesis differs in rectosigmoid and tonsillar tissues infected ex vivo with P51681 REA - and P61073 REA - tropic HIV - 1 . Gut-associated lymphoid tissue ( P07902 REA ) has been identified as the primary target of HIV - 1 infection . To investigate why P07902 REA is especially vulnerable to HIV - 1 , and to determine whether the selective transmission of P51681 REA - using viral variants ( R5 ) in vivo is the result of a greater susceptibility of P07902 REA to this viral variant , we performed comparative studies of P61073 REA - using ( X4 ) and R5 HIV - 1 infections of human lymphoid ( tonsillar ) and rectosigmoid tissues ex vivo under controlled laboratory conditions . We found that the relative level of R5 replication in rectosigmoid tissue is much greater than in tonsillar tissue . This difference is associated with the expression of the P51681 REA co-receptor on approximately 70 % of P01730 REA T cells in rectosigmoid tissue , whereas in tonsillar tissue it is expressed on fewer than 15 % of P01730 REA T cells . Furthermore , tonsillar tissue responds to X4 HIV - 1 infection by upregulating the secretion of CC-chemokines , providing a potential P51681 REA blockade and further resistance to R5 infection , whereas gut tissue failed to increase such innate immune responses . Our results show that rectosigmoid tissue is more prone than tonsillar lymphoid tissue to R5 HIV - 1 infection , primarily because of the high prevalence and availability of R5 cell targets and reduced chemokine blockade . The majority of P01730 REA T cells express P61073 REA , however , and X4 HIV - 1 readily replicates in both tissues , suggesting that although the differential expression of co-receptors contributes to the P07902 REA vulnerability to R5 HIV - 1 , it alone can not account for the selective R5 infection of the rectal mucosa in vivo .

F-actin involvement in guinea pig sperm motility . Sperm motility is a must for natural fertilization to occur . During their travel through the epididymis , mammalian spermatozoa gradually acquire the ability to move . This is accomplished through a sliding movement of the outer doublet microtubules of the axoneme which is energized by the dynein ATPase . Within its complex structure , the mammalian sperm flagellum contains F-actin and thus , we decided to test in the guinea pig sperm flagellum the role of F-actin in motility . During maturation , capacitation , and the acrosome reaction , a gradual decrease of the relative concentration of F-actin was observed . Motility increased as spermatozoa became able to fertilize . P06396 REA , phalloidin , and KI inhibited sperm motility . P06396 REA canceled sperm motility within 20 min of treatment while 0.6 M KI had immediate effects . Phalloidin diminished hyperactive sperm motility slightly . All three compounds significantly increased the relative concentration of F-actin . Latrunculins are conventional drugs that destabilize the F-actin cytoskeleton . DB02621 MEN ( O43561 REA A ) did not affect sperm motility ; but significantly increased F-actin relative concentration . The results suggested that in guinea pig spermatozoa , randomly severing F-actin filaments inhibits flagellar motility ; while end filament alteration does not . Thus , specific filament regions seem to be important for sperm motility .

Inhibition of brain prostaglandin endoperoxide synthase - 2 prevents the preparturient increase in fetal adrenocorticotropin secretion in the sheep fetus . Maturation of the fetal hypothalamus-pituitary-adrenal axis is critical for the timely somatic development of the fetus and readiness for birth . Recently , we proposed that prostaglandin generation within the fetal central nervous system is critical for the modulation of hypotension-induced fetal DB01285 secretion . The present study was designed to test the hypothesis that the preparturient increase in fetal DB01285 secretion is dependent upon fetal central nervous system prostaglandin synthesis mediated by the activity of prostaglandin endoperoxide synthase ( PGHS ) - 2 ( cyclooxygenase - 2 ) in the fetal brain . We performed two studies in chronically catheterized fetal sheep . In the first study , we infused nimesulide or vehicle intracerebroventricularly ( i . c . v ) into singleton fetal sheep and collected blood samples until spontaneous parturition . DB04743 MEN significantly delayed parturition , and inhibited fetal DB01285 and proopiomelanocortin secretion but did not prevent the preparturient increase in fetal plasma cortisol concentration . In the second study , we used twin fetuses . One fetus received intracerebroventricular nimesulide and the other intracerebroventricular vehicle . DB04743 MEN reduced brain tissue concentrations of prostaglandin estradiol , while not affecting plasma prostaglandin E ( 2 ) concentrations , demonstrating an action restricted to the fetal brain . DB04743 MEN reduced P35354 REA mRNA and increased P35354 REA protein , while not altering P23219 REA mRNA or protein in most brain regions , suggesting an effect of the inhibitor on P35354 REA turnover and relative specificity for P35354 REA in vivo . We conclude that the preparturient increase in fetal DB01285 and proopiomelanocortin is dependent upon the activity of P35354 REA in the fetal brain . However , we also conclude that the timing of parturition is not solely dependent upon DB01285 in this species .

