interacts_with DB00030?
Ex vivo binding of flibanserin to serotonin P08908 and 5- Q13049 receptors . DB04908 has been reported to be an agonist at P08908 -receptors and an antagonist at 5- Q13049 receptors , with higher affinity for P08908 receptors . Despite the fact that less receptor occupation is required by full agonists than by antagonists to exert their effects , flibanserin was shown to exert 5- Q13049 antagonism at doses ( 4-5 mg kg-1 ) that are lower or equal to those required to stimulate P08908 receptors . In order to understand this phenomenon , the interaction of flibanserin with P08908 and 5- Q13049 receptors was evaluated in ex vivo binding studies . This interaction was evaluated in the prefrontal cortex , hippocampus and midbrain by using [3H]8-OH-DPAT and [3H]ketanserin to label P08908 and 5- Q13049 receptors , respectively . DB04908 was given at 1 , 10 and 30 mg kg-1 intraperitoneally . The dose of 1 mg kg-1 displaced both radioligands preferentially in the frontal cortex . The doses of 10 and 30 mg kg-1 reduced the binding of both radioligands in all the three brain regions non-selectively by about 50 % and 70 % , respectively . The displacement was maximal after 0.5 h and was reduced or not evident after 3 h . We conclude that 5-HT2 antagonism brought about by low doses of flibanserin may reflect functional mechanisms more than receptor-mediated effects . Current treatment strategies for non-alcoholic fatty liver disease ( NAFLD ) . Nonalcoholic fatty liver disease ( NAFLD ) is recognized as the most common cause of chronic liver disease worldwide . NAFLD is a clinicopathologic syndrome ranging from simple steatosis , which is relatively benign , to the more severe form known as nonalcoholic steatohepatitis ( NASH ) , which may progress to cirrhosis , liver failure , and hepatocellular carcinoma . NAFLD is associated with significant liver related morbidity and mortality , and its underlying pathophysiology is thought to result from a multiple hit process . The initial insult is the accumulation of hepatic fat secondary to insulin resistance . In the setting of hepatic steatosis , the second hit can be caused by reactive oxygen species , inflammatory cytokines , and adipokines . Several therapeutic modalities that target these mechanisms are under investigation , but no proven treatment has yet emerged . P01308 sensitizers such as thiazolidinediones and metformin show promise , and several studies have explored the role of lipid lowering agents , antioxidants , and cytoprotective agents . Novel agents such as anti-obesity drugs , selective cannabinoid-1 receptor blockers , and dual Q07869 alpha and gamma agonists are also under investigation . Unfortunately , data on the long-term safety and efficacy of these agents and their impact on liver related histologic outcomes are currently lacking . NAFLD treatment currently focuses on reducing metabolic risk factors , with the mainstay of therapy focusing on life-style modifications such as gradual weight loss through diet and regular exercise . P01308 action on H292 bronchial carcinoma cells as compared to normal bronchial epithelial cells . DB00030 may contribute to bronchial carcinoma due to P08069 activation by high local concentrations . Therefore , effects of insulin and P05019 on human bronchial carcinoma cells ( H292 ) and normal bronchial epithelium cells ( P02100 ) were studied . TGF-β was included since it also influences carcinoma progression . H292 and P02100 cells expressed both the insulin receptor and the P08069 ; in H292 cells an additional , shorter , splicing variant ( IR-A ) of the insulin receptor was present . P06213 expression was around four to five times higher in H292 than in P02100 cells at mRNA and protein levels . P01308 and TGF-β exerted contrary actions on proliferation and gene expression in H292 cells . Genes regulated by insulin , P05019 , and TGF-β were linked to inflammation , cell adhesion , muscle contraction and differentiation . P01308 and P05019 also suppressed DNA repair genes . EC(50) for insulin-induced proliferation was around 5 nM in H292 and around 30 nM P02100 cells . The EC(50) values for gene expression ranged from 9 to 90 nM in both cell types , dependent on the gene studied . In H292 cells , the proliferative response was much stronger if TGF-β was present . In P02100 cells this interaction of insulin and TGF-β was not observed , and changes in gene expression were mostly lower by at least 10-fold as compared to H292 . All in all , the insulin effects in H292 were generally much stronger than in P02100 cells and - with regard to proliferation - occurred at