interacts_with DB09073?
Gene amplification is a poor prognostic factor in anaplastic oligodendrogliomas . Various gene amplifications have been observed in gliomas . Prognostic-genomic correlations testing simultaneously all these amplified genes have never been conducted in anaplastic oligodendrogliomas . A set of 38 genes that have been reported to be amplified in gliomas and investigated as the main targets of amplicons were studied in a series of 52 anaplastic oligodendrogliomas using bacterial artificial chromosome-array based comparative genomic hybridization and quantitative polymerase chain reaction . Among the 38 target genes , 15 were found to be amplified in at least one tumor . Overall , 27 % of anaplastic oligodendrogliomas exhibited at least one gene amplification . The most frequently amplified genes were epidermal growth factor receptor ( P00533 ) and cyclin-dependent kinase 4/sarcoma amplified sequence ( P11802 /SAS ) in 17 % and 8 % of anaplastic oligodendrogliomas , respectively . Gene amplification and codeletion of chromosome arms 1p/19q were perfectly exclusive ( p = 0.005 ) . In uni- and multivariate analyses , gene amplification was a negative prognostic factor for progression-free survival and overall survival in anaplastic oligodendrogliomas , providing complementary information to the classic prognostic factors identified in anaplastic oligodendrogliomas ( extent of surgery , KPS , and chromosome arms 1p/19q status ) . JTE-522 , a selective P35354 inhibitor , inhibits cell proliferation and induces apoptosis in RL95-2 cells . AIM : To investigate whether JTE-522 [ 4-(4-cyclohexyl-2-methyloxazol-5-yl)-2-fluorobenzenesulfonamide ] , a selective P35354 inhibitor , can induce apoptosis and inhibit cell proliferation in human endometrial cancer cell line RL95-2 cells and to explore the molecular mechanisms . METHODS : [ 3-(4,5)-dimethylthiazol-2-yl ] -2,5-diphenyl tetrazolium bromide ( MTT ) , DNA ladder , enzyme-linked immunosorbent assay ( ELISA ) , flow cytometry , RT-PCR , and Western blot analysis were employed to investigate effect of JTE-522 on human endometrial cancer cell line RL95-2 cells and the related molecular mechanisms . RESULTS : JTE-522 inhibited the growth of RL95-2 cells and induced the apoptosis . Furthermore , it arrested G0/ P55008 phase and inhibited S phase in RL95-2 cells . JTE-522 inhibited the expressions of P35354 mRNA , phosphorylated Rb , and P11802 proteins , while increased the levels of p53 , P38936 , cyclin D1 proteins , and the activity of caspase-3 in RL95-2 cells . CONCLUSION : JTE-522 inhibits cell proliferation and induces apoptosis in RL95-2 cells , which may be associated with the activation of caspase-3-like proteases , down-regulation of the expression of P35354 mRNA , phosphorylated Rb , and P11802 proteins , and up-regulation of the expressions of p53 , P38936 , and cyclin D1 proteins . The combined effects of single-nucleotide polymorphisms , tobacco products , and ethanol on normal resting blood mononuclear cells . INTRODUCTION : Tobacco and ethanol consumption are crucial factors in the development of various diseases including cancer . In this investigation , we evaluated the combined effects of a number of single nucleotide polymorphisms ( SNPs ) , with ethanol and tobacco products on healthy individuals . METHODS : Pure nicotine , cigarette smoke extract , and Swedish snuff ( snus ) extract were used . The effects were examined by means of in vitro cell cycle progression and cell death of peripheral blood mononuclear cells ( PBMCs ) obtained from healthy donors . RESULTS : After 3 days , in vitro , resting PBMCs entered the S and G2 stage in the presence of 100 µM nicotine . The PBMCs only proceeded to S stage , in the presence of 0.2 % ethanol . The nicotine- and ethanol-induced normal cell cycle progression correlated to a number of SNPs in the Q99665 , Rad 52 , O43543 , P04637 , P30281 , and O95477 genes . Certain SNPs in Caspases 8 , Q99665 , Rad 52 , P08253 , and Q00987 genes appeared to significantly influence the effects of EtOH- , snus- , and snus + EtOH-induced cell death . Importantly , the highest degree of cell death was observed in the presence of smoke + EtOH . The amount of cell death under this treatment condition also correlated to specific SNPs , located in the Q00987 , O95477 , or Q9H3R0 genes . CONCLUSIONS : Cigarette smoke in combination with ethanol strongly induced massive cell death . Long-term exposure to smoke and ethanol could provoke chronic inflammation , and this could be the initiation of disease including the development of cancer at various sites . Novel inhibitors of P15692 receptors-1 and -2 based on azole-5-carboxamide templates . We have developed a series of novel potent 1-(2-(pyridin-4-yl)ethyl)-1H-azole-5-carboxamides active against kinases P35968 and -1 . Both specific and dual DB00171 -competitive inhibitors of P35968 were identified . Kinase selectivity could be controlled by varying the 5-carboxamide substituent at the azole ring . The most specific molecules displayed > 10-fold selectivity for P35968 over P17948 . Compound activities in vitro and in cell-based assays ( IC(50) < 100 nM ) were similar to those of reported clinical and development candidates , including PTK787 ( DB04879 (trade) ) and DB05294 ( DB05294 ( trade mark ) ) . High permeability of active compounds across the Caco-2 cell monolayer ( > 40 x 10(-5)cm/min ) is indicative of their potential for intestinal absorption upon oral administration . Gestational exposure to the P35869 agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin induces BRCA-1 promoter hypermethylation and reduces BRCA-1 expression in mammary tissue of rat offspring : preventive effects of resveratrol . Studies with murine models suggest that maternal exposure to aromatic hydrocarbon receptor ( P35869 ) agonists may impair mammary gland differentiation and increase the susceptibility to mammary carcinogenesis in offspring . However , the molecular mechanisms responsible for these perturbations remain largely unknown . Previously , we reported that the P35869 agonists 2,3,7,8-tetrachlorodibenzo-p-dioxin ( TCDD ) induced CpG methylation of the breast cancer-1 ( BRCA-1 ) gene and reduced BRCA-1 expression in breast cancer cell lines . Based on the information both the human and rat BRCA-1 genes harbor xenobiotic responsive elements ( XRE = 5'-GCGTG-3' ) , which are binding targets for the P35869 , we extended our studies to the analysis of offspring of pregnant Sprague-Dawley rats treated during gestation with TCDD alone or in combination with the dietary P35869 antagonist resveratrol ( Res ) . We report that the in utero exposure to TCDD increased the number of