Decreasing Poly ( ADP - DB01936 ) Polymerase Activity Restores ΔF508 P13569 REA Trafficking . Most cystic fibrosis is caused by mutations in P13569 REA that prevent its trafficking from the ER to the plasma membrane and is associated with exaggerated inflammation , altered metabolism , and diminished responses to oxidative stress . P09874 REA is activated by oxidative stress and causes energy depletion and cell dysfunction . Inhibition of this enzyme protects against excessive inflammation and recent studies have also implicated it in intracellular protein trafficking . We hypothesized that P09874 REA activity is altered in CF and affects trafficking and function of the most common CF mutant ΔF508 P13569 REA . Indeed , P09874 REA activity was 2.9- fold higher in CF ( ΔF508 / ΔF508 ) human bronchial epithelial primary cells than in non-CF cells , and similar results were obtained by comparing CF vs . non-CF bronchial epithelial cell lines ( 2.5- fold higher in CFBE 41o ( - ) vs . 16HBE14o ( - ) , P < 0.002 ) . A P09874 REA inhibitor ( ABT - 888 , DB07232 MEN ) partially restored P13569 REA channel activity in CFBE 41o ( - ) cells overexpressing ΔF508 P13569 REA . Similarly , reducing P09874 REA activity by 85 % in ileum from transgenic CF mice ( Cftr ( tm1 ) Eur ) partially rescued ΔF508 P13569 REA activity to 7 % of wild type mouse levels , and similar correction ( 7.8 % ) was observed in vivo by measuring salivary secretion . Inhibiting P09874 REA with ABT - 888 or siRNA partially restored ΔF508 P13569 REA trafficking in cell lines , and most ΔF508 P13569 REA was complex glycosylated when heterologously expressed in P09874 REA ( - / - ) mouse embryonic fibroblasts . Finally , levels of the mature glycoform of P13569 REA were reduced by peroxynitrite , a strong activator of P09874 REA . These results demonstrate that P09874 REA activity is increased in CF , and identify a novel pathway that could be targeted by proteostatic correctors of P13569 REA trafficking .

Differential selectivity of insulin secretagogues : mechanisms , clinical implications , and drug interactions . The sulphonylurea receptor ( Q09428 REA ) subunits of K ( DB00171 ) channels are the targets for several classes of therapeutic drugs . Sulphonylureas close K ( DB00171 ) channels in pancreatic beta-cells and are used to stimulate insulin release in type 2 diabetes , whereas the K ( DB00171 ) channel opener nicorandil acts as an antianginal agent by opening K ( DB00171 ) channels in cardiac and vascular smooth muscle . The predominant type of Q09428 REA varies between tissues : Q09428 REA in beta-cells , SUR 2A in cardiac muscle , and SUR 2B in smooth muscle . Sulphonylureas and related drugs exhibit differences in tissue specificity , as the drugs interact to varying degrees with different types of Q09428 REA . DB01120 and tolbutamide are beta-cell selective and reversible . DB00222 MENMAX DB00222 MEN , glibenclamide , and repaglinide , however , inhibit cardiac and smooth muscle K ( DB00171 ) channels in addition to those in beta-cells and are only slowly reversible . Similar properties have been observed by recording K ( DB00171 ) channel activity in intact cells and in Xenopus oocytes expressing cloned K ( DB00171 ) channel subunits . While K ( DB00171 ) channels in cardiac and smooth muscle are largely closed under physiological conditions ( but open during ischaemia ) , they are activated by antianginal agents such as nicorandil . Under these conditions , they may be inhibited by sulphonylureas that block SUR 2 - type K ( DB00171 ) channels ( e . g . , glibenclamide ) . Care should , therefore , be taken when choosing a sulphonylurea if potential interactions with cardiac and smooth muscle K ( DB00171 ) channels are to be avoided .