lower concentrations . Thus , insulin will hardly induce cancer from normal bronchial cells but may favour progression of pre-existing tumours . [ Activation of coagulation cascade in children during an idiopathic nephrotic syndrome relapse ] . The objective of this study was to assess concentrations of selected markers of coagulation in children with relapse of idiopathic nephrotic syndrome during a 6-week therapy . Study groups : 22 subjects ( 32 relapses ) -- 14 males , 8 females ( mean age 7.15 +/- 1.5 y. ) with no thrombotic complications were included into the study . All children were clinically steroid-sensitive . METHODS : Coagulation markers ( platelet count , thrombin time , APTT , INR , fibrinogen 1 + 2 fragments ( F1 + 2 ) , thrombin-antithrombin complexes ( TAT ) , serum levels of D-dimer ( DD ) , fibrin monomers ( FM ) and antithrombin activity ( P01008 ) ) were measured three times : on admission , after 2 and 6 weeks . The control group consisted of 13 healthy children . RESULTS : Serum concentration of TAT or F1 + 2 did not differ between 3 stages ( p > 0.05 ) . However , values at 0 and 2 weeks were significantly higher than in control group ( p < 0.05 ) . We found no correlation between TAT or F1 + 2 and FBG , ALB , TCH , TG levels . [ table : see text ] CONCLUSIONS : The coagulation cascade in relapse of NS was activated during first 6 weeks of therapy whereas metabolic disturbances ( low ALB , high P02675 , TCH , TG , high platelets ) normalized . It is speculative whether it was caused by active immunological process but definitely it resulted in " prothrombotic state " in P01308 patients . 99th Dahlem conference on infection , inflammation and chronic inflammatory disorders : immune therapies of type 1 diabetes : new opportunities based on the hygiene hypothesis . P01308 -dependent ( type 1 ) diabetes is a prototypic organ-specific autoimmune disease resulting from the selective destruction of insulin-secreting beta cells within pancreatic islets of Langerhans by an immune-mediated inflammation involving autoreactive P01730 (+) and CD8(+) T lymphocytes which infiltrate pancreatic islets . Current treatment is substitutive , i.e. chronic use of exogenous insulin which , in spite of significant advances , is still associated with major constraints ( multiple daily injections , risks of hypoglycaemia ) and lack of effectiveness over the long term in preventing severe degenerative complications . Finding a cure for autoimmune diabetes by establishing effective immune-based therapies is a real medical health challenge , as the disease incidence increases steadily in industrialized countries . As the disease affects mainly children and young adults , any candidate immune therapy must therefore be safe and avoid a sustained depression of immune responses with the attendant problems of recurrent infection and drug toxicity . Thus , inducing or restoring immune tolerance to target autoantigens , controlling the pathogenic response while preserving the host reactivity to exogenous/unrelated antigens , appears to be the ideal approach . Our objective is to review the major progress accomplished over the last 20 years towards that aim . In addition , we would like to present another interesting possibility to access new preventive strategies based on the ' hygiene hypothesis ' , which proposes a causal link between the increasing incidence of autoimmune diseases , including diabetes , and the decrease of the infectious burden . The underlying rationale is to identify microbial-derived compounds mediating the protective activity of infections which could be developed therapeutically . Determination of fenofibric acid concentrations by HPLC after anion exchange solid-phase extraction from human serum . Triglycerides are increasingly being recognized as a risk factor for cardiovascular disease . Research efforts to identify sources of variability in triglyceride-lowering response to the lipid-lowering drug fenofibrate require quantification of the active acidic form of this Q07869 agonist . Anion-exchange solid-phase extraction , in combination with reverse-phase high-performance liquid chromatography ( HPLC ) , rapidly and accurately determines steady-state fenofibric acid serum concentrations . Chromatographic separation under isocratic conditions , with use of ultraviolet detection at 285 nm , provides clean baseline and sharp peaks for clofibric acid , 1-napthyl acetic acid ( internal standards ) , and fenofibric acid . Commonly prescribed and over-the-counter nonsteroidal anti-inflammatory drugs ( NSAIDs ) were screened for assay interference , and the assay was