terminal end buds ( TEB ) and reduced BRCA-1 expression in mammary tissue of offspring . The treatment with TCDD induced occupancy of the BRCA-1 promoter by DNA methyltransferase-1 ( P26358 -1 ) , CpG methylation of the BRCA-1 promoter , and expression of cyclin D1 and cyclin-dependent kinase-4 ( P11802 ) . These changes were partially overridden by pre-exposure to Res , which stimulated the expression of the A9YTQ3 ( A9YTQ3 ) and its recruitment to the BRCA-1 gene . These findings point to maternal exposure to P35869 agonists as a risk factor for breast cancer in offspring through epigenetic inhibition of BRCA-1 expression , whereas dietary antagonists of the P35869 may exert protective effects . Adverse effects of DB01262 on spermatogenesis include reduced sperm function and selective inhibition of de novo DNA methylation . The anticancer agent , DB01262 ( 5-azaCdR , decitabine ) , causes DNA hypomethylation and a robust , dose-dependent disruption of spermatogenesis . Previously , we have shown that altered testicular histology and reduced sperm production in 5-azaCdR-treated animals is associated with decreased global sperm DNA methylation and an increase in infertility and/or a decreased ability to support preimplantation embryonic development . The goal of this study was to determine potential contributors to 5-azaCdR-mediated infertility including alterations in sperm motility , fertilization ability , early embryo development , and sequence-specific DNA methylation . We find that although 5-azaCdR-treatment adversely affected sperm motility and the survival of sired embryos to the blastocyst stage , the major contributor to infertility was a marked ( 56-70 % ) decrease in fertilization ability . Sperm DNA methylation was investigated using Southern blot , restriction landmark genomic scanning , and quantitative analysis of DNA methylation by real-time polymerase chain reaction . Interestingly , hypomethylation was restricted to genomic loci that have been previously determined to acquire methylation during spermatogenesis , demonstrating that 5-azaCdR selectively inhibits de novo methylation activity . Similar to previous studies , we show that mice that are heterozygous for a nonfunctional P26358 gene are partially protected against the deleterious effects of 5-azaCdR ; however , methylation levels are not restored in these mice , suggesting that adverse effects are due to another mechanism(s) in addition to DNA hypomethylation . These results demonstrate that clinically relevant doses of 5-azaCdR specifically impair de novo methylation activity in male germ cells ; however , genotype-specific differences in drug responses suggest that adverse reproductive outcomes are mainly mediated by the cytotoxic properties of the drug . Genetic polymorphism and activities of human lung alcohol and aldehyde dehydrogenases : implications for ethanol metabolism and cytotoxicity . DB00898 dehydrogenase ( DB00067 ) and aldehyde dehydrogenase ( ALDH ) exhibit genetic polymorphism and tissue specificity . DB00067 and ALDH isozyme phenotypes from 39 surgical Chinese lung specimens were identified by agarose isoelectric focusing . The identity of the lung beta-ADHs was further demonstrated by their characteristic pH-activity profiles for ethanol oxidation , Km values for NAD and ethanol , and inhibition by DB01213 or 1,10-phenanthroline . The beta 2 allele , coding for beta 2 polypeptide , was found to be predominant in the lung specimens studied . The DB00067 activities in the lungs with the homozygous phenotype P00325 2-2 ( exhibiting beta 2 beta 2 ) and P00325 1-1 ( exhibiting beta 1 beta 1 ) and the heterozygous phenotype P00325 P35326 ( exhibiting beta 2 beta 2 , beta 2 beta 1 , and beta 1 beta 1 ) were determined to be 999 +/- 77 , 48 +/- 17 , and 494 +/- 61 nmol/min/g tissue , respectively . Fifty-one percent of the specimens studied lacked the P05091 activity band on the isoelectric focusing gels . The activities in the lung tissues with the P05091 -active phenotype and the inactive phenotype were determined to be 30 +/- 3 and 17 +/- 1 nmol/min/g tissue , respectively . These findings indicate that human pulmonary ethanol-metabolizing activities differ significantly with respect to genetic polymorphism at both the P00325 and the P05091 loci . The results suggest that individuals with high Vmax beta 2- DB00067 and deficient in low-Km mitochondrial P05091 , accounting for approximately 45 % of the Chinese population , may end up with acetaldehyde accumulation during alcohol consumption , rendering them vulnerable to tissue injury caused by this highly reactive and toxic metabolite . A double-blind , placebo-controlled outpatient trial of pergolide for cocaine dependence . Results of preclinical studies suggest that pergolide , a mixed D(1)/ P14416 agonist , may be useful in treating cocaine dependence . To empirically investigate this possibility , we conducted a 5-year , double-blind , placebo-controlled clinical trial of two doses of pergolide ( 0.05 and 0.25 mg bid ) in subjects with cocaine dependence and combined cocaine/alcohol dependence . Data analysis was performed on an intent to treat population ( N=358 ) and a per protocol population ( N=108 ) with urine drug screens ( UDS ) used as the main outcome measure . There were no significant effects on UDS at either pergolide dose . DB01186 had no significant effect on alcohol use in the comorbid alcohol/cocaine dependence group . DB01186 does not appear to have clinical value in the treatment of cocaine dependence or in decreasing alcohol use in cocaine-dependent individuals at the presently studied doses . Critical role of both p27KIP1 and p21CIP1/ P38936 in the antiproliferative effect of ZD1839 ( ' DB00317 ' ) , an epidermal growth factor receptor tyrosine kinase inhibitor , in head and neck squamous carcinoma cells . High expression of the epidermal growth factor receptor ( P00533 ) has been implicated in the development of squamous-cell carcinomas of head and neck ( SCCHN ) . ZD1839 ( ' DB00317 ' ) is an orally active , selective P00533 -TKI ( P00533 -tyrosine kinase inhibitor ) that blocks signal transduction pathways implicated in proliferation and survival of cancer cells , and other host-dependent processes promoting cancer growth . We have demonstrated that ZD1839 induces growth arrest in SCCHN cell lines by inhibiting P00533 -mediated signaling . Cell cycle kinetic analysis demonstrated that ZD1839 induces a delay in cell cycle progression and a P55008 arrest together with a partial G2/M block ; this was associated with increased expression of both p27( P46527 ) and P38936 (CIP1/ P38936 ) cyclin-dependent kinase ( CDK ) inhibitors . The activity of P24941 , the main target of CIP/ Q99828 CDK inhibitors , was reduced in a dose-dependent fashion after 24 h of ZD1839 treatment and this effect correlated to the increased amount of p27( P46527 ) and P38936 (CIP1/ P38936 ) proteins associated with P24941 -cyclin-E and P24941 -cyclin-A complexes . In addition , ZD1839-induced growth inhibition was significantly reduced in cell transfectants expressing p27( P46527 ) or P38936 (CIP1/ P38936 ) antisense constructs . Overall , these results as well as the timing of the effect of ZD1839 on P55008 arrest and p27( P46527 ) and P38936 (CIP1/ P38936 ) upregulation , suggest a mechanistic connection between these events . DB01599 inactivates O95477 in the plasma membrane with respect to its mediation of apolipoprotein binding and high density lipoprotein assembly and to its proteolytic degradation . DB01599 has been shown to inhibit the release of cellular lipid by helical apolipoprotein and thereby to reduce plasma high density lipoprotein . We attempted to explore the underlying mechanism for this effect in human fibroblast WI-38 . DB01599 inhibited the apoA-I-mediated cellular lipid release and binding of apoA-I to the cells in a dose-dependent manner . It did not influence cellular uptake of low density lipoprotein , transport of cholesterol to the cell surface whether de novo synthesized or delivered as low density lipoprotein , and overall cellular content of cholesterol , although biosynthesis of lipids from acetate was somewhat increased . DB01599 did not affect the mRNA level of O95477 , and O95477 was recovered along with marker proteins for plasma membrane regardless of the presence of probucol . However , the protein level of O95477 increased , and the rate of its decay in the presence of cycloheximide was slower in the probucol-treated cells . O95477 in the probucol-treated cells was resistant to digestion by calpain but not by trypsin . We concluded that probucol inactivates O95477 in the plasma membrane with respect to its function in mediating binding of and lipid release by apolipoprotein and with respect to proteolytic degradation by calpain . The effects of GM- P04141 , steel factor and MIP-1alpha on the expression and activation of Cdc25A phosphatase in Mo7e cells . Active cyclin-dependent kinases ( CDKs ) are required for progression through the P55008 phase of the cell cycle and entry into S phase . Activity of P55008 CDKs is controlled by mechanisms including phosphorylation of Thr14 and Tyr15 residues . Removal of inhibitory phosphates on these amino acid residues is required for P55008 CDK activation , and is mediated by the Cdc25A phosphatase . Regulation of active Cdc25A phosphatase levels may be important for the proliferation of hematopoietic progenitor cells , effects assessed in the human growth-factor-dependent cell line Mo7e . Constitutive Cdc25A protein levels were enhanced with granulocyte-macrophage colony-stimulating factor ( GM- P04141 ) plus steel factor ( SF ) . Cdc25A is thought to exert its activity in the nucleus , and nuclear protein levels of Cdc25A were also enhanced with GM- P04141 and SF . GM- P04141 plus SF promote synergistic growth of Mo7e cells . Pretreatment with macrophage inflammatory protein ( MIP-1alpha ) inhibited GM- P04141 - plus SF-induced growth and upregulation of Cdc25A protein levels . Stimulation with GM- P04141 and SF also rapidly increased Cdc25A phosphatase activity , an effect suppressed by MIP-1alpha . A concomitant inhibition of increased P11802 kinase activity correlated with increased phosphotyrosine levels on P11802 when cells were pretreated with MIP-1alpha prior to GM- P04141 and SF . These data suggest that Cdc25A expression and activity are regulated during proliferation of Mo7e cells . The effects of PTK787/ZK222584 , an inhibitor of VEGFR and PDGFRβ pathways , on intussusceptive angiogenesis and glomerular recovery from Thy1.1 nephritis . The aim of our study was to investigate the phenomenon of intussusceptive angiogenesis with a focus on its molecular regulation by vascular endothelial growth factor receptor ( VEGFR ) /platelet-derived growth factor receptor β ( PDGFRβ ) pathways and biological significance for glomerular recovery after acute injury . Glomerular healing by intussusception was examined in a particular setting of Thy1.1 nephritis , where the lysis of mesangial cells results in an initial collapse and successive rebuilding of glomerular capillary structure . Restoration of capillary structure after induction of Thy1.1 nephritis occurred by intussusceptive angiogenesis resulting in i ) rapid expansion of the capillary plexus with reinstatement of the glomerular filtration surface and ii ) restoration of the archetypical glomerular vascular pattern . Glomerular capillaries of nephritic rats after combined P35968 and PDGFRβ inhibition by PTK787/ZK222584 ( DB04879 ) were tortuous and irregular . However , the onset of intussusceptive angiogenesis was influenced only after long-term DB04879 treatment , providing an important insight into differential molecular regulation between sprouting and intussusceptive angiogenesis . DB04879 treatment abolished α-smooth muscle actin and tensin expression by injured mesangial cells , impaired glomerular filtration of microspheres , and led to the reduction of glomerular volume and the presence of multiple hemorrhages detectable in the tubular system . Collectively , treatment of nephritic patients with DB04879 compound is not recommended . Discovery of cyclin-dependent kinase inhibitor , CR229 , using structurebased drug screening . To generate new scaffold candidates as highly selective and potent cyclin-dependent kinase ( CDK ) inhibitors , structure-based drug screening was performed utilizing 3D pharmacophore conformations of known potent inhibitors . As a result , CR229 ( 6-bromo-2,3,4,9-tetrahydro-carbolin-1-one ) was generated as the hit-compound . A computational docking study using the X-ray crystallographic structure of P24941 in complex with CR229 was evaluated . This predicted binding mode study of CR229 with P24941 demonstrated that CR229 interacted effectively with the Leu83 and Glu81 residues in the DB00171 -binding pocket of P24941 for the possible hydrogen bond formation . Furthermore , biochemical studies on inhibitory effects of CR229 on various kinases in the human cervical cancer HeLa cells demonstrated that CR229 was a potent inhibitor of P24941 ( IC50 : 3 microM ) , P06493 ( IC50 : 4.9 microM ) , and P11802 ( IC50 : 3 microM ) , yet had much less inhibitory effect ( IC50 : > 20 microM ) on other kinases , such as casein kinase P35326 ( CK2- alpha1 ) , protein kinase A ( PKA ) , and protein kinase C ( PKC ) . Accordingly , these data