interacts_with DB06287?
A gene-centric analysis of activated partial thromboplastin time and activated protein C resistance using the HumanCVD focused genotyping array . Activated partial thromboplastin time ( aPTT ) is an important routine measure of intrinsic blood coagulation . Addition of activated protein C ( P25054 ) to the aPTT test to produce a ratio , provides one measure of P25054 resistance . The associations of some genetic mutations ( eg , factor V Leiden ) with these measures are established , but associations of other genetic variations remain to be established . The objective of this work was to test for association between genetic variants and blood coagulation using a high-density genotyping array . Genetic association with aPTT and P25054 resistance was analysed using a focused genotyping array that tests approximately 50 000 single-nucleotide polymorphisms ( SNPs ) in nearly 2000 cardiovascular candidate genes , including coagulation pathway genes . Analyses were conducted on 2544 European origin women from the British Women 's Heart and Health Study . We confirm associations with aPTT at the coagulation factor XII ( P00748 ) / P43250 ( P43250 ) and kininogen 1 ( P01042 ) /histidine-rich glycoprotein ( P04196 ) loci , and identify novel SNPs at the P16442 locus and novel locus kallikrein B ( P03952 ) / P03951 . In addition , we confirm association between P25054 resistance and factor V Leiden mutation , and identify novel SNP associations with P25054 resistance in the P04196 and P12259 /solute carrier family 19 member 2 ( O60779 ) regions . In conclusion , variation at several genetic loci influences intrinsic blood coagulation as measured by both aPTT and P25054 resistance . SynGAP regulates protein synthesis and homeostatic synaptic plasticity in developing cortical networks . Disrupting the balance between excitatory and inhibitory neurotransmission in the developing brain has been causally linked with intellectual disability ( ID ) and autism spectrum disorders ( P51689 ) . Excitatory synapse strength is regulated in the central nervous system by controlling the number of postsynaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors ( AMPARs ) . De novo genetic mutations of the synaptic P20936 ( SynGAP ) are associated with ID and P51689 . SynGAP is enriched at excitatory synapses and genetic suppression of SynGAP increases excitatory synaptic strength . However , exactly how SynGAP acts to maintain synaptic AMPAR content is unclear . We show here that SynGAP limits excitatory synaptic strength , in part , by suppressing protein synthesis in cortical neurons . The data presented here from in vitro , rat and mouse cortical networks , demonstrate that regulation of translation by SynGAP involves P29323 , P42345 , and the small Q15382 . Furthermore , these data show that Q13224 -containing NMDARs and the cognitive kinase CaMKII act upstream of SynGAP and that this signaling cascade is required for proper translation-dependent homeostatic synaptic plasticity of excitatory synapses in developing cortical networks . [ Enhancement of hypoxia tolerance and survival rate of Daphnia in severe hypoxia based on acidic preconditioning ] . pH homeostasis is essential for development , proliferation and apoptosis of cells . Once the pH balances are broken , cell functions and survival will be affected . Nevertheless , moderate acidosis could result in adaptive responses for cell survival and increase tolerance to harmful stress . Here we found that acidic preconditioning ( P25054 ) could significantly increase the survival rate of Daphnia pulex , a freshwater invertebrate , during severe hypoxic insult . Meanwhile , the acidic treatment significantly increased the gene expression of hypoxia inducible factor ( HIF ) . Both echinomycin , an inhibitor of HIF , and compound C , an inhibitor of AMP-activated protein kinase ( AMPK ) , could effectively eliminate the acid-induced hypoxic tolerance and the enhanced transcription of HIF . DB06287 , an inhibitor of mammalian Target of DB00877 ( P42345 ) , though effectively abolished the increased transcription of HIF , improved the P25054 -mediated protection . This result suggests that the involvement of the HIF and AMPK and P42345 could signal the pathways in P25054 -induced protection against hypoxic insult . Disabling the mitotic spindle and tumor growth by targeting a cavity-induced allosteric site of survivin . Survivin is a member of the inhibitor of apoptosis protein family and has an essential role in mitosis . Survivin is overexpressed in a large variety of human cancers and represents an attractive target for cancer therapy . P00533 and Her/neu-transformed human tumors in particular exhibit high levels of survivin . The survivin protein forms dimers through a conserved region that is critical for subcellular localization and biological functions of the protein . We identified small molecules that target a specific cavity adjacent to the survivin dimerization surfaces . P28222 , a lead compound identified in the screen , can bind to the survivin protein at the intended target site . Moreover , P28222 alters spindle formation , causing mitotic arrest and cell death , and inhibits tumor growth in vitro and in vivo . Cell death occurs in premetaphase stage following mitotic arrest and is not a consequence of general toxicity . Thus , the study validates a novel therapeutic target site in the survivin protein and provides a promising strategy to develop a new class of therapeutic small molecules for the treatment of human cancers . Modeling of Q14654 and inhibition mechanism of the natural ligand , ellagic acid , using molecular docking . Diabetes mellitus is a disorder in which blood sugar ( glucose ) levels are abnormally high because the body does not produce enough insulin to meet its needs . Post-prandial hyperglycemia ( PPHG ) is an independent risk factor for the development of macro vascular complications . It is now recognized that normalizing post-prandial blood glucose is more difficult than normalizing fasting glucose . DB01345 channels are the most widely distributed type of ion channel and are