employed to quantify fenofibric acid in more than 800 human subject specimens . DB01039 analysis was found to be linear over the range of 0.5 to 40 mg/L and was validated with either internal standard . Accuracies ranged from 98.65 % to 102.4 % , whereas the within- and between-day precisions ranged from 1.0 % to 2.2 % and 2.0 % to 6.2 % , respectively . NSAIDs had minimal interference with the assay , which succeeded in quantifying fenofibric acid in more than 843 of 846 serum samples from human subjects , many taking a variety of coadministered medications . Anion-exchange solid-phase extraction in combination with reverse-phase HPLC accurately determines steady-state fenofibric acid serum concentrations in humans without interference from NSAIDs or commonly administered medications . This method is suitable for quantification of fenofibric acid for clinical pharmacokinetic studies in patients with dyslipidemia . Cellular distribution and contribution of cyclooxygenase P35354 to diabetogenesis in NOD mouse . Unlike most other mammalian cells , beta-cells of Langerhans constitutively express cyclooxygenase ( P36551 ) -2 rather than P23219 . P35354 is also constitutively expressed in type 1 diabetes ( T1D ) patients ' periphery blood monocytes and macrophage . To understand the role of P35354 in the beta-cell , we investigated P35354 expression in beta-cells and islet infiltrates of NOD and BALB/c mice using fluorescence immunohistochemistry and cytochemical confocal microscopy and Western blotting . Immunostaining showed that P35354 is expressed in islet-infiltrating macrophages , and that the expression of insulin and P35354 disappeared concomitantly from the beta-cells when NOD mice progressed toward overt diabetes . Also cultured P01308 -1E cells coexpressed insulin and P35354 but clearly in different subcellular compartments . Treatment with celecoxib increased insulin release from these cells in a dose-dependent manner in glucose concentrations ranging from 5 to 17 mM . Excessive P35354 expression by the islet-infiltrating macrophages may contribute to the beta-cell death during insulitis . The effects of celecoxib on P01308 -1E cells suggest that PGE(2) and other downstream products of P35354 may contribute to the regulation of insulin release from the beta-cells . P01308 / P05019 signaling pathways enhances tumor cell invasion through bisecting GlcNAc N-glycans modulation . an interplay with P12830 . Changes in glycosylation are considered a hallmark of cancer , and one of the key targets of glycosylation modifications is P12830 . We and others have previously demonstrated that P12830 has a role in the regulation of bisecting GlcNAc N-glycans expression , remaining to be determined the P12830 -dependent signaling pathway involved in this N-glycans expression regulation . In this study , we analysed the impact of P12830 expression in the activation profile of receptor tyrosine kinases such as insulin receptor ( IR ) and P08069 ( IGF-IR ) . We demonstrated that exogenous P12830 expression inhibits IR , IGF-IR and P29323 1/2 phosphorylation . Stimulation with insulin and P05019 in MDA-MD-435 cancer cells overexpressing P12830 induces a decrease of bisecting GlcNAc N-glycans that was accompanied with alterations on P12830 cellular localization . Concomitantly , IR/IGF-IR signaling activation induced a mesenchymal-like phenotype of cancer cells together with an increased tumor cell invasion capability . Altogether , these results demonstrate an interplay between P12830 and IR/IGF-IR signaling as major networking players in the regulation of bisecting N-glycans expression , with important effects in the modulation of epithelial characteristics and tumor cell invasion . Here we provide new insights into the role that P01308 / P05019 signaling play during cancer progression through glycosylation modifications . DB08879 -- an anti- Q9Y275 human monoclonal antibody for rheumatoid arthritis . INTRODUCTION : Q9Y275 ( Q9Y275 ) is a major regulatory factor that controls the development and survival of B cells . Elevated serum levels of Q9Y275 have been associated with rheumatoid arthritis ( RA ) . DB08879 is a fully human monoclonal antibody that inhibits Q9Y275 and it is being developed for the treatment of RA . This review aims to summarize up-to-date pharmacological and clinical data of belimumab in the treatment of RA . AREAS COVERED : A literature search was performed on PubMed using keywords , including belimumab , LymphoStat-B , benlysta , Q9Y275 inhibitor , rheumatoid arthritis and autoimmune disease . References of relevant studies were searched by hand . Abstracts of