[ "Induction of apoptosis of Beta cells of the pancreas by advanced glycation end - products , important mediators of chronic complications of diabetes mellitus . We herein report cytotoxicity of advanced glycation end - products ( AGEs ) on pancreatic beta cells . AGEs stimulated reactive oxygen species ( ROS ) generation but did not arrest proliferation of the P01308 - 1 cell line . Pancreatic beta cell lines or primary cultured islets possess a receptor for P51606 ( RAGE ) , and its expression increased after P51606 treatment . TUNEL staining and FACS analysis using annexin V / PI antibodies showed that apoptosis increased in P01308 - 1 cells or primary cultured islets when incubated with BSA conjugated with glyceraldehyde ( AGE2 ) or glucoaldehyde ( AGE3 ) , compared with those conjugated with glucose ( AGE1 ) . Reaction of P01308 - 1 cells to Ki67 , which is a cellular marker for proliferation , was also increased after P51606 treatment . The ability of primary cultured islets to secrete insulin was retained even after P51606 treatment under either low or high glucose conditions . The antiserum against RAGE partially prevented P51606 - induced cellular events . Treatment of beta cells with the antioxidant metallothionein results in a significant reduction in pathologic changes . AGEs might be able to induce apoptosis as well as proliferation of pancreatic beta cell lines or primary cultured islets . Moreover , antibody array showed that Q06609 and P43351 were significantly decreased in AGE2 - treated P01308 - 1 cells . AGEs might inhibit homologous DNA recombination for repairing DNA of P01308 - 1 cells damaged by ROS generation . It might be suggested that treatment of AGEs resulted in ROS production and apoptosis through their receptor on pancreatic beta cells . AGEs might deteriorate function of pancreatic beta cells in patients with long - term hyperglycemia .", "Chronic daily tadalafil prevents the corporal fibrosis and veno - occlusive dysfunction that occurs after cavernosal nerve resection . OBJECTIVES : To determine whether a long - term single daily oral dose of a longer half - life phosphodiesterase - 5 ( O76074 ) inhibitor , tadalafil , has a similar effect to that of the shorter half - life O76074 inhibitors sildenafil and vardenafil , and can prevent the fibrosis and resultant corporal veno - occlusive dysfunction ( CVOD ) occurring after cavernosal nerve ( CN ) injury . MATERIALS AND METHODS : Male rats ( 10 per group ) had either a sham operation , unilateral CN resection ( P21554 ) or bilateral P21554 , and were left untreated or given retrolingually 5 mg / kg per day of tadalafil . After 45 days , CVOD was assessed via cavernosometry , and the underlying corporal tissue changes were examined by immunohistochemistry and histochemistry ( followed by quantitative image analysis ) , Western blots , and ad hoc methods . RESULTS : ___MASK2___ treatment normalized the low response to papaverine and high drop rate in the intracavernosal pressure measured by cavernosometry after P21554 compared with sham - operated rats . ___MASK2___ also normalized the increase in penile shaft collagen content , and the reduction in corporal smooth muscle cell ( SMC ) content , SMC / collagen , and replication index , and improved the lower collagen III / I ratio and the increase in apoptotic index , caused by P21554 , compared with sham operation . There were no effects of tadalafil on increased transforming growth factor beta1 , inducible nitric oxide synthase and xanthine oxidoreductase levels . CONCLUSIONS : A long - term single daily dose of tadalafil prevented CVOD and the underlying corporal fibrosis in the rat caused by CN damage , as effectively as the previously reported continuous treatment with vardenafil or sildenafil , through a cGMP - related mechanism that appears to be independent of inducible nitric oxide synthase induction .", "Potentiation of neurotoxicity in double - mutant mice with Pink1 ablation and A53T - P37840 overexpression . The common age - related neurodegeneration of Parkinson ' s disease can result from dominant causes like increased dosage of vesicle - associated alpha - synuclein ( P37840 ) or recessive causes like deficiency of mitophagy factor Q9BXM7 . Interactions between these triggers and their convergence onto shared pathways are crucial , but currently conflicting evidence exists . Here , we crossed previously characterized mice with A53T - P37840 overexpression and with Pink1 deletion to generate double mutants ( DMs ) . We studied their lifespan and behavior , histological and molecular anomalies at late and early ages . DM animals showed potentiated phenotypes in comparison with both single mutants ( SMs ) , with reduced survival and strongly reduced spontaneous movements from the age of 3 months onwards . In contrast to SMs , a quarter of DM animals manifested progressive paralysis at ages > 1 year and exhibited protein aggregates immunopositive for pSer129 - P37840 , p62 and ubiquitin in spinal cord and basal brain . Brain proteome quantifications of ubiquitination sites documented altered degradation of P37840 and the DNA - damage marker P16104 at the age of 18 months . Global brain transcriptome profiles and qPCR validation experiments identified many consistent transcriptional dysregulations already at the age of 6 weeks , which were absent from SMs . The observed downregulations for Dapk1 , Dcaf17 , Rab42 and the novel P37840 - marker Lect1 as well as the upregulations for Dctn5 , Mrpl9 , Tmem181a , Xaf1 and H2afx reflect changes in ubiquitination , mitochondrial / synaptic / microtubular / cell adhesion dynamics and DNA damage . Thus , our study confirmed that P37840 - triggered neurotoxicity is exacerbated by the absence of Q9BXM7 and identified a novel molecular signature that is detectable early in the course of this double pathology .", "P37840 A30P point - mutation generates age - dependent nigrostriatal deficiency in mice . Lewy bodies are mainly composed of alpha - synuclein ( P37840 ) and specific mutations in P37840 gene are related to familial forms of Parkinson ' s disease ( PD ) . The purpose of our study was to generate a mouse line with A30P knock - in point mutation in P37840 gene and to test if a single point - mutation is able to turn otherwise normal P37840 into a toxic form . The behavioral profile of P37840 A30P mice was followed for 16 months . Generally , these mice are healthy and viable without any obvious abnormalities . Starting from the age of 13 months mice developed a significant deficit in motor performance tests related to nigrostriatal function ( ink - test and beam walk ) . In other tests ( motility boxes , rotarod ) mice continuously performed normally . Moreover , P37840 A30P mice expressed the altered sensitivity to Q05940 inhibitor reserpine , possibly reflecting a functional deficiency of dopamine . Indeed , mice at 15 months of age had significantly reduced levels of dopamine and its major metabolite DOPAC in the striatum , and reduced levels of dopamine in the mesolimbic system . The present study confirms that P37840 plays an important role in the development of PD and an insertion of a single point mutation is sufficient to generate age - related decline in specific motor performance . The generated mouse line has a potential to become a model for PD with comparable time course and phenotype .", "Glucocorticoid - induced surface expression of annexin 1 blocks beta2 - integrin adhesion of human eosinophils to intercellular adhesion molecule 1 surrogate protein . BACKGROUND : Glucocorticoids attenuate the population of eosinophils and T lymphocytes in asthmatic airways . The decrease in airway eosinophilia is caused both by accelerated cell death and by induction of blockade of integrin adhesion . In this study , we examined the hypothesis that annexin 1 surface expression , which is upregulated by the glucocorticoid receptor , prevents integrin adhesion essential to cell migration by blocking intracellular translocation of cytosolic group IV phospholipase A2 ( P47712 ) . OBJECTIVE : To examine the relationship of the glucocorticoid on annexin 1 expression and the effect of blockade of annexin 1 activity on adhesion of human eosinophils in vitro . To determine the relationship between annexin 1surface expression and nuclear membrane translocation of P47712 . METHODS : Eosinophils isolated from human peripheral blood were pretreated with fluticasone propionate ( FP ) , and beta2 - integrin adhesion was measured after stimulation with P05113 or eotaxin . Effects of FP on P47712 expression , phosphorylation , and translocation were determined . The role of annexin 1 was examined by using annexin 1 blocking antibody and / or mimetic peptides . RESULTS : ___MASK42___ decreased stimulated eosinophil adhesion and caused 4 - fold increase in annexin 1 expression on the plasma membrane . Inhibition of adhesion by FP was blocked with annexin 1 blocking antibody . Annexin 1 N - terminal mimetic peptide also blocked beta2 - integrin adhesion . Translocation of P47712 to the nuclear membrane was significantly blocked by incubation with FP . Blockade was reversed with annexin 1 blocking antibody . CONCLUSION : Blockade of beta2 - integrin adhesion by glucocorticoid is regulated by annexin 1 , which blocks P47712 translocation to nuclear membrane .", "Growth - associated gene expression profiles by microarray analysis of trophoblast of molar pregnancies and normal villi . We used microarray analysis to investigate expression profiles of 589 known genes committed to cell growth control to characterize regulatory circuitry for cell proliferation in complete moles ( CMs ) . CMs are characterized by hyperplastic trophoblast and have a high propensity to give rise to choriocarcinoma . Characteristic alterations in gene expression profiles were observed when compared with normal villi . Fifty - seven genes were significantly up - regulated in CMs and involved the Ras - Map kinase 3 , Jak - P42229 , and Wnt signal pathways , implicating growth factor or cytokine - mediated signal pathways in the trophoblastic hyperplasia of CMs . Several genes associated with anti - apoptosis , cell structuring , and / or cell attachment were also up - regulated in CMs . In contrast , relatively fewer genes were down - regulated and these involved IGFBPs , versican , interleukin - 1 , tumor necrosis factor receptor , P16070 , and P43351 . Genes identified in this study may elucidate regulation mechanisms of trophoblastic proliferation and mechanisms causing a pathological phenotype in CMs .", "Reconstruction and functional analysis of altered molecular pathways in human atherosclerotic arteries . BACKGROUND : Atherosclerosis affects aorta , coronary , carotid , and iliac arteries most frequently than any other body vessel . There may be common molecular pathways sustaining this process . Plaque presence and diffusion is revealed by circulating factors that can mediate systemic reaction leading to plaque rupture and thrombosis . RESULTS : We used DNA microarrays and meta - analysis to study how the presence of calcified plaque modifies human coronary and carotid gene expression . We identified a series of potential human atherogenic genes that are integrated in functional networks involved in atherosclerosis . Caveolae and JAK / P35610 pathways , and P06702 / P05109 interacting proteins are certainly involved in the development of vascular disease . We found that the system of caveolae is directly connected with genes that respond to hormone receptors , and indirectly with the apoptosis pathway . Cytokines , chemokines and growth factors released in the blood flux were investigated in parallel . High levels of RANTES , IL - 1ra , MIP - 1 alpha , MIP - 1 beta , P60568 , P05112 , P05113 , P05231 , P13232 , Q16552 , DB00102 , P15692 and P01579 were found in plasma of atherosclerotic patients and might also be integrated in the molecular networks underlying atherosclerotic modifications of these vessels . CONCLUSION : The pattern of cytokine and P06702 / P05109 up - regulation characterizes atherosclerosis as a proinflammatory disorder . Activation of the JAK / P35610 pathway is confirmed by the up - regulation of P05231 , P42224 , Q00978 and Q13651 genes in coronary and carotid plaques . The functional network constructed in our research is an evidence of the central role of P35610 protein and the caveolae system to contribute to preserve the plaque . Moreover , Cav - 1 is involved in SMC differentiation and dyslipidemia confirming the importance of lipid homeostasis in the atherosclerotic phenotype .", "Inhibition of histamine H1 receptor activity modulates proinflammatory cytokine production of dendritic cells through c - Rel activity . BACKGROUND : DB11320 exerts diverse effects on immune regulation through four types of histamine receptors ( HRs ) . Among them , type 1 receptor ( P35367 ) plays an important role in allergic inflammation . Dendritic cells ( DCs ) , which express at least three types of HRs , are professional antigen - presenting cells controlling the development of allergic inflammation . However , the molecular mechanisms involved in P35367 - mediated NF - ĸB signaling of DCs remain poorly defined . METHODS : Bone - marrow ( BM ) - derived DCs ( BM - DCs ) were treated with P35367 inverse agonists to interrupt basal P35367 - mediated signaling . The crosstalk of P35367 - mediated signaling and the NF - ĸB pathway was examined by NF - ĸB cellular activity using a luciferase reporter assay , NF - ĸB subunit analysis using Western blotting and P01375 - α promoter activity using chromatin immunoprecipitation . RESULTS : Blockage of P35367 signaling by inverse agonists significantly inhibited P01375 - α and P05231 production of BM - DCs . P35367 - specific agonists were able to enhance P01375 - α production , but this overexpression was significantly inhibited by NF - ĸB inhibitor . The P35367 inverse agonist ketotifen also suppressed cellular NF - ĸB activity , suggesting crosstalk between P35367 and NF - ĸB signaling in DCs . After comprehensive analysis of NF - ĸB subunits , c - Rel protein expression was significantly down - regulated in ketotifen - treated BM - DCs , which led to inhibition of the promoter activity of P01375 - α . Finally , adoptive transfer of the ketotifen - treated BM - DCs did not induce significant allergic airway inflammation compared to that of control cells in vivo . CONCLUSIONS : Our results suggest that c - Rel controls P35367 - mediated proinflammatory cytokine production in DCs . This study provides a potential mechanism of P35367 - mediated signaling and NF - ĸB pathway crosstalk in allergic inflammation .", "Sources contributing to the average extracellular concentration of dopamine in the nucleus accumbens . Mesolimbic dopamine neurons fire in both tonic and phasic modes resulting in detectable extracellular levels of dopamine in the nucleus accumbens ( NAc ) . In the past , different techniques have targeted dopamine levels in the NAc to establish a basal concentration . In this study , we used in vivo fast scan cyclic voltammetry ( FSCV ) in the NAc of awake , freely moving rats . The experiments were primarily designed to capture changes in dopamine caused by phasic firing - that is , the measurement of dopamine ' transients ' . These FSCV measurements revealed for the first time that spontaneous dopamine transients constitute a major component of extracellular dopamine levels in the NAc . A series of experiments were designed to probe regulation of extracellular dopamine . DB00281 was infused into the ventral tegmental area , the site of dopamine cell bodies , to arrest neuronal firing . While there was virtually no instantaneous change in dopamine concentration , longer sampling revealed a decrease in dopamine transients and a time - averaged decrease in the extracellular level . Dopamine transporter inhibition using intravenous GBR12909 injections increased extracellular dopamine levels changing both frequency and size of dopamine transients in the NAc . To further unmask the mechanics governing extracellular dopamine levels we used intravenous injection of the vesicular monoamine transporter ( Q05940 ) inhibitor , tetrabenazine , to deplete dopamine storage and increase cytoplasmic dopamine in the nerve terminals . ___MASK10___ almost abolished phasic dopamine release but increased extracellular dopamine to ∼ 500 nM , presumably by inducing reverse transport by dopamine transporter ( Q01959 ) . Taken together , data presented here show that average extracellular dopamine in the NAc is low ( 20 - 30 nM ) and largely arises from phasic dopamine transients .", "Molecular determinants of trastuzumab efficacy : What is their clinical relevance ? ___MASK51___ - containing therapy is a standard of care for human epidermal growth factor receptor - 2 ( P04626 ) - positive breast cancer . In pre - clinical models , a wide range of molecular mechanisms have been associated with reduced sensitivity to trastuzumab in vitro . These include expression of the truncated P04626 receptor fragment p95HER2 , activating mutation of the gene encoding the class 1A catalytic subunit of phosphatidylinositol 3 - kinase ( P42336 ) , loss of phosphatase and tensin homolog ( P60484 ) , activation of other downstream signal transducers , prevention of cell cycle arrest , increased signaling through alternative ( HER or non - HER ) tyrosine kinase receptors , and resistance to antibody - dependent cellular cytotoxicity . However , the clinical significance of these mechanisms as determinants of trastuzumab efficacy in vivo has been unclear . Here , we review clinical studies of potential predictive biomarkers of trastuzumab efficacy in P04626 - positive breast cancer and consider whether evaluation of such markers might inform patient selection for therapy . We find that clinical evidence relating to potential predictive biomarkers is mostly limited to small , retrospective studies , many of which have yielded conflicting findings . Some trends are evident in the retrospective data and in biomarker analyses from randomized clinical trials , particularly relating to activation of the phosphatidylinositol 3 - kinase pathway , but none is sufficiently strong to form a basis for patient selection . This may be explained by the fact that multiple mechanisms of action determine the clinical efficacy of trastuzumab . In the absence of novel , validated biomarkers of efficacy , trastuzumab eligibility should continue to be based on evaluation of P04626 status according to standard methods .", "Recombinant P17936 inhibits allergic lung inflammation , P15692 production , and vascular leak in a mouse model of asthma . BACKGROUND : Vascular endothelial growth factor ( P15692 ) plays a pro - inflammatory mediator as well as a vascular permeability factor in bronchial asthma . P01308 - like growth factor ( IGF ) - I is also involved in the inflammatory process associated with bronchial asthma and stimulates P15692 expression . The IGF - binding proteins ( IGFBPs ) , especially P17936 , display distinctive properties and can interfere with various biological processes . METHODS : In this study , an ovalbumin ( OVA ) - induced murine model of allergic airway disease was used to investigate which mechanism is implicated in the preventive and therapeutic actions of P17936 administered exogenously on allergen - induced bronchial inflammation and airway hyper - responsiveness , in particular focusing on the regulation of P15692 expression . RESULTS : Administration of recombinant human P17936 to OVA - inhaled mice substantially attenuated the increases in hypoxia - inducible factor ( HIF ) - α activity , P05019 production , and P15692 protein levels in the lung . In addition , the blockade of P05019 action decreased the OVA - induced P15692 expression , airway inflammation , and bronchial hyper - responsiveness . The administration of recombinant human P17936 or CBO - P11 also reduced significantly increases in inflammatory cells , airway hyper - responsiveness , levels of P05112 , P05113 , P35225 , and vascular permeability in the lung of OVA - inhaled mice . Moreover , when recombinant human P17936 was administered after the completion of OVA inhalation , these therapeutic effects of P17936 were also observed . CONCLUSIONS : These results indicate that P17936 administered exogenously may attenuate antigen - induced airway inflammation and hyper - responsiveness through the modulation of vascular leakage and P15692 expression mediated by HIF - 1α / HIF - 2α signaling as well as P05019 action in allergic airway disease of mice .", "P10275 accelerates premature senescence of human dermal papilla cells in association with DNA damage . The dermal papilla , located in the hair follicle , expresses androgen receptor and plays an important role in hair growth . Androgen / P10275 actions have been implicated in the pathogenesis of androgenetic alopecia , but the exact mechanism is not well known . Recent studies suggest that balding dermal papilla cells exhibit premature senescence , upregulation of p16 ( INK4a ) , and nuclear expression of DNA damage markers . To investigate whether androgen / AR signaling influences the premature senescence of dermal papilla cells , we first compared frontal scalp dermal papilla cells of androgenetic alopecia patients with matched normal controls and observed that premature senescence is more prominent in the dermal papilla cells of androgenetic alopecia patients . Exposure of androgen induced premature senescence in dermal papilla cells from non - balding frontal and transitional zone of balding scalp follicles but not in beard follicles . Overexpression of the AR promoted androgen - induced premature senescence in association with p16 ( INK4a ) upregulation , whereas knockdown of the androgen receptor diminished the effects of androgen . An analysis of γ - P16104 expression in response to androgen / androgen receptor signaling suggested that DNA damage contributes to androgen / androgen receptor - accelerated premature senescence . These results define androgen / androgen receptor signaling as an accelerator of premature senescence in dermal papilla cells and suggest that the androgen / androgen receptor - mediated DNA damage - p16 ( INK4a ) axis is a potential therapeutic target in the treatment of androgenetic alopecia .", "DB00107 alleviates the neuroendocrine and cytokine response to bacterial endotoxin in healthy men . DB00107 is a hormone and neurotransmitter found to have anti - inflammatory functions in rodents . Here we used experimental bacterial endotoxinemia to examine the role of exogenous oxytocin administration on innate immune responses in humans . Ten healthy men received , in a randomized , placebo - controlled , crossover design , placebo , oxytocin , LPS , and LPS + oxytocin . DB00107 treatment resulted in a transient or prolonged reduction of endotoxin - induced increases in plasma DB01285 , cortisol , procalcitonin , P01375 , IL - 1 receptor antagonist , P05112 , P05231 , macrophage inflammatory protein - 1alpha , macrophage inflammatory protein - 1beta , monocyte chemoattractant protein - 1 ( P13500 ) , interferon - inducible protein 10 , and P15692 . In vitro , oxytocin had no impact on LPS effects in releasing P01375 , P05231 , and P13500 in monocytes and peripheral blood mononuclear cells from healthy human donors . In summary , oxytocin decreases the neuroendocrine and cytokine activation caused by bacterial endotoxin in men , possibly due to the pharmacological modulation of the cholinergic anti - inflammatory pathway . DB00107 might be a candidate for the therapy of inflammatory diseases and conditions associated with high cytokine and P15692 levels .", "Antenatal maternally - administered phosphodiesterase type 5 inhibitors normalize P29474 expression in the fetal lamb model of congenital diaphragmatic hernia . PURPOSE : Pulmonary hypertension ( pHTN ) , a main determinant of survival in congenital diaphragmatic hernia ( Q8NE62 ) , results from in utero vascular remodeling . Phosphodiesterase type 5 ( O76074 ) inhibitors have never been used antenatally to treat pHTN . The purpose of this study is to determine if antenatal O76074 inhibitors can prevent pHTN in the fetal lamb model of Q8NE62 . METHODS : Q8NE62 was created in pregnant ewes . Postoperatively , pregnant ewes received oral placebo or tadalafil , a O76074 inhibitor , until delivery . Near term gestation , lambs underwent resuscitations , and lung tissue was snap frozen for protein analysis . RESULTS : Mean cGMP levels were 0 . 53 ± 0 . 11 in placebo - treated fetal lambs and 1 . 73 ± 0 . 21 in tadalafil - treated fetal lambs ( p = 0 . 002 ) . Normalized expression of P29474 was 82 % ± 12 % in Normal - Placebo , 61 % ± 5 % in Q8NE62 - Placebo , 116 % ± 6 % in Normal - ___MASK2___ , and 86 % ± 8 % in Q8NE62 - ___MASK2___ lambs . Normalized expression of β - sGC was 105 % ± 15 % in Normal - Placebo , 82 % ± 3 % in Q8NE62 - Placebo , 158 % ± 16 % in Normal - ___MASK2___ , and 86 % ± 8 % in Q8NE62 - ___MASK2___ lambs . P29474 and β - sGC were significantly decreased in Q8NE62 ( p = 0 . 0007 and 0 . 01 for P29474 and β - sGC , respectively ) , and tadalafil significantly increased P29474 expression ( p = 0 . 