P05362 REA - independent lymphocyte transmigration across high endothelium : differential up-regulation by interferon gamma , tumor necrosis factor-alpha and interleukin 1 beta . The adhesion of lymphocytes to cytokine-treated high endothelium was studied using cultured high endothelial cells ( O14777 REA ) . Pretreatment of the O14777 REA layer with a variety of cytokines caused up-regulation of lymphocyte adhesion with the effects ordered interferon gamma ( P01579 REA ) greater than tumor necrosis factor-alpha ( P01375 REA ) greater than or equal to interleukin 1 beta ( IL 1 beta ) . Increased lymphocyte adhesion was found to be independent of P05362 REA as expression by O14777 REA was not increased by cytokines and antibodies against P05362 REA did not block adhesion . The peptide CS1 and anti-beta 1 integrin subunit antibodies , however , caused partial inhibition of lymphocyte adhesion thus indicating a role for fibronectin on O14777 REA and alpha 4 beta 1 on lymphocytes . Study of the kinetics of lymphocyte adhesion showed that the effects of P01579 REA and P01375 REA were persistent and remained detectable 2.5 h after removal of the cytokines whereas the effects of IL 1 beta were transient and were not sustained beyond 1 h . All of the cytokines used caused transient increases in the number of surface-bound lymphocytes with P01579 REA greater than P01375 REA greater than or equal to IL 1 beta , however , the most dramatic effect was on the transmigration of lymphocytes across the O14777 REA . Both P01579 REA and P01375 REA caused sustained increased transmigration with P01579 REA having the greater effect . IL 1 beta had little effect on transmigration . This model demonstrates that the binding and transmigration of lymphocytes across O14777 REA can be differentially regulated by the actions of individual cytokines . These results support the concept that locally produced cytokines regulate O14777 REA function within the lymph node .

The post-operative analgesic efficacy and tolerability of lumiracoxib compared with placebo and naproxen after total knee or hip arthroplasty . BACKGROUND : DB01283 MEN is a novel selective cyclooxygenase - 2 ( P35354 REA ) inhibitor in development for the treatment of chronic and acute pain . METHODS : This randomized , double-blind multicentre study enrolled 180 patients ( aged 18-80 years ) with moderate-to-severe pain ( > or = 2 on a 4 - point categorical scale ) within 48 h of unilateral total knee or total hip arthroplasty . Patients were randomized to receive lumiracoxib 400 mg once daily ( n = 60 ) , placebo ( n = 60 ) or naproxen 500 mg twice daily ( n = 60 ) . The study consisted of a 12 - h single-dose phase followed by a multiple-dose phase ( up to 96 h or until discontinuation ) . The primary efficacy measure was the summed ( time-weighted ) pain intensity difference over 0-8 h after the first dose ( SPID - 8 ) . RESULTS : DB01283 MEN and naproxen were comparable and both treatments were superior to placebo for the primary efficacy measure , SPID - 8 . Both treatments were generally similar and also superior to placebo for the secondary efficacy measures during both the single - and multiple-dose phases for up to 96 h . Both active treatments were well tolerated . CONCLUSION : DB01283 MEN is an effective alternative to traditional non-selective non-steroidal anti-inflammatory drugs ( NSAIDs ) for the treatment of post-operative pain .