international conferences up to October 2012 were also included . DB08879 was well tolerated in the treatment of RA over 24 weeks . It significantly increased American College of Rheumatology ( P10323 )20 responses at week 24 , especially in patients with high disease activity , positive rheumatoid factor , no anti- P01375 treatment experience and those who had failed methotrexate therapy . However , belimumab failed to demonstrate significantly improved ACR50 and ACR70 responses in the single Phase II clinical trial of RA . EXPERT OPINION : These results suggest that the clinical efficacy of belimumab for RA needs to be further investigated in future clinical trials . Careful patient selection may be necessary for belimumab to achieve optimal clinical outcomes in RA . Gender difference in the activity but not expression of estrogen receptors alpha and beta in human lung adenocarcinoma cells . The higher frequency of lung adenocarcinoma in women smokers than in men smokers suggests a role for gender-dependent factors in the etiology of lung cancer . We evaluated estrogen receptor ( ER ) alpha and beta expression and activity in human lung adenocarcinoma cell lines and normal lung fibroblasts . Q8N1N2 -length ERalpha and ERbeta proteins were expressed in all cell lines with higher ERbeta than ERalpha . Although estradiol ( E(2) ) binding was similar , E(2) stimulated proliferation only in cells from females , and this response was inhibited by anti-estrogens 4-hydroxytamoxifen ( DB04468 ) and DB00947 . In contrast , E(2) did not stimulate replication of lung adenocarcinoma cells from males and DB04468 or ICI did not block cell proliferation . Similarly , transcription of an estrogen response element-driven reporter gene was stimulated by E(2) in lung adenocarcinoma cells from females , but not males . P06401 ( PR ) expression was increased by E(2) in two out of five adenocarcinoma cell lines from females , but none from males . E(2) decreased P12830 protein expression in some of the cell lines from females , as it did in MCF-7 breast cancer cells , but not in the cell lines from males . Thus , ERalpha and ERbeta expression does not correlate with the effect of ER ligands on cellular activities in lung adenocarcinoma cells . On the other hand , coactivator Q15648 expression was higher in lung adenocarcinoma cells from females versus males and higher in adenocarcinoma cells than in normal human bronchial epithelial cells . Q15648 and other ER coregulators may contribute to differences in estrogen responsiveness between lung adenocarcinoma cells in females and males . Exposure to an organophosphate ( DB00677 ) during a defined period in neonatal life induces permanent changes in brain muscarinic receptors and behaviour in adult mice . The organophosphate DB00677 ( DB00677 ) is a well-known inhibitor of cholinesterases . We have recently observed that neonatal exposure to a single subsymptomal dose of DB00677 induces permanent alterations in muscarinic cholinergic receptors ( MAChRs ) and in spontaneous behaviour , in the mice as adults . In order to determine if there is a critical period for these effects , neonatal mice were given a single oral dose of 1.5 mg/kg DB00677 b.wt. on postnatal day 3 , 10 or 19 , causing equal inhibition of P22303 . At the adult age of 4 months the mice were tested for spontaneous motor behaviour , and were subsequently sacrificed for measurement of density of MAChRs and subpopulations of MAChRs in the cerebral cortex by using the antagonist quinuclidinyl benzilate ( [3H]QNB ) , and agonist carbachol , respectively . At adult age , mice exposed to DB00677 on postnatal day ( P01160 ) 3 or 10 showed significant ( P < or = 0.01 ) alterations in spontaneous motor behaviour and a significant ( P < or = 0.01 ) decrease in muscarinic receptor density . There were no alterations mice exposed on P01160 19 . The proportions and affinity-constants of high- and low-affinity MAChR binding sites were not affected in mice showing altered MAChR density . The lack of effect on mice exposed on P01160 19 was not due to differences in P22303 activity . P06401 level as a predictor of response to megestrol acetate in advanced breast cancer : a retrospective study . DB00351 ( 160 mg/day ) produced a response rate of 44 % in a retrospective series of 39 evaluable patients with advanced breast cancer . The estrogen-receptor ( ER ) level was greater than 10 fmols/mg of protein in 28 patients , and the progesterone-receptor ( PR ) level was greater than 10 fmols/mg of protein in 26 patients . ER and PR levels , age , and disease-free interval were analyzed for their relationship to