demonstrate that CR229 is a potent CDK inhibitor with anticancer efficacy . The potential role of PD0332991 ( DB09073 ) in the treatment of multiple myeloma . INTRODUCTION : Multiple myeloma ( MM ) remains an incurable malignancy indicating a need for continued investigation of novel therapies . Recent studies have highlighted the role of cyclin-dependent kinases ( CDK ) in the pathogenesis of MM . PD0332991 ( DB09073 ) is an orally bioavailable , highly selective inhibitor of the P11802 /6-cyclin complex and downstream retinoblastoma protein ( Rb ) activation pathway that induces cell cycle arrest in the P55008 phase . AREAS COVERED : In this review , the authors summarize the role of the P11802 /6 signaling pathway in MM . They also summarize the development of PD0332991 as a specific inhibitor of P11802 /6 , and the reported preclinical and clinical data supporting the potential role of PD0332991 in MM . EXPERT OPINION : While PD0332991 is essentially cytostatic , inducing prolonged P55008 arrest , it enhances the cytotoxic effect of other agents effective in MM , including bortezomib and lenalidomide , as confirmed in early phase clinical trials . However , with a plethora of other drugs of different classes being tested in MM , further development of PD0332991 will depend on defining the most efficacious combination with least toxicity . An unexplored opportunity remains the potential protective effect of PD0332991 against lytic bone lesions of MM . The next few years are likely to better define the place of PD0332991 in the treatment of MM . Dedifferentiated chondrosarcoma mimicking a giant cell tumor . Is this low grade dedifferentiated chondrosarcoma ? We report a very rare case of a dedifferentiated chondrosarcoma mimicking a benign giant cell tumor . A 22-year-old male was admitted to our hospital with a history of mild left wrist pain after a skiing trauma . Radiology revealed an extensive meta-epiphyseal osteolytic lesion in the distal ulna , which appeared to be a giant cell tumor . Histological examination showed a biphasic tumor comprising chondroid and non-chondroid areas with a giant cell-rich lesion resembling a conventional giant cell tumor of the bone . Immunohistochemistry showed no expression of p16(INK4a) , P17948 , P35968 ( P35968 ) , P35916 , cKIT , Q00987 or P11802 . However , high expression of the tyrosine kinases P16234 and P09619 was observed . Molecular analysis showed no amplification of the cMYC gene and no activating mutations in the cKIT ( exons 9 and 11 ) or P16234 ( exon 18 ) genes . He has been on follow-up for ten months , with no evidence of local recurrence or metastatic disease . In summary , this report highlights a very rare case of a dedifferentiated chondrosarcoma in which the dedifferentiated component of the tumor bears histologic resemblance to a conventional giant cell tumor of bone . We suggest that this tumor might be categorized in the group of low-grade dedifferentiated chondrosarcomas . DB09073 ( PD 0332991 ) : targeting the cell cycle machinery in breast cancer . INTRODUCTION : The cyclin D-cyclin-dependent kinases 4 and 6 ( P11802 /6 ) -retinoblastoma ( P06400 ) pathway , governing the cell cycle restriction point , is frequently altered in breast cancer and is a potentially relevant target for anticancer therapy . DB09073 ( PD 0332991 ) , a potent and selective inhibitor of P11802 and Q00534 , inhibits proliferation of several P06400 -positive cancer cell lines and xenograft models . AREAS COVERED : The basic features and abnormalities of the cell cycle in breast cancer are described , along with their involvement in estrogen signaling and endocrine resistance . The pharmacological features of palbociclib , its activity in preclinical models of breast cancer and the potential determinants of response are then illustrated , and its clinical development in breast cancer described . A literature search on the topic was conducted through PubMed and the proceedings of the main cancer congresses of recent years . EXPERT OPINION : The combination of palbociclib with endocrine agents is a very promising treatment and Phase III clinical trials are ongoing to confirm its efficacy . Further , potentially useful combinations are those with drugs targeting mitogenic signaling pathways , such as P04626 - and PI3K-inhibitors . Combination with chemotherapy seems more problematic , as antagonism has been reported in preclinical models . The identification of predictive factors , already explored in preclinical studies , must be further refined and validated in clinical trials . DB00174 synthetase : regulation by cell stress and involvement in tumor biology . DB00174 synthetase ( P08243 ) catalyzes the conversion of aspartate and glutamine to asparagine and glutamate in an DB00171 -dependent reaction . The enzyme is ubiquitous in its organ distribution in mammals , but basal expression is relatively low in tissues other than the exocrine pancreas . Human P08243 activity is highly regulated in response to cell stress , primarily by increased transcription from a single gene located on chromosome 7 . Among the genomic elements that control P08243 transcription is the C/EBP- P39905 response element ( CARE ) within the promoter . Protein limitation or an imbalanced dietary amino acid composition activate the P08243 gene through the amino acid response ( AAR ) , a process that is replicated in cell culture through limitation for any single essential amino acid . Endoplasmic reticulum stress also increases P08243 transcription through the Q9NZJ5 -eIF2- P18848 arm of the unfolded protein response ( UPR ) . Both the AAR and UPR lead to increased synthesis of P18848 , which binds to the CARE and induces P08243 transcription . Elevated expression of P08243 protein is associated with resistance to asparaginase therapy in childhood acute lymphoblastic leukemia and may be a predictive factor in drug sensitivity for certain solid tumors as well . Activation of the Q9P2K8 -eIF2- P18848 signaling pathway , leading to increased P08243 expression appears to be a component of solid tumor adaptation to nutrient deprivation and/or hypoxia . Identifying the roles of P08243 in fetal development , tissue differentiation , and tumor growth may reveal that P08243 function extends beyond asparagine biosynthesis . Targeting the P00533 / P00533 receptor to improve outcomes in non-small-cell lung cancer . Non-small-cell lung cancer represents a growing global burden and remains a therapeutic challenge . Only small improvements in survival have been made with standard chemotherapeutic approaches to advanced disease in recent history . Novel biologic targeted therapies offer the potential of improving patient