0002 ) . CONCLUSIONS : O76074 inhibitors can cross the placental barrier . β - sGC and P29474 are downregulated in fetal lambs with Q8NE62 . Antenatal O76074 inhibitors normalize P29474 and may prevent in utero vascular remodeling in Q8NE62 .", "Regulation of double - strand break - induced mammalian homologous recombination by P63165 , a Q96B01 . Mammalian Q06609 protein plays essential roles in DNA homologous recombination , DNA repair and cell proliferation . Q06609 activities are regulated by its associated proteins . It was previously reported that a ubiquitin - like protein , P63165 , associates with Q06609 in the yeast two - hybrid system . One function of P63165 is to covalently conjugate with target proteins and thus modify their function . In the present study we found that non - conjugated P63165 forms a complex with Q06609 and P43351 proteins in human cells . Overexpression of P63165 down - regulates DNA double - strand break - induced homologous recombination in CHO cells and reduces cellular resistance to ionizing radiation in HT1080 cells . With or without overexpressed P63165 , most homologous recombination products arise by gene conversion . However , overexpression of P63165 reduces the fraction of bidirectional gene conversion tracts . Overexpression of a mutant P63165 that is incapable of being conjugated retains the ability to inhibit homologous recombination . These results suggest a regulatory role for P63165 in homologous recombination .", "DB00184 induces cell proliferation , invasion and epithelial - mesenchymal transition in a variety of human cancer cell lines . Cigarette smoking is strongly correlated with the onset of nonsmall cell lung cancer ( NSCLC ) . DB00184 , an active component of cigarettes , has been found to induce proliferation of lung cancer cell lines . In addition , nicotine can induce angiogenesis and confer resistance to apoptosis . All these events are mediated through the nicotinic acetylcholine receptors ( nAChRs ) on lung cancer cells . In this study , we demonstrate that nicotine can promote anchorage - independent growth in NSCLCs . In addition , nicotine also induces morphological changes characteristic of a migratory , invasive phenotype in NSCLCs on collagen gel . These morphological changes were similar to those induced by the promigratory growth factor P15692 . The proinvasive effects of nicotine were mediated by alpha7 - nAChRs on NSCLCs . RT - PCR analysis showed that the alpha7 - nAChRs were also expressed on human breast cancer and pancreatic cancer cell lines . DB00184 was found to promote proliferation and invasion in human breast cancer . The proinvasive effects of nicotine were mediated via a nAChR , Src and calcium - dependent signaling pathway in breast cancer cells . In a similar fashion , nicotine could also induce proliferation and invasion of Aspc1 pancreatic cancer cells . Most importantly , nicotine could induce changes in gene expression consistent with epithelial to mesenchymal transition ( EMT ) , characterized by reduction of epithelial markers like P12830 expression , ZO - 1 staining and concomitant increase in levels of mesenchymal proteins like vimentin and fibronectin in human breast and lung cancer cells . Therefore , it is probable that the ability of nicotine to induce invasion and EMT may contribute to the progression of breast and lung cancers .", "Topoisomerase II - mediated DNA cleavage and mutagenesis activated by nitric oxide underlie the inflammation - associated tumorigenesis . AIMS : Both cancer - suppressing and cancer - promoting properties of reactive nitrogen and oxygen species ( RNOS ) have been suggested to play a role in tumor pathology , particularly those activities associated with chronic inflammation . Here , we address the impact of nitric oxide ( NO ) on the induction of DNA damage and genome instability with a specific focus on the involvement of topoisomerase II ( P11388 ) . We also investigate the contribution of NO to the formation of skin melanoma in mice . RESULTS : Similar to the P11388 - targeting drug , etoposide ( DB00773 ) , the NO - donor , S - nitrosoglutathione ( GSNO ) , induces skin melanomas formation in 7 , 12 - dimethyl - benz [ a ] anthracene ( DMBA ) - initiated mice . To explore the mechanism ( s ) underlying this NO - induced tumorigenesis , we use a co - culture model system to demonstrate that inflamed macrophages with inducible NO synthase ( P35228 ) expression cause γ - P16104 activation , p53 phosphorylation , and chromosome DNA breaks in the target cells . Inhibitor experiments revealed that NO and P11388 isozymes are responsible for the above described cellular phenotypes . Notably , NO , unlike DB00773 , preferentially induces the formation of TOP2β cleavable complexes ( TOP2βcc ) in cells . Moreover , GSNO induced P11388 - dependent DNA sequence rearrangements and cytotoxicity . Furthermore , the incidences of GSNO - and DB00773 - induced skin melanomas were also observed to be lower in the skin - specific top2β - knockout mice . Our results suggest that P11388 isozymes contribute to NO - induced mutagenesis and subsequent cancer development during chronic inflammation . INNOVATION AND CONCLUSIONS : We provide the first experimental evidence for the functional role of P11388 in NO - caused DNA damage , mutagenesis , and carcinogenesis . Notably , these studies contribute to our molecular understanding of the cancer - promoting actions of RNOS during chronic inflammation .", "Changing paradigms in management of metastatic Castration Resistant Prostate Cancer ( mCRPC ) . Recently , the standard of care for metastatic Castration Resistant Prostate Cancer ( mCRPC ) has changed considerably . Persistent androgen receptor ( AR ) signaling has been identified as a target for novel therapies and reengages the fact that AR continues to be the primary target responsible for metastatic prostate cancer . P10275 gene amplification and over expression have been found to result in a higher concentration of androgen receptors on tumor cells , making them extremely sensitive to low levels of circulating androgens . Additionally , prostate cancer cells are able to maintain dihydrotestosterone ( ___MASK66___ ) concentration in excess of serum concentrations to support tumor growth . For many years ketoconazole was the only P05093 inhibitor that was used to treat mCRPC . However , significant toxicities limit its use . Newly approved chemotherapeutic agents such as DB05812 ( an oral selective inhibitor of CYP17A ) , which blocks androgen biosynthesis both within and outside the prostate cancer cells ) , and enzalutamide ( blocks AR signaling ) have improved overall survival . There are also ongoing phase III trials for Orteronel ( P50750 - 700 ) , ARN - 509 and Galeterone ( TOK - 001 ) , which targets androgen signaling . In this review , we will present the rationale for the newly approved hormonal treatments , their indications and complications , and we will discuss ongoing trials that are being done to improve the efficacy of the approved agents . Finally , we will talk about the potential upcoming hormonal treatments for mCRPC .", "Sporadic breast carcinomas with somatic P38398 gene deletions share genotype / phenotype features with familial breast carcinomas . BACKGROUND : High frequencies of loss of heterozygosity ( LOH ) are found in familial breast carcinomas with BRCA mutations . Although LOH of P38398 does not coincide with somatic P38398 mutations , reduced P38398 protein expression and hypermethylation indicate the involvement of P38398 in sporadic carcinogenesis . To further investigate the role of BRCA we determined LOH of P38398 and correlated this with LOH in other breast cancer - associated regions . MATERIALS AND METHODS : A total of 105 sporadic breast carcinomas were analysed for LOH in the regions of P38398 , P51587 , P04637 , Caveolin1 , \" putative BRCA3 \" , P60484 , Q13315 and P12830 and correlated it with clinicopathological features . RESULTS : We found an overall increase of LOH in carcinomas with simultaneous LOH of P38398 . Significantly higher LOH rates were detected in the regions of P04637 ( 80 % : 34 . 7 % ; p < 0 . 005 ) , 8q21 ( 72 . 7 % : 30 . 6 % ; p < 0 . 010 ) and 10q22 - 23 ( 21 . 1 % : 5 . 9 % ; p = 0 . 043 ) . Moreover , estrogen receptor - negative carcinomas revealed LOH of P38398 more frequently than estrogen receptor - positive carcinomas ( 39 % : 12 % ; p = 0 . 003 ) . CONCLUSION : These data indicate that LOH of P38398 coincides with a defect of the DNA repair pathway . Therefore , LOH of P38398 determines a subgroup of sporadic breast carcinomas sharing genotype / phenotype features with familial breast carcinomas .", "Q00987 is a ubiquitin ligase of P12956 - Akt promotes cell survival by inhibiting Q00987 - dependent P12956 destabilization . Earlier , we have reported that 70 kDa subunit of Ku protein heterodimer ( P12956 ) binds and inhibits Bax activity in the cytosol and that ubiquitin ( Ub ) - dependent proteolysis of cytosolic P12956 facilitates Bax - mediated apoptosis . We found that Q00987 ( human homolog of murine double minute ) has an ability to ubiquitinate P12956 and that Q00987 overexpression in cultured cells causes a decrease in P12956 expression levels . An interaction between P12956 and Q00987 was shown by means of immunoprecipitation , whereas none could be shown between 80 kDa subunit of Ku protein heterodimer and Q00987 . Vascular endothelial growth factor ( P15692 ) is known to inhibit endothelial cell ( EC ) apoptosis through an Akt - mediated survival kinase signal ; however , the mechanism underlying this inhibition of apoptosis has not been fully elucidated . We found that P15692 inhibited cytosolic P12956 degradation induced by apoptotic stress . It is known that Akt - dependent phosphorylation of Q00987 causes nuclear translocation of Q00987 followed by Q00987 - mediated inactivation of p53 . We found that P15692 stimulated nuclear translocation of Q00987 in EC and efficiently inhibited P12956 degradation . We also found that constitutively active Akt , but not kinase - dead Akt , inhibited P12956 degradation in the cytosol . Furthermore , P12956 knockdown diminished antiapoptotic activity of Akt . Taken together , we propose that Q00987 is a P12956 Ub ligase and that Akt inhibits Bax - mediated apoptosis , at least in part , by maintaining P12956 levels through the promotion of Q00987 nuclear translocation .", "Loss of homologous recombination or non - homologous end - joining leads to radial formation following DNA interstrand crosslink damage . High levels of interstrand cross - link damage in mammalian cells cause chromatid breaks and radial formations recognizable by cytogenetic examination . The mechanism of radial formation observed following DNA damage has yet to be determined . Due to recent findings linking homologous recombination and non - homologous end - joining to the action of the Fanconi anemia pathway , we speculated that radials might be the result of defects in either of the pathways of DNA repair . To test this hypothesis , we have investigated the role of homologous recombination proteins Q06609 and P43351 , non - homologous end - joining proteins P12956 and P49917 , and protein P49959 in radial formation and cell survival following interstrand crosslink damage with mitomycin C . For the studies we used small inhibitory RNA to deplete the proteins from cells , allowing for evaluation of radial formation and cell survival . In transformed normal human fibroblasts , depletion of these proteins increased interstrand crosslink sensitivity as manifested by decreased cell survival and increased radial formation . These results demonstrate that inactivation of proteins from either of the two separate DNA repair pathways increases cellular sensitivity to interstrand crosslinks , indicating each pathway plays a role in the normal response to interstrand crosslink damage . We can also conclude that homologous recombination or non - homologous end - joining are not required for radial formation , since radials occur with depletion of these pathways .", "Identification of an acetylation - dependant P12956 / FLIP complex that regulates FLIP expression and HDAC inhibitor - induced apoptosis . FLIP is a potential anti - cancer therapeutic target that inhibits apoptosis by blocking caspase 8 activation by death receptors . We report a novel interaction between FLIP and the DNA repair protein P12956 that regulates FLIP protein stability by inhibiting its polyubiquitination . Furthermore , we found that the histone deacetylase ( HDAC ) inhibitor ___MASK71___ ( ___MASK71___ ) enhances the acetylation of P12956 , thereby disrupting the FLIP / P12956 complex and triggering FLIP polyubiquitination and degradation by the proteasome . Using in vitro and in vivo colorectal cancer models , we further demonstrated that ___MASK71___ - induced apoptosis is dependant on FLIP downregulation and caspase 8 activation . In addition , an Q9UBN7 - specific inhibitor Tubacin recapitulated the effects of ___MASK71___ , suggesting that Q9UBN7 is a key regulator of P12956 acetylation and FLIP protein stability . Thus , HDAC inhibitors with anti - Q9UBN7 activity act as efficient post - transcriptional suppressors of FLIP expression and may , therefore , effectively act as ' FLIP inhibitors ' .", "Mitoxantrone inhibits HIF - 1α expression in a topoisomerase II - independent pathway . PURPOSE : Solid tumors encounter a growth - limiting hypoxic microenvironment as they develop . Hypoxia - inducible factors ( HIF ) play important roles in hypoxia - associated tumor development and therapeutic resistance . Targeting the HIF pathway ( especially HIF - 1α ) represents a promising cancer treatment strategy . Here , we report a novel class of HIF - 1α inhibitors and the possible molecular basis of inhibition . EXPERIMENTAL DESIGN : We analyzed the inhibitory effects of clinically used topoisomerase II ( P11388 ) - targeting drugs on HIF - 1α expression with a primary focus on mitoxantrone . The potential role of P11388 in mitoxantrone - inhibited HIF - 1α expression was studied using pharmacologic inhibition , a knockdown approach , and P11388 mutant cells . Moreover , involvement of mitoxantrone in proteasome - mediated degradation , transcription , and translation of HIF - 1α was examined . RESULTS : The P11388 - targeting mitoxantrone , but neither doxorubicin nor etoposide ( DB00773 ) , strongly inhibited HIF - 1α expression under hypoxic conditions in a dose - and time - dependent manner . Surprisingly , the mitoxantrone - mediated inhibition of HIF - 1α expression was largely independent of two P11388 isozymes , proteasomal degradation , and transcription . Furthermore , mitoxantrone inhibited HIF - 1α expression and function in a similar fashion as cycloheximide , suggesting that mitoxantrone might inhibit HIF - 1α via a blockage at its translation step . In vitro translation experiments using HIF - 1α mRNA further confirmed inhibition of HIF - 1α translation by mitoxantrone . Interestingly , levels of the polysome - bound HIF - 1α and P15692 mRNA were elevated and decreased after mitoxantrone treatment , respectively . CONCLUSIONS : We have identified the P11388 - targeting compound , mitoxantrone , as an HIF - 1α inhibitor possibly through a translation inhibition mechanism , suggesting the possibility of an additional anticancer activity for mitoxantrone .", "Blockade of cannabinoid receptors reduces inflammation , leukocyte accumulation and neovascularization in a model of sponge - induced inflammatory angiogenesis . OBJECTIVE : Angiogenesis depends on a complex interaction between cellular networks and mediators . The endocannabinoid system and its receptors have been shown to play a role in models of inflammation . Here , we investigated whether blockade of cannabinoid receptors may interfere with inflammatory angiogenesis . MATERIALS AND METHODS : Polyester - polyurethane sponges were implanted in C57Bl / 6j mice . Animals received doses ( 3 and 10 mg / kg / daily , s . c . ) of the cannabinoid receptor antagonists SR141716A ( P21554 ) or SR144528 ( CB2 ) . Implants were collected at days 7 and 14 for cytokines , hemoglobin , myeloperoxidase , and N - acetylglucosaminidase measurements , as indices of inflammation , angiogenesis , neutrophil and macrophage accumulation , respectively . Histological and morphometric analysis were also performed . RESULTS : Cannabinoid receptors expression in implants was detected from day 4 after implantation . Treatment with P21554 or CB2 receptor antagonists reduced cellular influx into sponges at days 7 and 14 after implantation , although P21554 receptor antagonist were more effective at blocking leukocyte accumulation . There was a reduction in P01375 - α , P15692 , P09341 / KC , P13500 / JE , and P10147 / MIP - 1α levels , with increase in P13501 / RANTES . Both treatments reduced neovascularization . Dual blockade of cannabinoid receptors resulted in maximum inhibition of inflammatory angiogenesis . CONCLUSIONS : Blockade of cannabinoid receptors reduced leukocyte accumulation , inflammation and neovascularization , suggesting an important role of endocannabinoids in sponge - induced inflammatory angiogenesis both via P21554 and CB2 receptors .", "___MASK51___ has opposing effects on SN - 38 - induced double - strand breaks and cytotoxicity in P04626 - positive gastric cancer cells depending on administration sequence . AIM : We investigated the effects of trastuzumab , an anti - P04626 humanized monoclonal antibody , on DNA breaks induced by SN - 38 , a topoisomerase - 1 inhibitor , in gastric cancer cell lines positive or negative for P04626 expression . MATERIALS AND METHODS : NCI - N87 ( P04626 + ) and MKN74 ( P04626 - ) cells were exposed to SN - 38 in the presence or absence of trastuzumab . ___MASK51___ was added either prior to or after SN - 38 . Effects of trastuzumab on the induction of gamma - P16104 , a marker of DNA double - strand breaks , the cytotoxicity of SN - 38 and cell cycle progression were determined . RESULTS : When trastuzumab was administered following SN - 38 , it increased γ P16104 levels and cytotoxicity of SN - 38 in NCI - N87 cells , but not in MKN74 cells . In contrast , pretreatment with trastuzumab reduced SN - 38 - induced γ P16104 expression and cytotoxicity of SN - 38 in NCI - N87 cells , but not in MKN74 cells . ___MASK51___ delayed cell cycle progression in NCI - N87 cells only . CONCLUSION : ___MASK51___ has opposing effects on SN - 38 - induced double - strand breaks and cytotoxicity depending on the order of administration of the two agents .", "P35367 antagonist cetirizine impairs working memory processing speed , but not episodic memory . BACKGROUND AND PURPOSE : The histaminergic neurotransmitter system is currently under investigation as a target for drug treatment of cognitive deficits in clinical disorders . The therapeutic potential of new drugs may initially be screened using a model of histaminergic dysfunction , for example , as associated with the use of centrally active antihistamines . Of the selective second generation antihistamines , cetirizine has been found to have central nervous system effects . The aim of the present study was to determine whether cetirizine can be used as a tool to model cognitive deficits associated with histaminergic hypofunction . EXPERIMENTAL APPROACH : The study was conducted according to a three - way , double - blind , cross - over design . Treatments were single oral doses of cetirizine 10 and 20 mg and placebo . Effects on cognition were assessed using tests of word learning , memory scanning , vigilance , divided attention , tracking and visual information processing speed . KEY RESULTS : ___MASK16___ 10 mg impaired tracking performance and both doses impaired memory scanning speed . None of the other measures indicated impaired performance . CONCLUSION AND IMPLICATIONS : ___MASK16___ affects information processing speed , but these effects were not sufficient to serve as a model for cognitive deficits in clinical disorders .", "Guggulsterone inhibits angiogenesis by blocking P40763 and P15692 expression in colon cancer cells . The plant sterol guggulsterone has been shown to exert anti - tumor effects , making it a candidate chemotherapeutic agent . We investigated the anti - tumor effects of guggulsterone on colon cancer cells and elucidated the underlying molecular mechanisms related to angiogenesis . The apoptotic effects of guggulsterone were examined by cell survival assay . Western blot analysis was used to determine the levels of various down - stream intracellular proteins involved in angiogenesis , including signal transducer and activator of transcription 3 ( P40763 ) , vascular endothelial growth factor ( P15692 ) , hypoxia - inducible factor - 1alpha ( HIF - 1alpha ) and aryl hydrocarbon receptor nuclear translocator ( P27540 ) . Using chromatin immunoprecipitation assay , we tested whether guggulsterone affects the recruitment of P40763 , P27540 and HIF - 1alpha to the human P15692 promoter . To investigate the effect of guggulsterone on vascular endothelial cell migration and invasion , tube formation and migration assays were conducted using human umbilical vein endothelial cells ( HUVECs ) . Matrix metalloproteinase ( MMP ) - 2 and - 9 activities were measured by gelatin zymography . Guggulsterone significantly reduced cell viability in colon cancer cells in a dose - dependent manner and blocked P15692 , P27540 and P40763 expression prominently in hypoxic conditions . The recruitment of P40763 and P27540 , but not HIF - 1alpha , to the P15692 promoter was inhibited by guggulsterone treatment . HUVECs produced much foreshortened and severely broken tubes and showed decreased migration activity under guggulsterone effects . In addition , zymography revealed that P08253 and - 9 enzyme activities were markedly lower in the presence of guggulsterone . The results of this study suggest that guggulsterone not only induces apoptosis , but also inhibits angiogenesis and metastasis in colon cancer cells by blocking P40763 and P15692 expression , suggesting its therapeutic potential in the treatment of colorectal cancer .", "P10275 YAC transgenic mice recapitulate SBMA motor neuronopathy and implicate VEGF164 in the motor neuron degeneration . X - linked spinal and bulbar muscular atrophy ( SBMA ) is an inherited neuromuscular disorder characterized by lower motor neuron degeneration . SBMA is caused by polyglutamine repeat expansions in the androgen receptor ( AR ) . To determine the basis of AR polyglutamine neurotoxicity , we introduced human AR yeast artificial chromosomes carrying either 20 or 100 CAGs into mouse embryonic stem cells . The AR100 transgenic mice developed a late - onset , gradually progressive neuromuscular phenotype accompanied by motor neuron degeneration , indicating striking recapitulation of the human disease . We then tested the hypothesis that polyglutamine - expanded AR interferes with CREB binding protein ( CBP ) - mediated transcription of vascular endothelial growth factor ( P15692 ) and observed altered CBP - AR binding and P15692 reduction in AR100 mice . We found that mutant AR - induced death of motor neuron - like cells could be rescued by P15692 . Our results suggest that SBMA motor neuronopathy involves altered expression of P15692 , consistent with a role for P15692 as a neurotrophic / survival factor in motor neuron disease .", "Role of nitrative and oxidative DNA damage in inflammation - related carcinogenesis . Chronic inflammation induced by biological , chemical , and physical factors has been found to be associated with the increased risk of cancer in various organs . We revealed that infectious agents including liver fluke , Helicobacter pylori , and human papilloma virus and noninfectious agents such as asbestos fiber induced P35228 - dependent formation of 8 - nitroguanine and 8 - oxo - 7 , 8 - dihydro - 2 '- deoxyguanosine ( 8 - oxodG ) in cancer tissues and precancerous regions . Our results with the colocalization of phosphorylated Q13315 and γ - P16104 with 8 - oxodG and 8 - nitroguanine in inflammation - related cancer tissues suggest that DNA base damage leads to double - stranded breaks . It is interesting from the aspect of genetic instability . We also demonstrated P05231 - modulated P35228 expression via P40763 and P00533 in Epstein - Barr - virus - associated nasopharyngeal carcinoma and found promoter hypermethylation in several tumor suppressor genes . Such epigenetic alteration may occur by controlling the DNA methylation through P05231 - mediated JAK / P40763 pathways . Collectively , 8 - nitroguanine would be a useful biomarker for predicting the risk of inflammation - related cancers .", "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 .", "2 , 3 , 5 , 4 '- tetrahydroxystilbene - 2 - O - β - d - glucoside ameliorates vascular senescence and improves blood flow involving a mechanism of p53 deacetylation . BACKGROUND AND AIMS : 2 , 3 , 5 , 4 '- tetrahydroxystilbene - 2 - O - β - d - glucoside ( THSG ) , a resveratrol analog with glucoside , has been shown in various studies to inhibit proliferation of vascular smooth muscle cells , attenuate inflammation , and prevent vascular endothelial dysfunction . In the study , we examined the effects of THSG on vascular senescence and blood flow . METHODS AND RESULTS : Oral administration of THSG for 14 weeks , resulted in notable increases in blood flow in spontaneously hypertensive rats ( SHRs ) ; and effective inhibition of vascular senescence as indicated by senescence - associated β - galactosidase ( SA - β - gal ) staining , phosphorylation of γ P16104 observed by stain analysis of immunofluorescence , and K373 acetylation of p53 in the aortic arches of SHRs . Oral administration of THSG also induced P29474 expression and urinary NOx production . THSG weekly activated Q96EB6 activity , stimulated P29474 promoter reporter gene activity , and ameliorated H ( 2 ) O ( 2 )- induced cellular senescence and K373 acetylation of p53 in cultured human umbilical vein endothelial cells ( HUVECs ) . CONCLUSIONS : THSG improves blood flow and ameliorates vascular senescence by increasing P29474 expression and Sirt1 activity and decreasing acetylation of p53 at K373 site , at least in part , both in vitro and in vivo .", "Amsacrine and etoposide hypersensitivity of yeast cells overexpressing DNA topoisomerase II . Increasing the cellular concentration of DNA topoisomerase II in yeast by expressing constitutively a plasmid - borne P11388 gene encoding the enzyme greatly increases the sensitivity of the cells to amsacrine and etoposide ( DB00773 ) . This increased drug sensitivity at a higher intracellular DNA topoisomerase II level is observed in both P43351 + repair - proficient strains and rad52 mutants that are defective in the repair of double - stranded breaks . These results provide strong support of the hypothesis that the cellular target of these drugs is DNA topoisomerase II , and that these drugs kill cells by converting DNA topoisomerase II into a DNA damaging agent .", "Program death - 1 engagement upon TCR activation has distinct effects on costimulation and cytokine - driven proliferation : attenuation of Q9Y6W8 , P05112 , and Q9HBE4 , but not P10747 , P13232 , and P40933 responses . The program death 1 ( P18621 ) receptor and its ligands , P18621 ligand ( PD - L ) 1 and Q9BQ51 , define a novel regulatory pathway with potential inhibitory effects on T , B , and monocyte responses . In the present study , we show that human P01730 (+) T cells express P18621 , Q9NZQ7 , and Q9BQ51 upon activation , and Abs to the receptor can be agonists or antagonists of the pathway . Under optimal conditions of stimulation , Q9Y6W8 but not P10747 costimulation can be prevented by P18621 engagement . P60568 levels induced by costimulation are critical in determining the outcome of the P18621 engagement . Thus , low to marginal P60568 levels produced upon Q9Y6W8 costimulation account for the greater sensitivity of this pathway to P18621 - mediated inhibition . Interestingly , exogenous P60568 , P13232 , and P40933 but not P05112 and Q9HBE4 can rescue P18621 inhibition , suggesting that among these cytokines only those that activate P42229 can rescue P18621 inhibition . As P42229 has been implicated in the maintenance of IL - 2Ralpha expression , these results suggest