response . The PR was the single best predictor of response to megestrol acetate ; the addition of ER added 2 % to the predictive accuracy rate of PR alone . [ Effect of the monophase oral contraceptive combination with 20 ug ethinyl estradiol/150 ug desogestrel on haemostasis ] . The authors examined the changes in the haemostasis during the use of the oral contraceptive combination with 20 microg ethynil estradiol/150 microg desogestrel at 35 women , a basic group , who used the oral contraceptive in the duration of 12 months and a control group ( n=35 ) , who do not use the pills . We found statistically significant increase of Antithrombin III ( P01008 ) ( p < 0.011 ) , Cofactor II of DB01109 ( HCII ) ( p < 0.001 ) , the activity of plasminogen ( p < 0.026 ) and beta2-antiplasmin ( 0.026 ) , significant decrease of P02810 ( PrC ) ( p < 0.0001 ) and of total Protein S ( TPrS ) ( p < 0.03 ) in the basic group in comparision with the control one . We do not observe significant changes in the rest of the haemostatic variables between the two groups . During the use of the oral contraceptive combination with 20 microg ethynil estradiol/150 microg desogestrel the changes in the system of the natural inhibitors are balanced by these in the system of fibrinolysis . Dietary soy protein isolate attenuates metabolic syndrome in rats via effects on Q07869 , LXR , and SREBP signaling . To determine the effects of feeding soy or isoflavones on lipid homeostasis in early development , weanling rats were fed AIN-93G diets made with casein , soy protein isolate ( SPI+ ) , isoflavone-reduced SPI+ ( SPI- ) , or casein supplemented with genistein or daidzein for 14 d . PPARalpha-regulated genes and proteins involved in fatty acid degradation were upregulated by SPI+ ( P < 0.05 ) accompanied by increased promoter binding and expression of PPARalpha mRNA ( P < 0.05 ) . Feeding SPI- or pure isoflavones did not alter PPARalpha-regulated pathways . SPI+ feeding had similar effects on PPARgamma signaling . SPI+ , SPI- , and casein plus isoflavones all increased liver Q9UBH6 (LXR)alpha-regulated genes and enzymes involved in cholesterol homeostasis . Feeding SPI+ increased promoter binding of LXRalpha , expression of the transcription factor mRNA , and protein ( P < 0.05 ) . In a second experiment , male Sprague-Dawley rats were fed casein diets from postnatal d ( P01160 ) 24 to PND64 or were fed high-fat Western diets containing 5 g x kg(-1) cholesterol made with either casein or SPI+ . P01308 resistance , steatosis , and hypercholesterolemia in the Western diet-fed rats were partially prevented by SPI+ ( P < 0.05 ) . Nuclear sterol receptor element binding protein ( SREBP ) -1c protein and mRNA and protein expression of enzymes involved in fatty acid synthesis were increased by feeding Western diets containing casein but not SPI+ ( P < 0.05 ) . These data suggest that activation of Q07869 and LXR signaling and inhibition of SREBP-1c signaling may contribute to insulin sensitization and improved lipid homeostasis in SPI+-fed rats after consumption of diets high in fat and cholesterol . Activation of c-Jun-N-terminal-kinase is crucial for the induction of a cell cycle arrest in human colon carcinoma cells caused by flurbiprofen enantiomers . The unselective cyclooxygenase ( P36551 ) inhibitor DB00712 and its-in terms of P36551 -inhibition- " inactive " enantiomer R-flurbiprofen have been previously found to inhibit tumor development and growth in various animal models . The underlying mechanisms are unknown . Here , we show that both R- and DB00712 reduce survival of three colon cancer cell lines , which differ in the expression of P35354 ( HCT-15 , no P35354 ; Caco-2 , inducible P35354 ; and HT-29 , constitutive P35354 ) . The IC50 for S- and R-flurbiprofen ranged from 250 to 450 microM . Both flurbiprofen enantiomers induced apoptosis in all three cell lines as indicated by DNA- and PARP-cleavage . In addition , R- and DB00712 caused a P55008 -cell cycle block . The latter was associated with an activation of c-Jun N-terminal kinase ( JNK ) , an increase of the DNA binding activity of the transcription factor AP-1 and down-regulation of cyclin D1 expression . Western blot analysis , as well as supershift experiments , revealed that the AP-1 activation was associated with a change of AP-1 composition toward an increase of JunB . The JNK inhibitor SP600125 antagonized R- and DB00712 -induced AP-1 DNA binding , suppression of cyclin D1 expression , and the P55008 -cell cycle block . However , JNK inhibition had no effect on flurbiprofen-induced apoptosis . Hence , the cell cycle arrest is obviously