management and treatment outcomes in non-small-cell lung cancer . Prominent among these novel agents are the P00533 /epithelial growth factor receptor ( P00533 ) inhibitors . One of these agents , gefitinib ( DB00317 ) , is already approved for use in advanced , refractory non-small-cell lung cancer . Erlotinib ( Tarceva ) is a promising P00533 / P00533 inhibitor in phase III evaluation as first-line therapy combined with chemotherapy and as second-/third-line monotherapy in advanced non-small-cell lung cancer . In addition , erlotinib is being evaluated in combination with the angiogenesis inhibitor bevacizumab ( DB00112 ) , a strategy combining two new modalities in cancer treatment . Results of these trials will provide important information on optimal use of these new targeted therapies and may offer the promise of improving the treatment of non-small-cell lung cancer . Association of genetic polymorphisms with personality profile in individuals without psychiatric disorders . OBJECTIVE : Population-based twin studies demonstrate that approximately 40-50 % of the variability in personality dimensions results from genetic factors . This study assessed selected polymorphisms in the P21964 Val158Met , P21397 3'VNTR , 5HTTLPR , 102T/C 5- Q13049 , Q01959 3'VNTR and P14416 exon 8 genes and evaluated their association with personality profiles , anxiety levels , and depressiveness in healthy subjects . METHODS : This study included 406 unrelated ( mean age 38.51 years ) , mentally and somatically healthy Caucasian subjects of Polish origin . The prevalence of the gene variants mentioned above and their association with personality profiles , anxiety levels , and depressiveness was assessed using the Temperament and Character Inventory , NEO Five-Factor Inventory , Spielberger 's State-Trait Anxiety Inventory and Beck 's Depression Inventory . RESULTS : The effects of the 5HTTLPR gene on the s/s genotype and empathy ( P06681 ) were lowest in the entire group . The effects of gender , age and the Q13049 gene for the T/T genotype and attachment ( Q7Z3Z2 ) were highest in women . The effects of gender , age and the Q01959 gene on the 9/9 Q01959 genotype , compassion ( C4 ) and cooperativeness ( C ) were lowest in women . The effects of gender , age and the P21964 gene on the DB00134 / DB00134 genotype and neuroticism ( P04626 ) NEO-FFI were also lowest in women . CONCLUSIONS : Our results suggest considerable influence of individual genes on the formation of personality traits . PPARgamma activation abolishes LDL-induced proliferation of human aortic smooth muscle cells via SOD-mediated down-regulation of superoxide . Native LDL would be a mitogenic and chemotactic stimulus of VSMC proliferation and differentiation in the atherosclerotic lesion where endothelial disruption occurred . In previous studies , our group investigated the molecular mechanisms by which LDL induces P10145 production and by which PPARalpha activation abolishes LDL effects in human aortic SMCs ( hAoSMCs ) . Herein is the first report of PPARgamma activation by troglitazone ( TG ) exerting its inhibitory effects on LDL-induced cell proliferation via generation not of H(2)O(2) , but of O2(.-) , and the subsequent activation of Erk1/2 in hAoSMCs . Moreover , in this study TG abolished the LDL-accelerated G(1)-S progression to control levels via down-regulation of active cyclinD1/ P11802 and cyclinE/ P24941 complexes and up-regulation of P38936 (Cip1) expression . TG exerted its anti-proliferative effects through the up-regulation of basal superoxide dismutase ( SOD ) expression . This data suggests that the regulation of O2(.-) is located at the crossroads between LDL signaling and cell proliferation . Xaliproden ( SR57746A ) induces P08908 receptor-mediated Q96HU1 kinase activation in PC12 cells . Neurotrophic growth factors are involved in cell survival . However , natural growth factors have a very limited therapeutic use because of their short half-life . In the present study , we investigated the mechanism of action of a non-peptidic neurotrophic drug , Xaliproden , a potential molecule for the treatment of motoneuron diseases , since the transduction pathways of this synthetic P08908 agonist are very poorly understood . Xaliproden does not activate the Trk receptor but causes a rapid increase in the activities of the P27361 and P28482 isoforms of Q96HU1 kinase , which then rapidly decrease to the basal level . We demonstrate that isoforms of the P29353 adapter protein are phosphorylated independently of each other and are probably not the source of the Xaliproden-induced Q96HU1 kinases activation . The inhibitor of Ras farnesylation , FPT-1 , and the protein kinase C inhibitors , GF 109203X and chelerythrine , inhibited the Xaliproden-induced Q96HU1 kinase activation , suggesting p21Ras and PKC involvement . Moreover , the observations that the P08908 antagonist , pindobind , and pertussis toxin abolished the Xaliproden-induced P29323 stimulation suggested that Xaliproden activates the Q96HU1 kinase pathways by stimulating the G protein-coupled receptor , P08908 . These results demonstrate clearly that the non-peptidic compound , Xaliproden , exerts its neurotrophic effects through a mechanism of action differing from that of neurotrophins . These findings suggest that this compound does not involve MAPK activation by TrkA receptor stimulation but acts by Q96HU1 kinase pathway by a pertussis toxin-sensitive mechanism involving P08908 receptors , P38936 Ras and MEK-1 and by PKC and Akt pathways . A combination of molecular cytogenetic analyses reveals complex genetic alterations in conventional renal cell carcinoma . Here we report the complex pattern of genomic imbalances and rearrangements in a panel of 19 renal cell carcinoma cell lines detected with molecular cytogenetic analysis . Consistent heterogeneity in chromosome number was found , and most cell lines showed a near-triploid chromosome complement . Several cell lines showed deletions of the P04637 ( alias p53 ) , CDKN2A ( alias p16 ) , and P40337 genes . Multiplex fluorescence in situ hybridization ( M- Q5TCZ1 ) analysis revealed chromosome 3 translocated to several other partners chromosomes , as well as breakage events commonly affecting chromosomes 1 , 5 , 8 , 10 , and 17 . The most common abnormality detected with comparative genomic hybridization ( CGH ) was deletions of chromosome 3p , with loss of the Q9NS23 , P49789 , and p44S10 loci frequently involved . CGH gain of 5q showed overrepresentation of the P18146 and P07333 genes . Recurrent alterations to chromosome 7 included rearrangement of 7q11 and gains of the P00533 , O15164 , and P35250 genes . Several lines exhibited