that P13232 and P40933 restore proliferation under conditions of P18621 engagement by enhancing high - affinity IL - 2R expression and hence , P60568 responsiveness .", "Regulation of microphthalmia - associated transcription factor O75030 protein levels by association with the ubiquitin - conjugating enzyme hUBC9 . The basic helix - loop - helix / leucine zipper ( bHLH / Q8N5A5 ) microphthalmia - associated transcription factor ( O75030 ) regulates transcription of genes encoding enzymes essential for melanin biosynthesis in melanocytes and retinal pigmented epithelial cells . To determine how O75030 activity is regulated , we used the yeast two - hybrid system to identify proteins expressed by human melanoma cells that interact with O75030 . The majority of clones that showed positive interaction with a 158 - amino - acid region of O75030 containing the bHLH / Q8N5A5 domain ( aa 168 - 325 ) encoded the ubiquitin conjugating enzyme hUBC9 . The association of O75030 with hUBC9 was further confirmed by an in vitro Q86UG4 pull - down assay . Although hUBC9 is known to interact preferentially with SENTRIN / P63165 , in vitro transcription / translation analysis demonstrated greater association of O75030 with ubiquitin than with SENTRIN . Importantly , cotransfection of O75030 and hUBC9 expression vectors resulted in O75030 protein degradation . O75030 protein was stabilized by the proteasome inhibitor MG132 , indicating the role of the ubiquitin - proteasome system in O75030 degradation . DB00133 73 , which is located in a region rich in proline , glutamic acid , serine , and threonine ( PEST ) , regulates O75030 protein stability , since a serine to alanine mutation prevented hUBC9 - mediated O75030 ( S73A ) degradation . Furthermore , we identified lysine 201 as a potential ubiquitination site . A lysine to arginine mutation abolished O75030 ( K201R ) degradation by hUBC9 in vivo . Our experiments indicate that by targeting O75030 for proteasome degradation , hUBC9 is a critical regulator of melanocyte differentiation .", "P60484 sumo - wrestles human P43351 to mystery land .", "___MASK42___ - induced regulation of the balance within macrophage subpopulations . In asthma , treatment with inhaled corticosteroids reduces chronic peribronchial inflammation and restores the balance within macrophage subpopulations . This study investigates whether corticosteroids can regulate monocyte differentiation in vitro and thereby influence the balance of functionally distinct macrophages . Graded doses of fluticasone propionate ( FP ) were added to cultures of normal peripheral blood monocytes in the presence or absence of P05112 . Cells were harvested after 7 days ' culture . Double immunofluorescence studies were performed on cytospins of differentiated macrophages using the MoAbs RFD1 and RFD7 to distinguish inductive and suppressive macrophages by their respective phenotypes . Macrophage function was determined by quantifying allostimulation in a mixed leucocyte reaction and by measuring tumour necrosis factor - alpha ( P01375 ) production . FP reduced the number of mature cells with a D1 + antigen - presenting phenotype and up - regulated the development of cells with the D1 / D7 + and D7 + phenotypes . Functionally , this was associated with reduced stimulation of T cell proliferation in a mixed leucocyte reaction ( P08235 ) . ___MASK42___ also reversed the increase in both D1 + expression and P01375 production induced by P05112 . The effect of FP persisted for 24 h after removal of FP from the culture medium . These results suggest that FP treatment of asthmatics may have a direct beneficial effect by normalizing the macrophage subset imbalance that contributes to the chronic peribronchial inflammation present in this condition .", "New perspectives of vesicular monoamine transporter 2 chemical characteristics in mammals and its constant expression in type 1 diabetes rat models . Vesicular monoamine transporter 2 ( Q05940 ) has been exploited as a biomarker of β - cell mass in human islets . However , a current report suggested no immunoreactivity of Q05940 in the β cells of rat islets . To investigate the cellular localization of Q05940 in islets further , the pancreatic tissues from monkeys and humans were compared with those of rats and mice . The study was performed using among - species comparisons and a type 1 diabetes model ( T1DM ) for rats by Western blotting , double - label immunofluorescence , and confocal laser scanning microscopy . We found that Q05940 - immunoreactivity ( IR ) was distributed peripherally in the islets of rodents , but was widely scattered throughout the islets of primates . Consistent with rodent islets , Q05940 - IR did not exist in insulin ( P01308 ) - IR cells but was abundantly present in glucagon ( GLU ) - IR and pancreatic polypeptide ( PP ) - IR cells in monkey and human islets . Q05940 - IR had no colocalization with P01308 - IR in any part of the rat pancreas ( head , body , and tail ) . P01308 - IR cells were reduced dramatically in T1DM rat islets , but no significant alteration in the proportion of Q05940 - IR cells and GLU - IR cells was observed . Furthermore , a strong colocalization of Q05940 - IR with GLU - IR was distributed in the peripheral regions of diabetic islets . For the first time , the current study demonstrates the presence of Q05940 in α cells and PP cells but not in β cells in the islets of monkeys and humans . This study provides convinced morphologic evidence that Q05940 is not present in β cells . There needs to be studies for new markers for β cell mass .", "Selective inhibition of histone deacetylase 6 ( Q9UBN7 ) induces DNA damage and sensitizes transformed cells to anticancer agents . Q9UBN7 ( Q9UBN7 ) is structurally and functionally unique among the 11 human zinc - dependent histone deacetylases . Here we show that chemical inhibition with the Q9UBN7 - selective inhibitor tubacin significantly enhances cell death induced by the topoisomerase II inhibitors etoposide and doxorubicin and the pan - HDAC inhibitor ___MASK71___ ( vorinostat ) in transformed cells ( LNCaP , MCF - 7 ) , an effect not observed in normal cells ( human foreskin fibroblast cells ) . The inactive analogue of tubacin , nil - tubacin , does not sensitize transformed cells to these anticancer agents . Further , we show that down - regulation of Q9UBN7 expression by shRNA in LNCaP cells enhances cell death induced by etoposide , doxorubicin , and ___MASK71___ . Tubacin in combination with ___MASK71___ or etoposide is more potent than either drug alone in activating the intrinsic apoptotic pathway in transformed cells , as evidenced by an increase in PARP cleavage and partial inhibition of this effect by the pan - caspase inhibitor Z - VAD - fmk . Q9UBN7 inhibition with tubacin induces the accumulation of γ P16104 , an early marker of DNA double - strand breaks . Tubacin enhances DNA damage induced by etoposide or ___MASK71___ as indicated by increased accumulation of γ P16104 and activation of the checkpoint kinase Chk2 . Tubacin induces the expression of P35638 ( P35638 / P35638 ) , a transcription factor up - regulated in response to cellular stress . P35638 induction is further increased when tubacin is combined with ___MASK71___ . These findings point to mechanisms by which Q9UBN7 - selective inhibition can enhance the efficacy of certain anti - cancer agents in transformed cells .", "Prolonged treatment with bicalutamide induces androgen receptor overexpression and androgen hypersensitivity . BACKGROUND : Various hormone refractory prostate cancer cell models have been established with androgen depletion and have helped to clarify the mechanism for the transition into androgen - depletion independent status . However , the mechanism of bicalutamide resistance remains unclear because few cell models have been generated . METHODS : We generated a bicalutamide - resistant subline , LNCaP - O43633 , from LNCaP after prolonged treatment with bicalutamide . Androgen and / or bicalutamide responsiveness for proliferation and prostate - specific antigen ( PSA ) secretion were examined in vitro and in vivo . DB00624 and dihydrotestosterone ( ___MASK66___ ) levels in xenografted tumors were analyzed by liquid chromatography - tandem mass spectrometry . P10275 ( AR ) gene mutation and amplification and AR and pAR ( 210 ) expression were determined . RESULTS : LNCaP - O43633 did not grow in an androgen - depleted medium and proliferation was stimulated in a tenfold lower concentration of androgen than that of LNCaP . LNCaP - O43633 grew in castrated male mice , and the ___MASK66___ level in grafted LNCaP - O43633 tumors was 7 . 7 - fold lower than in LNCaP tumors . DB01128 stimulated LNCaP - O43633 proliferation and PSA secretion in vitro and the antitumor activity of bicalutamide against LNCaP - O43633 was weaker than that of LNCaP in vivo . Additional AR mutation and AR gene amplification were not detected in LNCaP - O43633 , but AR and pAR ( 210 ) expression and PSA secretion in LNCaP - O43633 were higher than in LNCaP . CONCLUSIONS : DB01128 - resistant LNCaP - O43633 exhibited AR overexpression and hypersensitivity to low levels of androgen . Our data suggests that AR overexpression is a significant mechanism of bicalutamide resistance similar to resistance from chronic androgen depletion . In addition , pAR ( 210 ) overexpression could be a potential mechanism for hypersensitivity to low androgen in LNCaP - O43633 .", "Current researches on breast cancer epidemiology in Korea . As a cause of death in women , breast cancer ranks second to stomach cancer in Korea . Age - standardized mortality rates for breast cancer steadily increased during the 1980s and 1990s . There are big differences in the incidence rates for breast cancer compared with Western countries . Epidemiological features , trends in morbidity and mortality , various age - specific incidence curves , migrant study results , and analysis of the risk factors , however , suggest that the incidence of breast cancer might be further increasing in Korea . The key epidemiological hormonal risk factors for breast cancer are all explicable in terms of the estrogen augmented by progesterone hypothesis . These include older age , family history of breast cancer , early menarche , late menopause , late full - term pregnancy , and never a breast feeding . Both the establishment of high - risk groups and the estimation of lifetime risk are essential to develop a control strategy against breast cancer . Invasive ductal carcinoma is the most common histologic type of breast cancer in Korea , and the five - year survival rate has been estimated as 80 - 83 % . Recent studies on the identification of susceptibility factors such as genetic polymorphisms of P09488 / T1 / P1 , P21964 , P05181 , P11511 , P05093 , P03372 , P18887 , O43542 , P43351 , TGF - alpha , P01375 , IL - 1B , IL - 1RN , P50613 etc . that predispose individuals to breast cancer by gene - environment or gene - gene interactions may possibly give further insight into both the etiology and the prevention of this malignancy .", "Acidic pH induces topoisomerase II - mediated DNA damage . Acidic pH plays an important role in various pathophysiological states and has been demonstrated to be carcinogenic in animal models . Recent studies have also implicated acidic pH in the development of preneoplastic Barrett ' s esophagus in human . However , little is known about the molecular mechanism underlying acidic pH - induced carcinogenesis . In the current study , we show that acidic pH , like the topoisomerase II ( P11388 ) poison DB00773 ( demethylepipodophyllotoxin ethylidene - beta - D - glucoside ) , induces tumors in 9 , 10 - dimethyl - 1 , 2 - benzanthracene ( DMBA )- initiated mice . The following studies in tissue culture models have suggested that acidic pH acts like a P11388 poison to induce P11388 - mediated DNA damage : ( i ) acidic pH induces P11388 - dependent DNA damage signals as evidenced by up - regulation of p53 and DB00133 - 139 phosphorylation of P16104 [ a substrate for ataxia telangiectasia mutated ( Q13315 ) Q13315 and Rad3 - related ( ATR ) kinases ] ; ( ii ) acidic pH - induced cytotoxicity in tumor cells is reduced in P11388 - deficient cells ; ( iii ) acidic pH increases the mutation frequency of the hypoxanthine phosphoribosyl transferase ( P00492 ) gene in a P11388 - dependent manner ; and ( iv ) acidic pH induces reversible P11388 - mediated DNA strand breaks in vitro . We discuss the possibility that P11388 - mediated DNA damage may contribute to acidic pH - induced carcinogenesis .", "Senescence - associated secretory phenotype in a mouse model of bleomycin - induced lung injury . DB00290 produces DNA damage , apoptosis and senescence , all of which play crucial roles in the development of pulmonary fibrosis . Recently , close attention has been paid to a DNA damage - induced phenotypic change ( senescence - associated secretory phenotype ; SASP ) as a trigger for the secretion of various mediators which modify the processes of tissue injury , inflammation , repair and fibrosis . We characterized the SASP in a murine model of bleomycin - induced lung injury . Mice were intratracheally administered bleomycin or control saline , and the lungs were obtained on days 7 , 14 and 21 . The occurrence of DNA damage and the SASP in the lungs was examined by immunostaining . γ P16104 immunostaining of the bleomycin - treated lungs revealed double - strand breaks ( DSBs ) , largely within P12830 - positive , β4 - integirn - positive alveolar epithelial cells . The DSBs were associated with phosphorylation of Q13315 / ATR , a central signal transducer mediating the DNA damage response , and upregulation of the cyclin - dependent kinase inhibitor P38936 ( CIP1 ) . The DSBs persisted for at least 21 days after the bleomycin exposure , although it began to wane after 7 days . A subpopulation of the γ P16104 - positive , DNA - damaged cells exhibited the SASP , characterized by overexpression of P05231 , TNFα , P08253 and P14780 , in association with the phosphorylation of IKKα / β and p38 MAPK . Persistent DNA damage and the SASP are induced in the process of bleomycin - induced lung injury and repair , suggesting that these events play an important role in the regulation of inflammation and tissue remodeling in bleomycin - induced pneumopathy .", "___MASK43___ , a gastric proton pump inhibitor , inhibits melanogenesis by blocking Q04656 trafficking . ___MASK43___ is a proton pump inhibitor used in the treatment of peptic ulcer disease and gastrosophageal reflux disease and acts by irreversibly blocking P20648 , a P - type H +/ K + ATPase in gastric parietal cells . We found that omeprazole and its closely related congeners inhibited melanogenesis at micromolar concentrations in B16 mouse melanoma cells , normal human epidermal melanocytes , and in a reconstructed human skin model . ___MASK43___ topically applied to the skin of UV - irradiated human subjects significantly reduced pigment levels after 3 weeks compared with untreated controls . ___MASK43___ had no significant inhibitory effect on the activities of purified human tyrosinase or on the mRNA levels of tyrosinase , dopachrome tautomerase , Pmel17 , or O75030 mRNA levels . Although melanocytes do not express P20648 , they do express Q04656 , a copper transporting P - type ATPase in the trans - Golgi network that is required for copper acquisition by tyrosinase . Q04656 relocalization from the trans - Golgi network to the plasma membrane in response to elevated copper concentrations in melanocytes was inhibited by omeprazole . ___MASK43___ treatment increased the proportion of EndoH sensitive tyrosinase , indicating that tyrosinase maturation was impaired . In addition , omeprazole reduced tyrosinase protein abundance in the presence of cycloheximide , suggestive of increased degradation . Our findings are consistent with the hypothesis that omeprazole reduces melanogenesis by inhibiting Q04656 and by enhancing degradation of tyrosinase .", "___MASK2___ , a further innovation in the treatment of sexual dysfunction . In recognition of the large number of sufferers of sexual dysfunction worldwide , and the variety of etiologies of the condition , investigation into effective pharmacological agents has been expanded . One method of intervention is inhibition of the phosphodiesterase type 5 ( O76074 ) enzyme , which has already been exploited with a considerable degree -- though not complete -- success . A number of new agents that inhibit O76074 are under development . Notable among these is tadalafil , which has demonstrated a high level of selectivity for O76074 over the other phosphodiesterases and has shown efficacy in improving erectile function and sexual satisfaction in phase III trials . Throughout the clinical development program for tadalafil , the drug has been well tolerated and without serious side effects . The manufacturer , Lilly Q9Y6W8 , received an approvable letter from the US Food and Drug Administration for use of the drug as a treatment for erectile dysfunction on April 30 , 2002 . Lilly Q9Y6W8 hopes to market tadalafil , with the trade name ___MASK2___ , in the USA in 2003 .", "A p53 axis regulates B cell receptor - triggered , innate immune system - driven B cell clonal expansion . Resting mature human B cells undergo a dynamic process of clonal expansion , followed by clonal contraction , during an in vitro response to surrogate C3d - coated Ag and innate immune system cytokines , P05112 and Q9Y275 . In this study , we explore the mechanism for clonal contraction through following the time - and division - influenced expression of several pro - and anti - apoptotic proteins within CFSE - labeled cultures . Several findings , involving both human and mouse B cells , show that a mitochondria - dependent apoptotic pathway involving p53 contributes to the high activation - induced cell death ( AICD ) susceptibility of replicating blasts . Activated B cell clones exhibit elevated p53 protein and elevated mRNA / protein of proapoptotic molecules known to be under direct p53 transcriptional control , Bax , Bad , Puma , Bid , and procaspase 6 , accompanied by reduced anti - apoptotic Bcl - 2 . Under these conditions , Bim levels were not increased . The finding that full - length Bid protein significantly declines in AICD - susceptible replicating blasts , whereas Bid mRNA does not , suggests that Bid is actively cleaved to short - lived , proapoptotic truncated Bid . AICD was diminished , albeit not eliminated , by p53 small interfering RNA transfection , genetic deletion of p53 , or Bcl - 2 overexpression . DNA damage is a likely trigger for p53 - dependent AICD because susceptible lymphoblasts expressed significantly elevated levels of both phosphorylated ataxia telangiectasia mutated - DB00133 ( 1980 ) and phospho - P16104 - DB00133 ( 139 ) . Deficiency in activation - induced cytosine deaminase diminishes but does not ablate murine B cell AICD , indicating that activation - induced cytosine deaminase - induced DNA damage is only in part responsible . Evidence for p53 - influenced AICD during this route of T cell - independent clonal expansion raises the possibility that progeny bearing p53 mutations might undergo positive selection in peripherally inflamed tissues with elevated levels of P05112 and Q9Y275 .", "Stimulation of epithelial repair is a likely mechanism for the action of mifepristone in reducing duration of bleeding in users of progestogen - only contraceptives . Many women using progestogen ( P ) - only contraceptives experience uterine bleeding problems . In clinical trials , a single low dose of mifepristone , given to ___MASK92___ users at the beginning of a bleeding episode reduced the number of bleeding days by approximately 50 % compared with controls . In this study , a single dose of mifepristone was administered to etonogestrel ( P17813 ) - exposed pseudo - pregnant mice , 5 days after artificial decidualization was induced when the endometrium showed signs of bleeding . Control mice received vehicle alone . Mice were culled 12 - , 18 - , 24 - and 48 - h post - treatment . In the continued presence of P17813 , a single dose of mifepristone stimulated tissue breakdown followed by very rapid repair : most treated tissues were fully restored to the pre - decidualized state by 48 h post - treatment . During repair , proliferating cells ( Ki67 immunostained ) were localized to a band of cells around the basal area in breaking down tissues and to the repairing luminal epithelium and glands . P06401 - positive cells were largely localized to the basal area of the breaking down tissue in treated mice compared with decidual cells in controls . Oestrogen receptor - positive cells were observed in the repairing luminal epithelium and glands compared with the decidua and the basal region in control tissues . It is concluded that mifepristone treatment stimulates rapid restoration of luminal epithelial integrity : such action may be a key event in reducing the number of bleeding days observed in women using ___MASK92___ who were treated with a single dose of mifepristone .", "A new role for the P40763 inhibitor , Q9Y6X2 : a repressor of microphthalmia transcription factor . In vitro and in vivo evidence suggest that microphthalmia transcription factor ( O75030 ) plays a key regulatory role in tissue - specific gene regulation in several cell types , including melanocytes , osteoclasts , and mast cells . A yeast two - hybrid search , using a portion of a nonmutated O75030 gene as the bait in the screening of a mast cell library , resulted in the isolation of the P40763 inhibitor , Q9Y6X2 . Q9Y6X2 is a transcriptional inhibitor that acts by specifically inhibiting P40763 ' s DNA binding activity . We found that it can directly associate with O75030 using an in vitro pull - down assay . Immunoprecipitation of O75030 from rat basophilic leukemic cells or mouse melanocytes resulted in the specific co - immunoprecipitation of Q9Y6X2 . Co - transfection of O75030 with Q9Y6X2 in NIH 3T3 fibroblasts containing an mMCP - 6 promoter - luciferase reporter demonstrated up to 94 % inhibition of O75030 - mediated transcriptional activation . Using a gel - shift assay , it was shown that Q9Y6X2 can block DNA binding activity . It was also found that P40763 does not interfere , either in vitro or in vivo , with the interaction between Q9Y6X2 and O75030 . These data suggest that Q9Y6X2 functions in vivo as a key molecule in supressing the transcriptional activity of O75030 , a role of considerable importance in mast cell and melanocyte development ." ]

[ "___MASK10___", "___MASK16___", "___MASK2___", "___MASK42___", "___MASK43___", "___MASK51___", "___MASK66___", "___MASK71___", "___MASK92___" ]

[ "Prolonged treatment with bicalutamide induces androgen receptor overexpression and androgen hypersensitivity . BACKGROUND : Various hormone refractory prostate cancer cell models have been established with androgen depletion and have helped to clarify the mechanism for the transition into androgen - depletion independent status . However , the mechanism of bicalutamide resistance remains unclear because few cell models have been generated . METHODS : We generated a bicalutamide - resistant subline , LNCaP - O43633 , from LNCaP after prolonged treatment with bicalutamide . Androgen and / or bicalutamide responsiveness for proliferation and prostate - specific antigen ( PSA ) secretion were examined in vitro and in vivo . DB00624 and dihydrotestosterone ( ___MASK58___ ) levels in xenografted tumors were analyzed by liquid chromatography - tandem mass spectrometry . P10275 ( AR ) gene mutation and amplification and AR and pAR ( 210 ) expression were determined . RESULTS : LNCaP - O43633 did not grow in an androgen - depleted medium and proliferation was stimulated in a tenfold lower concentration of androgen than that of LNCaP . LNCaP - O43633 grew in castrated male mice , and the ___MASK58___ level in grafted LNCaP - O43633 tumors was 7 . 7 - fold lower than in LNCaP tumors . DB01128 stimulated LNCaP - O43633 proliferation and PSA secretion in vitro and the antitumor activity of bicalutamide against LNCaP - O43633 was weaker than that of LNCaP in vivo . Additional AR mutation and AR gene amplification were not detected in LNCaP - O43633 , but AR and pAR ( 210 ) expression and PSA secretion in LNCaP - O43633 were higher than in LNCaP . CONCLUSIONS : DB01128 - resistant LNCaP - O43633 exhibited AR overexpression and hypersensitivity to low levels of androgen . Our data suggests that AR overexpression is a significant mechanism of bicalutamide resistance similar to resistance from chronic androgen depletion . In addition , pAR ( 210 ) overexpression could be a potential mechanism for hypersensitivity to low androgen in LNCaP - O43633 .", "Reconstruction and functional analysis of altered molecular pathways in human atherosclerotic arteries . BACKGROUND : Atherosclerosis affects aorta , coronary , carotid , and iliac arteries most frequently than any other body vessel . There may be common molecular pathways sustaining this process . Plaque presence and diffusion is revealed by circulating factors that can mediate systemic reaction leading to plaque rupture and thrombosis . RESULTS : We used DNA microarrays and meta - analysis to study how the presence of calcified plaque modifies human coronary and carotid gene expression . We identified a series of potential human atherogenic genes that are integrated in functional networks involved in atherosclerosis . Caveolae and JAK / P35610 pathways , and P06702 / P05109 interacting proteins are certainly involved in the development of vascular disease . We found that the system of caveolae is directly connected with genes that respond to hormone receptors , and indirectly with the apoptosis pathway . Cytokines , chemokines and growth factors released in the blood flux were investigated in parallel . High levels of RANTES , IL - 1ra , MIP - 1 alpha , MIP - 1 beta , P60568 , P05112 , P05113 , P05231 , P13232 , Q16552 , DB00102 , P15692 and P01579 were found in plasma of atherosclerotic patients and might also be integrated in the molecular networks underlying atherosclerotic modifications of these vessels . CONCLUSION : The pattern of cytokine and P06702 / P05109 up - regulation characterizes atherosclerosis as a proinflammatory disorder . Activation of the JAK / P35610 pathway is confirmed by the up - regulation of P05231 , P42224 , Q00978 and Q13651 genes in coronary and carotid plaques . The functional network constructed in our research is an evidence of the central role of P35610 protein and the caveolae system to contribute to preserve the plaque . Moreover , Cav - 1 is involved in SMC differentiation and dyslipidemia confirming the importance of lipid homeostasis in the atherosclerotic