Light and X-ray scattering show decorin to be a dimer in solution . P07585 REA is a widely distributed member of the extracellular matrix small leucine-rich repeat glycoprotein / proteoglycan family . For investigation of its physical properties , decorin from two sources ( young steer skin and a recombinant adenovirus ) was used . The first sample was extracted into 7 m urea and purified , while the second was isolated from medium conditioned by 293A cells infected with adenovirus and purified without chaotropes . The only chemical differences detected between these materials were a slightly shorter glycosaminoglycan chain and the retention of the propeptide on the latter . Circular dichroism spectra of the two samples were virtually identical , showing a high proportion of beta-sheet and beta-turn and little alpha-helix . The protein cores were completely denatured in 2.25 m guanidine HCl ( GdnHCl ) but recovered their secondary structure on removal of chaotrope . Light scattering of material eluted from gel-filtration columns in DB03754 MEN - buffered saline , pH 7.0 , gave molecular mass values of 165 + / - 1 kDa and 84.6 + / - 4 kDa for intact decorin and the glycoprotein core produced by digestion with chondroitin ABC lyase , respectively . Intact recombinant prodecorin had a mass of 148 + / - 18 kDa . These values , which are double those estimated from SDS gel electrophoresis or from the known sequences and compositions , were halved in 2.5 m GdnHCl . Data from solution x-ray scattering of intact decorin and its core in DB03754 MEN - buffered saline are consistent with a dimeric particle whose protein component has a radius of gyration of 31.6 + / - 0.4 A , a maximum diameter of 98 + / - 5 A , and approximates two intertwined C shapes .

P06396 REA as a negative prognostic factor and effector of motility in erbB - 2 - positive epidermal growth factor receptor-positive breast cancers . PURPOSE : erbB - 2 and epidermal growth factor receptor ( P00533 REA ) may mediate motility via signaling that enables changes in the actin cytoskeleton . A physical basis for this motility may depend on the coexpression of gelsolin , a M ( r ) 80,000 actin-binding protein . EXPERIMENTAL DESIGN : The expression of erbB - 2 , P00533 REA , and gelsolin was analyzed in 790 archival invasive breast cancers . These data were compared with histological , clinical , and outcome data ( median follow-up , 16.3 years ) . RESULTS : Protein overexpression was observed in overlapping subsets of breast cancers ( 38 % of cases were erbB - 2 + ; 15 % of cases were P00533 REA + ; and 56 % of cases were gelsolin + ) . Tumor gelsolin was associated with overexpression of erbB - 2 and P00533 REA , as well as with an aggressive tumor phenotype . By univariate and multivariate analyses , tumor gelsolin alone was not a prognostic factor . Overexpression of all three factors significantly predicted poor clinical outcome by univariate and multivariate analyses . For example , in node-positive patients , coexpression of all three markers was associated with a 3 - year disease-specific survival ( as compared with erbB - 2 + , P00533 REA + , gelsolin - patients , who had a median survival of 6 years ) . CONCLUSIONS : These data suggest that gelsolin coexpression may be an important additional prognostic factor in erbB - 2 + , P00533 REA + breast cancer patients . We hypothesize that this is due to the role of gelsolin in mediating motility and invasion .

Inactivation of caspase - 1 in rodent brain : a novel anticonvulsive strategy . PURPOSE : Cytokines and related inflammatory mediators are rapidly synthesized in the brain during seizures . We previously found that intracerebral administration of interleukin - 1 ( IL - 1 ) - beta has proconvulsant effects , whereas its endogenous receptor antagonist ( IL - 1Ra ) mediates potent anticonvulsant actions in various models of limbic seizures . In this study , we investigated whether seizures can be effectively inhibited by blocking the brain production of IL - 1beta , by using selective inhibitors of interleukin-converting enzyme ( ICE / caspase - 1 ) or through caspase - 1 gene deletion . METHODS : P29466 REA was selectively blocked by using pralnacasan or DB05507 MEN . IL - 1beta release was induced in mouse organotypic hippocampal slice cultures by proinflammatory stimuli [ lipopolysaccharide ( LPS ) + adenosine triphosphate ( DB00171 ) ] and measured with enzyme-linked immunosorbent assay ( ELISA ) . IL - 1beta production during seizures was measured in the rat hippocampus by Western blot . Seizures were induced in freely moving mice and rats by intrahippocampal injection of kainic acid and recorded by EEG analysis . RESULTS : P29466 REA inhibition reduced the release of IL - 1beta in organotypic slices exposed to LPS + DB00171 . Administration of pralnacasan ( intracerebroventricular , 50 microg ) or DB05507 MEN ( intraperitoneal , 25-200 mg / kg ) to rats blocked seizure-induced production of IL - 1beta in the hippocampus , and resulted in a twofold delay in seizure onset and 50 % reduction in seizure duration . Mice with caspase - 1 gene deletion showed a 70 % reduction in seizures and an approximate fourfold delay in their onset . CONCLUSIONS : Inhibition of caspase - 1 represents an effective and novel anticonvulsive strategy , which acts by selectively reducing the brain availability of IL - 1beta .