mediated , at least in part , through JNK-activation , whereas R- and DB00712 -induced apoptosis is largely independent of JNK . Although in vitro effects of R- and DB00712 were indistinguishable , only R-flurbiprofen inhibited HCT-15 tumor growth in nude mice , suggesting the involvement of additional in vivo targets , which are differently affected by R- and DB00712 . Expression of P20839 and P12268 after transplantation and initiation of immunosuppression . BACKGROUND : DB01024 ( DB00603 ) mediates immunosuppressive effects by inhibiting inosine monophosphate dehydrogenase ( IMPDH ) . Induction of IMPDH activity has been observed in whole blood and erythrocyte samples during immunosuppressive therapy . Information concerning the mechanisms for increased IMPDH activity is limited and the potential implications of induction have been debated . METHODS : Whole blood , P01730 + cell , and reticulocyte samples were collected from 30 renal transplant patients pre- and posttransplantation . The expressions of two IMPDH isoforms , type 1 and 2 , were analyzed by real-time reverse-transcription polymerase chain reaction and quantified using a housekeeping gene index . The IMPDH activity was determined by ultraviolet high-performance liquid chromatography . RESULTS : Transplantation and the initiation of immunosuppressive therapy was associated with increased P20839 ( 50-88 % , P < 0.0005 ) and decreased P12268 ( 42-56 % , P < 0.0005 ) expression . In P01730 + cells , however , P12268 increased ( 15 % , P=0.009 ) . These changes are probably related to glucocorticoid effects . Two weeks posttransplant , DB00603 -treated patients displayed elevated P20839 and 2 in reticulocytes , suggesting enzyme induction in these cells during prolonged DB00603 therapy . Patients with acute rejection during follow-up demonstrated higher P12268 expression in P01730 + cells pretransplant than nonrejecting patients ( median expression 1.26 vs. 0.87 respectively , P=0.017 ) . CONCLUSIONS : Knowledge of changes in P20839 and 2 expression after transplantation and initiation of immunosuppression is important considering the action of DB00603 on IMPDH and the potential for pharmacodynamic monitoring of DB00603 by measuring IMPDH activity . The expression of P12268 in P01730 + cells pretransplant may be an indicator of immune activation . Adipose tissue tumor necrosis factor and interleukin-6 expression in human obesity and insulin resistance . Adipose tissue expresses tumor necrosis factor ( P01375 ) and interleukin ( IL ) -6 , which may cause obesity-related insulin resistance . We measured P01375 and P05231 expression in the adipose tissue of 50 lean and obese subjects without diabetes . P01308 sensitivity ( S(I) ) was determined by an intravenous glucose tolerance test with minimal-model analysis . When lean [ body mass index ( BMI ) < 25 kg/m(2) ] and obese ( BMI 30-40 kg/m(2) ) subjects were compared , there was a 7.5-fold increase in P01375 secretion ( P < 0.05 ) from adipose tissue , and the P01375 secretion was inversely related to S(I) ( r = -0.42 , P < 0.02 ) . P05231 was abundantly expressed by adipose tissue . In contrast to P01375 , plasma ( rather than adipose ) P05231 demonstrated the strongest relationship with obesity and insulin resistance . Plasma P05231 was significantly higher in obese subjects and demonstrated a highly significant inverse relationship with S(I) ( r = -0.71 , P < 0.001 ) . To separate the effects of BMI from S(I) , subjects who were discordant for S(I) were matched for BMI , age , and gender . By use of this approach , subjects with low S(I) demonstrated a 3.0-fold increased level of P01375 secretion from adipose tissue and a 2.3-fold higher plasma P05231 level ( P < 0.05 ) compared with matched subjects with a high S(I) . Plasma P05231 was significantly associated with plasma nonesterified fatty acid levels ( r = 0.49 , P < 0.002 ) . Thus the local expression of P01375 and plasma P05231 are higher in subjects with obesity-related insulin resistance . DB00227 , a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor , induces apoptosis and differentiation in human anaplastic thyroid carcinoma cells . Although only 1 % of differentiated thyroid cancers transform into anaplastic thyroid cancer , this disease is always fatal . Differentiation therapy may provide a new therapeutic approach to increasing the survival rate in such patients . 