phenotype .", "Targeting Q01196 / Q06455 - histone deacetylase repressor complex : a novel mechanism for valproic acid - mediated gene expression and cellular differentiation in Q01196 / Q06455 - positive acute myeloid leukemia cells . In t ( 8 ; 21 ) acute myeloid leukemia ( AML ) , the Q01196 / Q06455 fusion protein promotes leukemogenesis by recruiting class I histone deacetylase ( HDAC ) - containing repressor complex to the promoter of Q01196 target genes . Valproic acid ( ___MASK6___ ) , a commonly used antiseizure and mood stabilizer drug , has been shown to cause growth arrest and induce differentiation of malignant cells via HDAC inhibition . ___MASK6___ causes selective proteasomal degradation of Q92769 but not other class I HDACs ( i . e . , HDAC 1 , 3 , and 8 ) . Therefore , we raised the question of whether this drug can effectively target the leukemogenic activity of the Q01196 / Q06455 fusion protein that also recruits Q13547 , a key regulator of normal and aberrant histone acetylation . We report here that ___MASK6___ treatment disrupts the Q01196 / Q06455 - Q13547 physical interaction , stimulates the global dissociation of Q01196 / Q06455 - Q13547 complex from the promoter of Q01196 / Q06455 target genes , and induces relocation of both Q01196 / Q06455 and Q13547 protein from nuclear to perinuclear region . Furthermore , we show that mechanistically these effects associate with a significant inhibition of HDAC activity , histone H3 and H4 hyperacetylation , and recruitment of RNA polymerase II , leading to transcriptional reactivation of target genes ( i . e . , P08700 ) otherwise silenced by Q01196 / Q06455 fusion protein . Ultimately , these pharmacological effects resulted in significant antileukemic activity mediated by partial cell differentiation and caspase - dependent apoptosis . Taken together , these data support the notion that ___MASK6___ might effectively target Q01196 / Q06455 - driven leukemogenesis through disruption of aberrant Q13547 function and that ___MASK6___ should be integrated in novel therapeutic approaches for Q01196 / Q06455 - positive AML .", "Glucocorticoid - induced surface expression of annexin 1 blocks beta2 - integrin adhesion of human eosinophils to intercellular adhesion molecule 1 surrogate protein . BACKGROUND : Glucocorticoids attenuate the population of eosinophils and T lymphocytes in asthmatic airways . The decrease in airway eosinophilia is caused both by accelerated cell death and by induction of blockade of integrin adhesion . In this study , we examined the hypothesis that annexin 1 surface expression , which is upregulated by the glucocorticoid receptor , prevents integrin adhesion essential to cell migration by blocking intracellular translocation of cytosolic group IV phospholipase A2 ( P47712 ) . OBJECTIVE : To examine the relationship of the glucocorticoid on annexin 1 expression and the effect of blockade of annexin 1 activity on adhesion of human eosinophils in vitro . To determine the relationship between annexin 1surface expression and nuclear membrane translocation of P47712 . METHODS : Eosinophils isolated from human peripheral blood were pretreated with fluticasone propionate ( FP ) , and beta2 - integrin adhesion was measured after stimulation with P05113 or eotaxin . Effects of FP on P47712 expression , phosphorylation , and translocation were determined . The role of annexin 1 was examined by using annexin 1 blocking antibody and / or mimetic peptides . RESULTS : ___MASK26___ decreased stimulated eosinophil adhesion and caused 4 - fold increase in annexin 1 expression on the plasma membrane . Inhibition of adhesion by FP was blocked with annexin 1 blocking antibody . Annexin 1 N - terminal mimetic peptide also blocked beta2 - integrin adhesion . Translocation of P47712 to the nuclear membrane was significantly blocked by incubation with FP . Blockade was reversed with annexin 1 blocking antibody . CONCLUSION : Blockade of beta2 - integrin adhesion by glucocorticoid is regulated by annexin 1 , which blocks P47712 translocation to nuclear membrane .", "P10275 YAC transgenic mice recapitulate SBMA motor neuronopathy and implicate VEGF164 in the motor neuron degeneration . X - linked spinal and bulbar muscular atrophy ( SBMA ) is an inherited neuromuscular disorder characterized by lower motor neuron degeneration . SBMA is caused by polyglutamine repeat expansions in the androgen receptor ( AR ) . To determine the basis of AR polyglutamine neurotoxicity , we introduced human AR yeast artificial chromosomes carrying either 20 or 100 CAGs into mouse embryonic stem cells . The AR100 transgenic mice developed a late - onset , gradually progressive neuromuscular phenotype accompanied by motor neuron degeneration , indicating striking recapitulation of the human disease . We then tested the hypothesis that polyglutamine - expanded AR interferes with CREB binding protein ( CBP ) - mediated transcription of vascular endothelial growth factor ( P15692 ) and observed altered CBP - AR binding and P15692 reduction in AR100 mice . We found that mutant AR - induced death of motor neuron - like cells could be rescued by P15692 . Our results suggest that SBMA motor neuronopathy involves altered expression of P15692 , consistent with a role for P15692 as a neurotrophic / survival factor in motor neuron disease .", "Expression of vitamin D3 receptor and retinoid receptors in human breast cancer : identification of potential heterodimeric receptors . DB00169 ( VD ) and all - trans - retinoic acid ( ___MASK39___ ) have been postulated as a novel treatment option for breast carcinoma . Since the combined effects of retinoids and VD derivatives are attributed to heterodimeric interactions between members of the nuclear receptor family , the expression patterns of the heterodimers formed by vitamin D3 receptor ( P11473 ) and the retinoid receptors RARs ( P10276 , P10826 and P13631 ) and RXRs ( RXR - alpha , RXR - beta and RXR - gamma ) have been studied by immunohistochemistry in benign and malignant breast tissues . Present results revealed that immunoexpressions to all receptor types studied were higher in both in situ and infiltrative carcinomas than in benign breast diseases . In a variable number of cases of infiltrative carcinoma , immunostaining appeared in the nucleus , whereas in the other two disorders immunostaining was only cytoplasmic . The correlation established between P11473 and the different isoforms of retinoid receptors revealed that P11473 seems to select mainly P10276 to form heterodimers and to exert their properties as transcription factor . The results of this study suggest that this heterodimer plays a critical role in cancer malignancy , and its presence indicates those patient groups presenting a better response to adjuvant therapies based on the combination of vitamin D and ___MASK39___ .", "DB00184 induces cell proliferation , invasion and epithelial - mesenchymal transition in a variety of human cancer cell lines . Cigarette smoking is strongly correlated with the onset of nonsmall cell lung cancer ( NSCLC ) . DB00184 , an active component of cigarettes , has been found to induce proliferation of lung cancer cell lines . In addition , nicotine can induce angiogenesis and confer resistance to apoptosis . All these events are mediated through the nicotinic acetylcholine receptors ( nAChRs ) on lung cancer cells . In this study , we demonstrate that nicotine can promote anchorage - independent growth in NSCLCs . In addition , nicotine also induces morphological changes characteristic of a migratory , invasive phenotype in NSCLCs on collagen gel . These morphological changes were similar to those induced by the promigratory growth factor P15692 . The proinvasive effects of nicotine were mediated by alpha7 - nAChRs on NSCLCs . RT - PCR analysis showed that the alpha7 - nAChRs were also expressed on human breast cancer and pancreatic cancer cell lines . DB00184 was found to promote proliferation and invasion in human breast cancer . The proinvasive effects of nicotine were mediated via a nAChR , Src and calcium - dependent signaling pathway in breast cancer cells . In a similar fashion , nicotine could also induce proliferation and invasion of Aspc1 pancreatic cancer cells . Most importantly , nicotine could induce changes in gene expression consistent with epithelial to mesenchymal transition ( EMT ) , characterized by reduction of epithelial markers like P12830 expression , ZO - 1 staining and concomitant increase in levels of mesenchymal proteins like vimentin and fibronectin in human breast and lung cancer cells . Therefore , it is probable that the ability of nicotine to induce invasion and EMT may contribute to the progression of breast and lung cancers .", "Identification of an acetylation - dependant P12956 / FLIP complex that regulates FLIP expression and HDAC inhibitor - induced apoptosis . FLIP is a potential anti - cancer therapeutic target that inhibits apoptosis by blocking caspase 8 activation by death receptors . We report a novel interaction between FLIP and the DNA repair protein P12956 that regulates FLIP protein stability by inhibiting its polyubiquitination . Furthermore , we found that the histone deacetylase ( HDAC ) inhibitor ___MASK14___ ( ___MASK14___ ) enhances the acetylation of P12956 , thereby disrupting the FLIP / P12956 complex and triggering FLIP polyubiquitination and degradation by the proteasome . Using in vitro and in vivo colorectal cancer models , we further demonstrated that ___MASK14___ - induced apoptosis is dependant on FLIP downregulation and caspase 8 activation . In addition , an Q9UBN7 - specific inhibitor Tubacin recapitulated the effects of ___MASK14___ , suggesting that Q9UBN7 is a key regulator of P12956 acetylation and FLIP protein stability . Thus , HDAC inhibitors with anti - Q9UBN7 activity act as efficient post - transcriptional suppressors of FLIP expression and may , therefore , effectively act as ' FLIP inhibitors ' .", "DB00107 alleviates the neuroendocrine and cytokine response to bacterial endotoxin in healthy men . DB00107 is a hormone and neurotransmitter found to have anti - inflammatory functions in rodents . Here we used experimental bacterial endotoxinemia to examine the role of exogenous oxytocin administration on innate immune responses in humans . Ten healthy men received , in a randomized , placebo - controlled , crossover design , placebo , oxytocin , LPS , and LPS + oxytocin . DB00107 treatment resulted in a transient or prolonged reduction of endotoxin - induced increases in plasma DB01285 , cortisol , procalcitonin , P01375 , IL - 1 receptor antagonist , P05112 , P05231 , macrophage inflammatory protein - 1alpha , macrophage inflammatory protein - 1beta , monocyte chemoattractant protein - 1 ( P13500 ) , interferon - inducible protein 10 , and P15692 . In vitro , oxytocin had no impact on LPS effects in releasing P01375 , P05231 , and P13500 in monocytes and peripheral blood mononuclear cells from healthy human donors . In summary , oxytocin decreases the neuroendocrine and cytokine activation caused by bacterial endotoxin in men , possibly due to the pharmacological modulation of the cholinergic anti - inflammatory pathway . DB00107 might be a candidate for the therapy of inflammatory diseases and conditions associated with high cytokine and P15692 levels .", "Modulatory effects of heparin and short - length oligosaccharides of heparin on the metastasis and growth of LMD MDA - MB 231 breast cancer cells in vivo . Expression of the chemokine receptor P61073 allows breast cancer cells to migrate towards specific metastatic target sites which constitutively express P48061 . In this study , we determined whether this interaction could be disrupted using short - chain length heparin oligosaccharides . Radioligand competition binding assays were performed using a range of heparin oligosaccharides to compete with polymeric heparin or heparan sulphate binding to I ( 125 ) P48061 . DB01109 dodecasaccharides were found to be the minimal chain length required to efficiently bind P48061 ( 71 % inhibition ; P < 0 . 001 ) . These oligosaccharides also significantly inhibited P48061 - induced migration of P61073 - expressing LMD MDA - MB 231 breast cancer cells . In addition , heparin dodecasaccharides were found to have less anticoagulant activity than either a smaller quantity of polymeric heparin or a similar amount of the low molecular weight heparin pharmaceutical product , ___MASK25___ . When given subcutaneously in a SCID mouse model of human breast cancer , heparin dodecasaccharides had no effect on the number of lung metastases , but did however inhibit ( P < 0 . 05 ) tumour growth ( lesion area ) compared to control groups . In contrast , polymeric heparin significantly inhibited both the number ( P < 0 . 