O14777 REA binds to the seventh regulatory subunit of the 26 S proteasome and modulates the proteolysis of mitotic cyclins . A newly identified nuclear protein rich in leucine heptad repeats called O14777 REA is important for mitosis . To elucidate its mechanism of action , the region containing leucine heptad repeats was used to identify cellular proteins that potentially interact with O14777 REA . Complementary DNAs encoding several proteins including P35998 REA , P29466 REA , Nek 2 , and Smc 1 / Smc 2 , known to be important for G2 / M progression , were identified . The interaction between O14777 REA and P35998 REA , the seventh regulatory subunit of the 26 S proteasome , was further demonstrated by in vitro Q86UG4 pull-down assays . O14777 REA is not a part of the 26 S proteasome and interacts with P35998 REA only when it is dissociated from the complex during M phase . Purified P35998 REA specifically hydrolyzes DB00171 , an activity inhibited by O14777 REA . In addition , O14777 REA inhibits the proteolysis of mitotic cyclin B in vitro . Consistent with this biochemical activity , ectopic expression of O14777 REA inhibits the degradation of mitotic cyclins after telophase , resulting eventually in cell death . These results show that O14777 REA is a negative regulator of P35998 REA and suggest that it may modulate M phase progression , in part , through the regulation of proteasome-mediated degradation of cell cycle regulatory proteins .

Positive correlation between galactose - 1 - phosphate uridyltransferase ( P07902 REA ) and DB03501 MEN - 4 ' - epimerase ( Q14376 REA ) activities . OBJECTIVES : The aim of our study was to determine whether the activities of galactose - 1 - phosphate uridyltransferase and DB03501 MEN - 4 ' - epimerase are correlated , and in what way they may influence one another . DESIGN AND METHODS : Enzyme activities were measured in red blood cells from 214 individuals . RESULTS : A statistically significant ( p < 0.001 ) positive correlation was observed between P07902 REA and Q14376 REA activities . CONCLUSIONS : Our results suggest that P07902 REA and Q14376 REA activities are correlated and that Q14376 REA activity has a greater impact on P07902 REA activity than vice versa .

Triple negative breast cancer : therapeutic and prognostic implications . Triple negative breast cancers ( TNBC ) lack oestrogen receptor ( ER ) , progesterone receptor ( PR ) , nor over-express human epidermal growth factor receptor 2 ( P04626 REA ) . Epidemiologic studies demonstrate that women diagnosed with TNBC manifest a significantly different set of clinic-pathologic features and risk factors when compared to women with other subtypes of breast cancer . They are associated with poor prognosis , as defined by low five-year survival . To date many studies have examined the utility of traditional chemotherapy for the treatment of patients with TNBC and have confirmed the benefits of these agents in both the adjuvant and neoadjuvant settings . Targeted therapy options involving P09874 REA and P00533 REA inhibition , are currently in different phases of development and will hopefully change the paradigm of how patients with TNBC are treated . The present commentary aims to summarize the latest findings on chemotherapy in the treatment of TNBC in both the neoadjuvant and adjuvant setting and explore the ongoing development of newer targeted agents .

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

Human decorin regulates proliferation and migration of human lung cancer A549 cells . BACKGROUND : P07585 REA is a small leucine-rich proteoglycan and it plays an important role in regulation of cell growth and migration in various tumor cell lines . P07585 REA was found down-regulated in non-small cell lung cancer tissue and may be involved in regulation of lung cancer development . METHODS : In this study , lentivirus-mediated RNA interference and over expression were employed to change the expression levels of decorin in lung cancer A549 cells . We tested the cell cycle of A549 cells and the expression of transforming growth factor ( TGF ) - β , cyclin D1 , epidermal growth factor receptor ( P00533 REA ) , P04637 REA , and P21 . RESULTS : We found that up-regulation of decorin could inhibit proliferation , block cell cycle at P55008 and decrease invasive activity of A549 cells . Moreover , we also show that up-regulation of decorin induced significant decreases of TGF-β 1 , cyclin D1 expression , phosphorylation of P00533 REA , and increases of P04637 REA and P21 expression . Opposite results were observed in A549 cells with down-regulation of decorin . CONCLUSION : Our results suggest that decorin is a key regulator involved in proliferation and migration of A549 cells .