rearrangement of 12q11 approximately q14 and overrepresentation of P11802 and SAS loci . M- Q5TCZ1 revealed several other recurrent translocations , and CGH findings included loss of 9p , 14q , and 18q and gain of 8q , 12 , and 20 . Further genomic microarray changes included loss of Q13126 , IGH@ , P28222 , and Q13485 ( previously Q13485 ) and gains of MYC and P11387 . An excellent correlation was observed between the genomic array and Q5TCZ1 data , demonstrating that this technique is effective and accurate . The aberrations detected here may reflect important pathways in renal cancer pathogenesis . The effects of 5-aza-2'- deoxycytidine and trichostatin A on gene expression and DNA methylation status in cloned bovine blastocysts . We previously found that treatment of both donor cells and early cloned embryos with combination of DB01262 ( 5-aza-dC ) and trichostatin A ( P32119 ) significantly improve the in vitro and full-term development of nuclear transfer ( NT ) bovine embryos . To investigate how this treatment improved the epigenetic reprogramming of somatic cell nuclei , we compared the expression levels of DNA methylation- , chromatin structure- , and development-related genes in in vitro fertilized ( IVF group ) , NT ( C-NT group ) , and 5-aza-dC and P32119 -treated NT ( T-NT group ) single blastocyst using quantitative real-time PCR . We also compared the DNA methylation status of satellite I among three groups using bisulfite sequencing analysis and combined bisulfite restriction analysis ( COBRA ) . There were significantly lower levels of P26358 , DNMT3b , Q92769 , and P01344 transcripts in T-NT blastocysts than in C-NT blastocysts , whereas the relative abundance of Q01860 and P48431 mRNA was significantly increased in T-NT blastocysts compared to C-NT blastocysts . In addition , the treatment also reduced the DNA methylation levels of NT blastocysts on satellite I sequence . It is likely that P32119 may act synergistically with 5-aza-dC to exert such modifications in gene expression and DNA methylation , subsequently enhancing developmental potential ( in vitro and full-term ) of treated cloned embryos . Glycyrrhetinic acid induces G1‑phase cell cycle arrest in human non‑small cell lung cancer cells through endoplasmic reticulum stress pathway . Glycyrrhetinic acid ( GA ) is a natural compound extracted from liquorice , which is often used in traditional Chinese medicine . The purpose of the present study was to investigate the antitumor effect of GA in human non‑small cell lung cancer ( NSCLC ) , and its underlying mechanisms in vitro . We have shown that GA suppressed the proliferation of A549 and NCI‑H460 cells . Flow cytometric analysis showed that GA arrested cell cycle in G0/ P55008 phase without inducing apoptosis . Western blot analysis indicated that GA mediated G1‑phase cell cycle arrest by upregulation of cyclin‑dependent kinase inhibitors ( CKIs ) ( p18 , p16 , p27 and P38936 ) and inhibition of cyclins ( cyclin‑D1 , ‑D3 and ‑E ) and cyclin‑dependent kinases ( CDKs ) ( P11802 , 6 and 2 ) . GA also maintained P06400 phosphorylation status , and inhibited E2F transcription factor 1 ( E2F‑1 ) in both cell lines . GA upregulated the unfolded proteins , Bip , Q9NZJ5 and P13667 . Accumulation of unfolded proteins in the endoplasmic reticulum ( ER ) triggered the unfolded protein response ( UPR ) , which could be the mechanism by which GA inhibited cell proliferation in NSCLC cells . GA then coordinated the induction of ER chaperones , which decreased protein synthesis and induced cell cycle arrest in the P55008 phase . This study provides experimental evidence to support the development of GA as a chemotherapeutic agent for NSCLC . Inhibition of SKF 38393- and pergolide-induced circling in rats with unilateral 6-OHDA lesion is correlated to dopamine D-1 and D-2 receptor affinities in vitro . The effects of 30 dopamine ( DA ) antagonists , including 4 as stereoisomeric pairs , on circling behaviour induced by the D-1 agonist SKF 38393 and the D-2 agonist pergolide in rats with unilateral 6-hydroxy-DA lesions have been studied . SKF 38393-induced circling was selectively blocked by the specific D-1 antagonists P35240 23390 and SKF 83566 , and was furthermore blocked by other DA antagonists with potencies correlating to their affinities to D-1 receptors labelled by 3H- P35240 23390 in vitro . DB01186 -antagonistic potencies in contrast correlated to affinities to D-2 receptors labelled by 3H-spiperone in vitro . DB01186 -induced circling was selectively blocked by the specific D-2 antagonists in the benzamide series . No interaction between D-1 and D-2 antagonists was observed in combination experiments with P35240 23390 and YM 09151-2 in both circling models . Among other reference neurotransmitter antagonists acting on alpha- and beta-adrenoceptors , histamine , serotonin and muscarinic receptors , only the alpha 1-adrenoceptor antagonist prazosin was effective in high doses . In contrast , the alpha 2- and beta-adrenoceptor agonists clonidine and clenbuterol as well as the muscarinic agonist RS 86 inhibited circling induced by SKF 38393 as well as pergolide . The P08908 agonist 8-OHDPAT inhibited pergolide-induced circling only . It is concluded that these two behavioural models are selective in vivo measures of relative D-1 and D-2 receptor activity of DA antagonists . Pharmacologic suppression of hepatic O95477 activity in mice reduces high-density lipoprotein cholesterol levels but promotes reverse cholesterol transport . BACKGROUND : The role of hepatic O95477 ( O95477 ) in maintaining plasma high density lipoprotein cholesterol ( HDL-C ) levels is well established , but its role in reverse cholesterol transport ( RCT ) is unclear . DB01599 is a compound that reduces HDL-C levels but also reduces atherosclerosis in animal models and xanthomas in humans . The aim of the present study was to test the hypothesis that probucol inhibits hepatic O95477 activity , thereby reducing HDL-C levels but promoting RCT from macrophages . METHODS AND RESULTS : Wild-type ( WT ) C57BL/6 mice and scavenger receptor class B type I ( Q8WTV0 ) knockout mice were fed a chow diet containing 0.5 % probucol or normal chow for 2 weeks . In WT mice , probucol , despite decreasing HDL-C by > 80 % , effectively maintained macrophage RCT . In Q8WTV0 knockout mice , probucol also substantially reduced HDL-C but significantly increased macrophage RCT . Furthermore , probucol significantly enhanced the excretion of HDL-derived cholesterol into feces in both WT and Q8WTV0 knockout mice . DB01599 inhibited O95477 -dependent cholesterol efflux from mouse primary hepatocytes , and this effect was shown to be responsible for the effect