001 ) and area of metastases , suggesting a differing mechanism for the action of polymeric and heparin - derived oligosaccharides in the inhibition of tumour growth and metastases .", "Modeling the neurovascular niche : murine strain differences mimic the range of responses to chronic hypoxia in the premature newborn . Preterm birth results in significant cognitive and motor disabilities , but recent evidence suggests that there is variable recovery over time . One possibility that may explain this variable recovery entails variable neurogenic responses in the subventricular zone ( SVZ ) following the period of chronic hypoxia experienced by these neonates . In this report , we have characterized the responses to chronic hypoxia of two mouse strains that represent a wide range of susceptibility to chronic hypoxia . We determined that C57BL / 6 pups and neural progenitor cells ( NPCs ) derived from them exhibit a blunted response to hypoxic insult compared with CD - 1 pups and NPCs . Specifically , C57BL / 6 pups and NPCs exhibited blunted in vivo and in vitro proliferative and increased apoptotic responses to hypoxic insult . Additionally , C57BL / 6 NPCs exhibited lower baseline levels and hypoxia - induced levels of selected transcription factors , growth factors , and receptors ( including HIF - 1alpha , Q9GZT9 , P23560 , P15692 , P48061 , TrkB , Nrp - 1 , P61073 , and NO ) that determine , in part , the responsiveness to chronic hypoxic insult compared with CD - 1 pups and NPCs , providing insight into this important and timely problem in perinatology .", "4 -[ 3 , 5 - Bis ( trimethylsilyl ) benzamido ] benzoic acid inhibits angiogenesis in colon cancer through reduced expression of vascular endothelial growth factor . 4 -[ 3 , 5 - bis ( trimethylsilyl ) benzamido ] Benzoic acid ( TAC - 101 ) has potent antiproliferative , antiangiogenic , and antitumor effects in vitro and in vivo . These effects might be due to TAC - 101 binding to retinoic acid receptor alpha ( P10276 ) and interfering with the binding of activator protein - 1 ( AP - 1 ) to DNA . However , little is known about the detailed mechanism of TAC - 101 function . We investigated the mechanism of the antiangiogenic effect of TAC - 101 using a rat hepatic metastatic model in vivo and DLD - 1 human colon cancer cells in vitro . Liver metastases were induced by portal injection of Q15293 - 9 rat colonic cancer cells into F344 rats . TAC - 101 ( 8 mg / kg ) was orally administered 5 days per week for 4 weeks and then hepatic tumors were immunohistochemically evaluated for microvessel density ( P53602 ) and vascular endothelial growth factor ( P15692 ) . TAC - 101 significantly reduced both P53602 and P15692 expression . Northern blot analysis and ELISA indicated that TAC - 101 efficiently inhibited production of P15692 mRNA and protein in DLD - 1 cells in a time - and dose - dependent manner . These findings suggest that TAC - 101 may inhibit progression and metastasis in colon cancer by interfering with tumor production of P15692 .", "A curated database of miRNA mediated feed - forward loops involving MYC as master regulator . BACKGROUND : The MYC transcription factors are known to be involved in the biology of many human cancer types . But little is known about the Myc / microRNAs cooperation in the regulation of genes at the transcriptional and post - transcriptional level . METHODOLOGY / PRINCIPAL FINDINGS : Employing independent databases with experimentally validated data , we identified several mixed microRNA / Transcription Factor Feed - Forward Loops regulated by Myc and characterized completely by experimentally supported regulatory interactions , in human . We then studied the statistical and functional properties of these circuits and discussed in more detail a few interesting examples involving Q01094 , P60484 , P06400 and P15692 . CONCLUSIONS / SIGNIFICANCE : We have assembled and characterized a catalogue of human mixed Transcription Factor / microRNA Feed - Forward Loops , having Myc as master regulator and completely defined by experimentally verified regulatory interactions .", "DB09079 , a triple angiokinase inhibitor , enhances cytotoxic therapy response in pancreatic cancer . Angiogenesis remains a sensible target for pancreatic ductal adenocarcinoma ( PDAC ) therapy . P15692 , PDGF , FGF and their receptors are expressed at high levels and correlate with poor prognosis in human PDAC . DB09079 is a triple angiokinase inhibitor that targets P17948 / 2 / 3 , P11362 / 2 / 3 and PDGFRα / β signaling . We investigated the antitumor activity of nintedanib alone or in combination with the cytotoxic agent gemcitabine in experimental PDAC . DB09079 inhibited proliferation of cells from multiple lineages found in PDAC , with gemcitabine enhancing inhibitory effects . DB09079 blocked PI3K / MAPK activity and induced apoptosis in vitro and in vivo . In a heterotopic model , net local tumor growth compared to controls ( 100 % ) was 60 . 8 ± 10 . 5 % in the gemcitabine group , - 2 . 1 ± 9 . 9 % after nintedanib therapy and - 12 . 4 ± 16 % after gemcitabine plus nintedanib therapy . Effects of therapy on intratumoral proliferation , microvessel density and apoptosis corresponded with tumor growth inhibition data . In a PDAC survival model , median animal survival after gemcitabine , nintedanib and gemcitabine plus nintedanib was 25 , 31 and 38 days , respectively , compared to 16 days in controls . The strong antitumor activity of nintedanib in experimental PDAC supports the potential of nintedanib - controlled mechanisms as targets for improved clinical PDAC therapy .", "Q00987 is a ubiquitin ligase of P12956 - Akt promotes cell survival by inhibiting Q00987 - dependent P12956 destabilization . Earlier , we have reported that 70 kDa subunit of Ku protein heterodimer ( P12956 ) binds and inhibits Bax activity in the cytosol and that ubiquitin ( Ub ) - dependent proteolysis of cytosolic P12956 facilitates Bax - mediated apoptosis . We found that Q00987 ( human homolog of murine double minute ) has an ability to ubiquitinate P12956 and that Q00987 overexpression in cultured cells causes a decrease in P12956 expression levels . An interaction between P12956 and Q00987 was shown by means of immunoprecipitation , whereas none could be shown between 80 kDa subunit of Ku protein heterodimer and Q00987 . Vascular endothelial growth factor ( P15692 ) is known to inhibit endothelial cell ( EC ) apoptosis through an Akt - mediated survival kinase signal ; however , the mechanism underlying this inhibition of apoptosis has not been fully elucidated . We found that P15692 inhibited cytosolic P12956 degradation induced by apoptotic stress . It is known that Akt - dependent phosphorylation of Q00987 causes nuclear translocation of Q00987 followed by Q00987 - mediated inactivation of p53 . We found that P15692 stimulated nuclear translocation of Q00987 in EC and efficiently inhibited P12956 degradation . We also found that constitutively active Akt , but not kinase - dead Akt , inhibited P12956 degradation in the cytosol . Furthermore , P12956 knockdown diminished antiapoptotic activity of Akt . Taken together , we propose that Q00987 is a P12956 Ub ligase and that Akt inhibits Bax - mediated apoptosis , at least in part , by maintaining P12956 levels through the promotion of Q00987 nuclear translocation .", "Pharmacological properties of thalidomide and its analogues . Thalidomide and its immunomodulatory imide drugs ( IMiDs ) analogues DB00480 ( DB00480 , DB00480 ) and CC - 4047 ( Actimid , ___MASK23___ ) have been used as anti - inflammatory and anticancerous drugs in the recent years . Thalidomide and IMiDs inhibit the cytokines tumour necrosis factor - alpha ( P01375 ) , interleukins ( IL ) 1 - beta , 6 , 12 , and granulocyte macrophage - colony stimulating factor ( GM - P04141 ) . They also costimulate primary human T , NKT and NK lymphocytes inducing their proliferation , cytokine production , and cytotoxic activity . On the other hand , the compounds are anti - angiogenic , anti - proliferative , and pro - apoptotic . Thalidomide analogues have been used as inhibitors of alpha glucosidase and could be potential drugs for diabetes treatment . In this review , we explore the current trend of the different structures , the new patents , and the possible new applications in different pathologies .", "Loss of epigenetic Kruppel - like factor 4 histone deacetylase ( KLF - 4 - HDAC ) - mediated transcriptional suppression is crucial in increasing vascular endothelial growth factor ( P15692 ) expression in breast cancer . Vascular endothelial growth factor ( P15692 ) is recognized as an important angiogenic factor that promotes angiogenesis in a series of pathological conditions , including cancer , inflammation , and ischemic disorders . We have recently shown that the inflammatory transcription factor P56270 is , at least in part , responsible for the marked increase of P15692 levels in breast cancer . Here , we show that P56270 - mediated induction of P15692 is repressed by KLF - 4 transcription factor . KLF - 4 is abundantly present in normal breast epithelial cells , but its level is considerably reduced in breast cancer cells and clinical cancer tissues . In the human P15692 promoter , P56270 - and KLF - 4 - binding elements are overlapping , whereas P56270 induces and KLF - 4 suppresses P15692 expression . Ectopic overexpression of KLF - 4 and RNAi - mediated inhibition of endogenous KLF - 4 supported the role of KLF - 4 as a transcriptional repressor of P15692 and an inhibitor of angiogenesis in breast cancer cells . We show that KLF - 4 recruits histone deacetylases ( HDACs ) - 2 and - 3 at the P15692 promoter . Chronological ChIP assays demonstrated the occupancy of KLF - 4 , Q92769 , and O15379 in the P15692 promoter in normal MCF - 10A cells but not in MDA - MB - 231 cancer cells . Co - transfection of KLF - 4 and HDAC expression plasmids in breast cancer cells results in synergistic repression of P15692 expression and inhibition of angiogenic potential of these carcinoma cells . Together these results identify a new mechanism of P15692 up - regulation in cancer that involves concomitant loss of KLF - 4 - HDAC - mediated transcriptional repression and active recruitment of P56270 - mediated transcriptional activation .", "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 .", "Stimulation of epithelial repair is a likely mechanism for the action of mifepristone in reducing duration of bleeding in users of progestogen - only contraceptives . Many women using progestogen ( P ) - only contraceptives experience uterine bleeding problems . In clinical trials , a single low dose of mifepristone , given to ___MASK62___ users at the beginning of a bleeding episode reduced the number of bleeding days by approximately 50 % compared with controls . In this study , a single dose of mifepristone was administered to etonogestrel ( P17813 ) - exposed pseudo - pregnant mice , 5 days after artificial decidualization was induced when the endometrium showed signs of bleeding . Control mice received vehicle alone . Mice were culled 12 - , 18 - , 24 - and 48 - h post - treatment . In the continued presence of P17813 , a single dose of mifepristone stimulated tissue breakdown followed by very rapid repair : most treated tissues were fully restored to the pre - decidualized state by 48 h post - treatment . During repair , proliferating cells ( Ki67 immunostained ) were localized to a band of cells around the basal area in breaking down tissues and to the repairing luminal epithelium and glands . P06401 - positive cells were largely localized to the basal area of the breaking down tissue in treated mice compared with decidual cells in controls . Oestrogen receptor - positive cells were observed in the repairing luminal epithelium and glands compared with the decidua and the basal region in control tissues . It is concluded that mifepristone treatment stimulates rapid restoration of luminal epithelial integrity : such action may be a key event in reducing the number of bleeding days observed in women using ___MASK62___ who were treated with a single dose of mifepristone .", "17 ___MASK27___ - mediated growth inhibition of MDA - MB - 468 cells stably transfected with the estrogen receptor : cell cycle effects . P03372 ( ER ) - negative MDA - MB - 468 human breast cancer cells were stably transfected with wild - type human ER and utilized as a model for investigating estrogen - and aryl hydrocarbon ( Ah ) - responsiveness . Treatment of the stably transfected cells with 10 nM 17 beta - estradiol ( E2 ) resulted in a significant inhibition ( > 60 % ) of cell proliferation and DNA synthesis , which was blocked by 10 (- 7 ) M ICI 182 780 . Analysis by flow cytometry indicated that treatment with E2 increased the percentage of cells in G0 / P55008 ( from 68 . 8 to 89 . 4 ) and decreased cells in S ( from 18 . 4 to 3 . 4 ) and G2 / M ( from 12 . 8 to 7 . 2 ) phases of the cell cycle . The effects of E2 on the major cyclins , cyclin - dependent kinases and cyclin - dependent kinase inhibitors , retinoblastoma protein ( RB ) , Q01094 , and cyclin - dependent kinase activities were also investigated in the stably transfected MDA - MB - 468 cells . The results demonstrated that the growth inhibitory effects of 10 (- 8 ) M E2 in ER stably transfected MDA - MB - 468 cells were associated with modulation of several factors required for cell cycle progression and DNA synthesis , including significant induction of the cyclin - dependent kinase inhibitor p21cip - 1 ( > 4 - fold increase after 12 h ) and decreased Q01094 and P12004 protein levels . These results show that the growth - inhibitory effects of E2 in the stably transfected cells were due to multiple factors which result in growth arrest in G0 / P55008 and inhibition of DNA synthesis ." ]

[ "___MASK14___", "___MASK23___", "___MASK25___", "___MASK26___", "___MASK27___", "___MASK39___", "___MASK58___", "___MASK62___", "___MASK6___" ]

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