Cl - DB05511 MEN enhances P01375 REA - α release in peritoneal macrophages stimulated with LPS . P0DMS8 ( A3R ) belongs to the Gi / Gq-coupled receptor family , that leads to the intracellular DB02527 reduction and intracellular calcium increase , respectively . A3R is widely expressed and it can play a crucial role in many patho-physiological conditions , including inflammation . Here we investigate the effect of Cl - DB05511 MEN , A3R agonist , on the production of P01375 REA - α . We found that Cl - DB05511 MEN enhances LPS-induced P01375 REA - α release in peritoneal macrophages . This effect is reduced by MRS 1191 , A3R antagonist and by forskolin , activator of adenylyl cyclase . pIκBα increased in LPS + Cl - DB05511 MEN - treated macrophages , while total IκB kinase-β ( IKKβ ) reduced . Indeed , p65NF - κB nuclear translocation increased in cells treated with LPS + Cl - DB05511 MEN . Moreover , IMD 0354 , IKKβ inhibitor , significantly abrogated the effect of Cl - DB05511 MEN on P01375 REA - α release . Inhibition of protein kinase C ( PKC ) significantly reduced Cl - DB05511 MEN - induced P01375 REA - α release in LPS-stimulated macrophages . Furthermore , LY - 294002 , PI3K inhibitor , reduced the P01375 REA - α production enhanced by Cl - DB05511 MEN , although the phosphorylation status of Akt did not change in cells treated with LPS + Cl - DB05511 MEN than LPS alone . In summary , these data show that Cl - DB05511 MEN is able to enhance P01375 REA - α production in LPS-treated macrophages in an NF-κB - dependent manner .

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

C . elegans vulval development as a model system to study the cancer biology of P00533 REA signaling . Molecular genetic studies of C . elegans vulval development have helped to define an evolutionarily conserved signaling pathway from an P01133 REA - like ligand through P01133 REA - receptor , Ras and Q96HU1 kinase to the nucleus . Further studies have identified novel positive regulators such as Q8IVT5 - 1 and Q09428 REA - 8/ Q5T124 - 2 and negative regulators such as cbl / SLI - 1 . The many negative regulatory proteins might serve to prevent inappropriate signaling , and thus are analogous to tumor suppressor genes .

P14210 REA induces anoikis resistance by up-regulation of cyclooxygenase - 2 expression in uterine endometrial cancer cells . P35354 REA ( P35354 REA ) has been implicated in the promotion of carcinogenesis . Although the role of P35354 REA in endometrial cancer remains unclear , recent experiments suggest that P35354 REA antagonizes cell apoptosis , increases the invasiveness of malignant cells , and promotes angiogenesis . P14210 REA ( P14210 REA ) is a mesenchymal-derived cytokine and the interaction between P14210 REA and its tyrosine kinase receptor , c - DB00134 proto-oncogene , is associated with tumor progression and metastasis . To investigate the molecular mechanism of P14210 REA - induced anoikis resistance , we analyzed the signal transduction and P35354 REA expression in endometrial cancer cells . Here , we show i ) the expression of P35354 REA protein significantly increased in a dose-dependent manner after P14210 REA stimulation in endometrial cancer cell lines ( O14777 REA - IB and RL95 - 2 ) , reaching 200-270 % stimulation at the highest doses of P14210 REA tested ( 40 ng / ml ) ; ii ) flow cytometry and TUNEL analyses revealed that P14210 REA significantly inhibited anoikis of RL95 - 2 cells ; iii ) phosphatidylinositol 3 - kinase ( PI3K ) inhibitor ( LY294002 ) , but not mitogen-activated protein kinase / P29323 REA kinase ( MEK ) inhibitor ( PD98059 ) , specifically blocked P14210 REA - mediated anoikis resistance in RL95 - 2 cells ; and iv ) P35354 REA inhibitor , Meloxicam , abrogated P14210 REA - mediated anoikis resistance . Our data suggest that P14210 REA induces anoikis resistance in endometrial cancer cells possibly through PI3K / Akt pathway-dependent up-regulation of P35354 REA expression .