3-Hydroxy-3-methylglutaryl coenzyme A ( HMG- DB01992 ) reductase inhibitors are reported to promote cellular apoptosis and differentiation in many cancer cells ; these effects are unrelated to lipid reduction . Recently , we found that TNFalpha induces cytomorphological differentiation in anaplastic thyroid cancer cells and increases thyroglobulin expression ; however , P01375 is cytotoxic for normal human tissue . The aim of this study was to determine whether lovastatin , an P04035 inhibitor , could induce apoptosis and differentiation in anaplastic thyroid cancer cells . Anaplastic thyroid cancer cells were treated with lovastatin , then examined for cellular apoptosis and cytomorphological differentiation by DNA fragmentation , phosphatidylserine externalization/flow cytometry , and electron microscopy . Thyroglobulin levels in the culture medium were also measured . Our results showed that at a higher dose ( 50 micro M ) , lovastatin induced apoptosis of anaplastic thyroid cancer cells , whereas at a lower dose ( 25 micro M ) , it promoted 3-dimensional cytomorphological differentiation . It also induced increased secretion of thyroglobulin by anaplastic cancer cells . Our results show that lovastatin not only induces apoptosis , but also promotes redifferentiation in anaplastic thyroid cancer cells , and suggest that it and other P04035 inhibitors merit further investigation as differentiation therapy for the treatment of anaplastic thyroid cancer . Neuronal ablation of p-Akt at Ser473 leads to altered P08908 /2A receptor function . The serotonergic system regulates a wide range of behavior , including mood and impulsivity , and its dysregulation has been associated with mood disorders , autism spectrum disorder , and addiction . Diabetes is a risk factor for these conditions . P01308 resistance in the brain is specifically associated with susceptibility to psychostimulant abuse . Here , we examined whether phosphorylation of Akt , a key regulator of the insulin signaling pathway , controls serotonin ( 5-HT ) signaling . To explore how impairment in Akt function regulates 5-HT homeostasis , we used a brain-specific rictor knockout ( KO ) mouse model of impaired neuronal phosphorylation of Akt at Ser473 . Cortical P08908 and 5- Q13049 receptor binding was significantly elevated in rictor KO mice . Concomitant with this elevated receptor expression , the P08908 receptor agonist 8-Hydroxy-2-(di-n-propylamino)tetralin ( 8-OH-DPAT ) led to an increased hypothermic response in rictor KO mice . The increased cortical P08908 receptor density was associated with higher P08908 receptor levels on the cortical cell surface . In contrast , rictor KO mice displayed significantly reduced head-twitch response ( HTR ) to the 5- Q13049 /C agonist 2,5-dimethoxy-4-iodoamphetamine ( DOI ) , with evidence of impaired 5- Q13049 /C receptor signaling . In vitro , pharmacological inhibition of Akt significantly increased P08908 receptor expression and attenuated DOI-induced 5- Q13049 receptor signaling , thereby lending credence to the observed in vivo cross-talk between neuronal Akt signaling and 5-HT receptor regulation . These data reveal that defective central Akt function alters 5-HT signaling as well as 5-HT-associated behaviors , demonstrating a novel role for Akt in maintaining neuronal 5-HT receptor function . The relationship between albuminuria and hormone therapy in postmenopausal women . BACKGROUND : Elevated urinary albumin excretion and hormone therapy ( HT ) are associated with increased risk for cardiovascular events . We assessed the relationship between albuminuria and the use of hormonal preparations in postmenopausal women . METHODS : Data from the P01308 Resistance Atherosclerosis Study were obtained at baseline and 5-year follow-up for analysis . The generalized estimating equation procedure accounting for repeated measures was used for this analysis . HT was the main predictor variable , and log(e) urine albumin-creatinine ratio ( P10323 ) was the main outcome variable . RESULTS : Four hundred ninety-one menopausal women were included in the analysis , 36 % ( n = 179 ) of whom received HT ( either oral estrogen , progesterone , or combination therapy ) . At baseline , abnormal albuminuria ( P10323 > or = 25 mg/g ) was present in 11 % of women on HT and 17 % not on HT ( P = 0.02 ) . After adjusting for demographics , the presence of diabetes and hypertension , and kidney function , HT was associated with a 19 % reduction in P10323 ( P = 0.008 ) and an odds ratio of 0.67 ( 95 % confidence interval , 0.43 to 1.01 ; P = 0.06 ) for the presence of abnormal albuminuria . Other predictors of abnormal albuminuria included diabetes , blood pressure , and triglyceride level . CONCLUSION : Results of this study suggest that HT is associated with a reduction in urinary albumin excretion in postmenopausal women .