of probucol on increasing the fecal excretion of HDL-derived cholesterol in vivo . CONCLUSIONS : We demonstrate that pharmacological inhibition of hepatic O95477 activity with probucol reduced HDL-C levels but promoted RCT through diversion of HDL-derived cholesterol from efflux back into plasma instead to excretion in the bile . These results explain the beneficial effects of probucol on atherosclerosis and xanthomas despite its HDL-lowering effects and suggest that inactivation of hepatic O95477 leads to increased RCT despite reducing plasma HDL-C levels . Pharmacokinetics and pharmacodynamics of the DB00669 antimigraine agents : a comparative review . The current approach to antimigraine therapy comprises potent serotonin P28222 /1D receptor agonists collectively termed triptans . Sumatriptan was the first of these compounds to be developed , and offered improved efficacy and tolerability over ergot-derived compounds . The development of sumatriptan was quickly followed by a number of ' second generation ' DB00669 compounds , characterised by improved pharmacokinetic properties and/or tolerability profiles . Triptans are believed to effect migraine relief by binding to serotonin ( 5-hydroxy-tryptamine ) receptors in the brain , where they act to induce vasoconstriction of extracerebral blood vessels and also reduce neurogenic inflammation . Although the pharmacological mechanism of the triptans is similar , their pharmacokinetic properties are distinct . For example , bioavailability of oral formulations ranges between 14 % ( sumatriptan ) and 74 % ( naratriptan ) , and their elimination half-life ranges from 2 hours ( sumatriptan and rizatriptan ) to 25 hours ( frovatriptan ) . Clearly , such diverse pharmacokinetic properties will influence the effectiveness of the compounds and favour the prescription of one over another in different patient populations . This article reviews the pharmacological properties of the triptans ( time to peak plasma concentration , half-life , bioavailability and receptor binding ) and relates these properties to efficacy and time of onset . It also considers the effects of concomitant medication , food , age and disease on the pharmacokinetics of the compounds . In addition , the relative merits , such as headache recurrence , tolerability and route of administration , are discussed . Finally , the performance of the triptans is considered in the context of direct head-to-head comparative trials that have assessed the efficacy profile of the compounds . [ Rizatriptan : experience after 15 years of clinical use ] . We review the development of rizatriptan , one of the seven P28222 /1D agonists available for the symptomatic treatment of migraine , emphasizing the most relevant contributions carried out from our country . Rizatriptan has shown the quickest onset of action , both in controlled studies and in the different metaanalyses , which translates in high efficacy levels at two hours . Its tolerability and safety profile is similar to that of the other compounds in this pharmacological group . Postlaunching studies have shown that its high efficacy leads to pharmacoeconomic savings and to a robust preference and satisfaction by the patient for this DB00669 . Its efficacy is improved with an early use within migraine attacks and recent data have shown also efficacy in adolescents . This global profile places rizatriptan as a DB00669 of first choice for any kind of migraine attacks . DB00174 Synthetase Deficiency : New Inborn Errors of Metabolism . BACKGROUND : DB00174 synthetase deficiency ( P51689 ) is a newly identified neurometabolic disorder characterized by severe congenital microcephaly , severe global developmental delay , intractable seizure disorder , and spastic quadriplegia . Brain Q9BWK5 showed brain atrophy , delayed myelination , and simplified gyriform pattern . METHODS : We report P51689 deficiency in a 2- and 4-year-old sibling . On them , we described clinical , biochemical , and molecular findings , and we compared our results with previously reported cases . RESULTS : We identified a homozygous novel missense mutation in P08243 gene in both probands and we demonstrated low P04141 and plasma asparagine in both patients . CONCLUSIONS : Clinicians should suspect P51689 deficiency in any newborn presented with severe congenital microcephaly followed by severe epileptic encephalopathy and global developmental delay . P04141 asparagine level is low in this disorder while plasma may be low . Oxidation of alcohols and reduction of aldehydes derived from methyl- and dimethylpyrenes by cDNA-expressed human alcohol dehydrogenases . Some methylated pyrenes can form DNA adducts in rat tissues after benzylic hydroxylation and sulpho conjugation . However , oxidation of the intermediate alcohols to carboxylic acids is an important competing pathway leading to detoxification . We previously showed that co-administration of ethanol or DB01213 strongly enhances DNA adduct formation by 1-hydroxymethylpyrene , indicating an involvement of alcohol dehydrogenases ( ADHs ) in the detoxification . This mechanism may be involved in the observed synergism of smoking and alcohol consumption in certain human cancers . In a preceding study , cDNA-expressed human P00325 efficiently oxidised 1- , 2- and 4-hydroxymethylpyrene ; these reactions were inhibited in the presence of ethanol or DB01213 . Here we report that P00326 , P00326 and P08319 also show substantial activity towards these substrates and two further congeners , 1-hydroxymethyl-6-methylpyrene and 1-hydroxymethyl-8-methylpyrene . All four DB00067 forms also catalysed the reverse reaction , implying that the aldehydes have to be sequestered by other enzymes , such as aldehyde dehydrogenases , for final detoxification . P00326 and P08319 activities towards hydroxymethylpyrenes were more strongly inhibited in the presence of ethanol and DB01213 than those of P00325 . P00326 was only inhibited at very high concentrations of the modulators . In conclusions , several human ADHs are capable of detoxifying benzylic alcohols of alkylated polycyclic aromatic hydrocarbons . However , some competing substrates and inhibitors may affect all these redundant detoxification systems , although to various extents . Targeted inactivation of Q92769 restores p16INK4a activity and exerts antitumor effects on human gastric cancer . Aberrant regulation of histone deacetylase 2 ( Q92769 ) was reported for gastric cancers . However , responsive cancer genes in disease onset and progression are less understood . Q92769 expression was studied by quantitative RT-PCR and Western blotting . The functional consequences of Q92769 knockdown on cell-cycle regulation , programmed cell death , and gene target identification was investigated by flow cytometry , Western blotting , electron microscopy , anchorage-independent colony formation , and cell migration assay and by whole-genome microarray . Therapeutic efficacy of Q92769 knockdown was determined in nude mice with small hairpin expressing human gastric cancer cells . Epigenetic regulation of p16(INK4a) was studied by methylation-specific PCR and chromatin-IP to evidence Q92769 or acetylated-histone-H4 binding at gene specific promoter sequences . Q92769 gene and protein expression was significantly upregulated in different histopathologic grades of human gastric cancers and cancer cell lines . Q92769 inactivation significantly reduced cell motility , cell invasion , clonal expansion , and tumor growth . Q92769 knockdown-induced G(1)-S cell cycle arrest and restored activity of p16(INK4a) and the proapoptotic factors . This treatment caused PARP cleavage and hypophosphorylation of the Rb-protein , repressed cyclinD1 , P11802 , and Bcl-2 expression and induced autophagic phenotype , that is , LC3B-II conversion . Some gastric tumors and cancer cells displayed p16(INK4a) promoter hypermethylation but treatment with 5-aza-deoxycitidine restored activity . With others the methylation status was unchanged . Here , chromatin-IP evidenced Q92769 binding . Nonetheless , expression of p16(INK4a) was restored by Q92769 knockdown with notable histone-H4-acetylation , as determined by chromatin-IP . Thus , p16(INK4a) is regulated by Q92769 . Q92769 is a bona fide target for novel molecular therapies in gastric cancers . Evaluation of a microarray for genotyping polymorphisms related to xenobiotic metabolism and DNA repair . We present an oligonucleotide microarray ( " MetaboChip " ) based on the arrayed primer extension ( P27695 ) technique , allowing genotyping of single nucleotide polymorphisms ( SNPs ) in genes of interest for cancer susceptibility and pharmacogenetics . P27695 consists of a sequencing reaction primed by an oligonucleotide anchored with its 5' end to a glass slide and terminating one nucleotide before the polymorphic site . The extension with one fluorescently labeled dideoxynucleotide complementary to the template reveals the polymorphism . Ninety-three SNPs in 42 genes were selected among those resequenced in the context of the SNP500 project , using a set of 102 reference DNA samples from the Coriell Biorepository . Selected SNPs belong to the following genes : P00325 , P05091 , P27695 , CDKN2A , P21964 , P04798 , P05177 , Q16678 , P11509 , P33261 , P11712 , P05181 , P08684 , P14416 , P21917 , P07099 , P07992 , P18074 , Q92889 , P28715 , P30550 , O15217 , P21266 , P09211 , GSTT2 , LIG3 , Q00987 , P16455 , P05164 , NAT1 , NAT2 , P15559 , O15527 , P12004 , P06746 , Q01959 , P04179 , P04637 , P18887 , O43543 , O43542 , and O15287 . We assessed the performance of P27695 by comparing the results obtained with MetaboChip against those reported by the SNP500 . Among 88 SNPs that yielded signals , 6 showed less than 99 % of concordance , whereas 82 performed accurately , showing that P27695 is a reliable and sensitive genotyping method . Coadministrating luteolin minimizes the side effects of the aromatase inhibitor letrozole . P11511 inhibitors ( AIs ) have been used as adjuvant therapeutic agents for breast cancer . Their adverse side effect on blood lipid is well documented . Some natural compounds have been shown to be potential AIs . In the present study , we compared the efficacy of the flavonoid luteolin to the clinically approved AI letrozole ( DB01006 ; Novartis Pharmaceuticals , East Hanover , NJ ) in a cell and a mouse model . In the in vitro experimental results for aromatase inhibition , the Ki values of luteolin and letrozole were estimated to be 2.44 µM and 0.41 nM , respectively . Both letrozole and luteolin appeared to be competitive inhibitors . Subsequently , an animal model was used for the comparison . P11511 -expressing MCF-7 cells were transplanted into ovariectomized athymic mice . Luteolin was given by mouth at 5 , 20 , and 50 mg/kg , whereas letrozole was administered by intravenous injection . Similar to letrozole , luteolin administration reduced plasma estrogen concentrations and suppressed the xenograft proliferation . The regulation of cell cycle and apoptotic proteins-such as a decrease in the expression of Bcl-xL , cyclin-A/D1/E , P24941 /4 , and increase in that of Bax-was about the same in both treatments . The most significant disparity was on blood lipids . In contrast to letrozole , luteolin increased fasting plasma high-density lipoprotein concentrations and produced a desirable blood lipid profile . These results suggested that the flavonoid could be a coadjuvant therapeutic agent without impairing the action of AIs . P11511 inhibitors and cyclooxygenase-2 ( P35354 ) inhibitors in endometriosis : new questions -- old answers ? The medical treatment of endometriosis needs to be optimized . Therapeutic management strategies for endometriosis-associated pain or recurrent disease are primarily aimed at downregulating ovarian function or antagonizing the effect of estrogen in ectopic endometrial implants . In this context , basic research is providing important results for the development of new , specific treatment modalities . P11511 overexpression has recently been detected in endometriotic tissue . P11511 ( p450arom ) is responsible for converting C19 androgens into estrogen in several types of human tissue . P11511 activity causes local estrogen biosynthesis , which , in turn , stimulates prostaglandin E2 production by upregulating cyclooxygenase-2 ( P35354 ) . Thus , a positive feedback cycle develops between the two systems . Another abnormality in endometriosis , the deficient 17beta-hydroxysteroiddehydrogenase type II ( 17beta-HSD-Type-II ) expression , impairs the inactivation of estradiol to estrone . In contrast to the eutopic endometrium , these molecular aberrations increase the amount of local estradiol and prostaglandin E2 in endometriosis . In several human cell lines , prostaglandin and estrogen concentrations are associated with proliferation , migration , angiogenesis , apoptosis resistance and even invasiveness . Consequently , aromatase and P35354 are thought to be promising new therapeutic targets . Thus , specific aromatase inhibitors ( e.g. DB01006 / DB01006 , DB01217 /Arimidex or Exemestan/Aromasin ) or selective P35354 inhibitors ( e.g. Celecoxib/ DB00482 , DB00533 /Vioxx , DB00580 /Bextra ) are of great interest and should be studied in clinical trials in premenopausal woman with endometriosis to expand the spectrum of currently available treatment options .