found in virtually all living organisms . The function of KATP channels is best understood in pancreatic beta cells , the membrane potential of which is responsive to external glucose concentration . Beta cells show a remarkably complex electrical bursting behavior in response to an increase in glucose level . DB00731 and DB00222 are a class of insulin secretagog agents that lowers blood glucose levels by stimulating insulin secretion from the pancreas . These compounds interact with the DB00171 -sensitive potassium ( K+ DB00171 ) channel in pancreatic beta cells . However , the side effects of these drugs overpass their uses , and the need to identify compounds with less adverse effects is exigent . In our research study , we used the natural compound ellagic acid , which is an already proven anti-carcinogen , anti-mutagen , and anticancer initiator , for its anti-diabetic activity in comparison to the two commercial drugs ( DB00731 and DB00222 ) . The drugs and the compounds were docked to the DB00171 -dependent potassium channel and their energy value showed that the compound had higher binding value than the commercial drugs . Then an ADME/Tox analysis for the compound was carried out which showed that ellagic can be a possible lead molecule . No contractile effect for P28221 and P30939 receptor agonists in human and bovine cerebral arteries : similarity with human coronary artery . 1. Using subtype-selective 5-HT1 receptor agonists and/or the 5-HT1 receptor antagonist GR127935 , we characterized in vitro the 5-HT receptor that mediates the contraction of human and bovine cerebral arteries . Further , we investigated which sumatriptan-sensitive receptors are present in human coronary artery by reverse-transcriptase polymerase chain reaction ( RT-PCR ) . 2 . Agonists with affinity at the P28222 receptor , such as sumatriptan , alniditan and/or IS-159 , elicited dose-dependent contraction in both human and bovine cerebral arteries . They behaved as full agonists at the sumatriptan-sensitive 5-HT1 receptors in both species . In contrast , PNU-109291 and LY344864 , selective agonists at P28221 and P30939 receptors , respectively , were devoid of any significant vasocontractile activity in cerebral arteries , or did not affect the sumatriptan-induced vasocontraction . The rank order of agonist potency was similar in both species and could be summarized as 5-HT = alniditan > sumatriptan = IS-159 >>> PNU-109291 = LY344864 . 3 . In bovine cerebral arteries , the 5-HT1 receptor antagonist GR127935 dose-dependently inhibited the vasoconstrictions elicited by both 5-HT and sumatriptan , with respective pA2 values of 8.0 and 8.6 . 4 . RT-PCR studies in human coronary arteries showed a strong signal for the P28222 receptor while message for the P30939 receptor was weak and less frequently detected . Expression of P28221 receptor mRNA was not detected in any sample . 5 . The present results demonstrate that the DB00669 -induced contraction in brain vessels is mediated exclusively by the P28222 receptor , which is also present in a majority of human coronary arteries . These results suggest that selective P28221 and P30939 receptor agonists might represent new antimigraine drugs devoid of cerebro- and cardiovascular effects . FTY720 induces autophagy-related apoptosis and necroptosis in human glioblastoma cells . FTY720 is a potent immunosuppressant which has preclinical antitumor efficacy in various cancer models . However , its role in glioblastoma remains unclear . In the present study , we found that FTY720 induced extrinsic apoptosis , necroptosis and autophagy in human glioblastoma cells . Inhibition of autophagy by either RNA interference or chemical inhibitors attenuated FTY720-induced apoptosis and necrosis . Furthermore , autophagy , apoptosis and necrosis induction were dependent on reactive oxygen species-c-Jun N-terminal kinase-protein 53 ( ROS-JNK-p53 ) loop mediated phosphatidylinositide 3-kinases/protein kinase B/mammalian target of rapamycin/p70S6 kinase ( PI3K/AKT/ P42345 /p70S6K ) pathway . In addition , receptor-interacting protein 1 and 3 ( Q13546 and RIP3 ) served as an upstream of ROS-JNK-p53 loop . However , the phosphorylation form of FTY720 induced autophagy but not apoptosis and necroptosis . Finally , the in vitro results were validated in vivo in xenograft mouse of glioblastoma cells . In conclusion , the current study provided novel insights into understanding the mechanisms and functions of FTY720-induced apoptosis , necroptosis and autophagy in human glioblastoma cells . P10275 inducing bladder cancer progression by promoting an epithelial-mesenchymal transition . The study investigated the role of androgen receptor ( AR ) as a potential target for the treatment of bladder cancer in regulating epithelial-mesenchymal transition or transformation ( EMT ) . Cell proliferation , and migration capacity were determined in bladder cancer T24 cells treated with small interfering RNA directed against AR , and expression levels of P12830 , β-catenin and N- cadherin were assessed using quantitative reverse transcription PCR ( qRT-PCR ) . Tumour cell growth was evaluated in vivo in T24 tumour-bearing nude mice receiving electroporation-assisted administration of anti-AR small interfering RNA . It was found that low AR expression decreased proliferation and migration of bladder cancer cells . In vivo experiments showed that silencing AR expression significantly suppressed AR-positive bladder tumour growth with decreased cell proliferation . Low AR level of T24 bladder cancer cells treated with DB01541 ( DB02901 ) decreased expression of P12830 , β-catenin and P19022 expression , indicating a strong sensitivity to the EMT and In cells with low AR content , TGF-β induced down-regulation of P12830 and β-catenin . It is concluded that suppression of AR expression decreased the production of TGF-β , inhibiting EMT and bladder cancer cell growth in vitro and in vivo , implying that its use might be a potential therapeutic target for the treatment of bladder cancer . Structure and function of eritadenine and its 3-deaza analogues : potent inhibitors of S-adenosylhomocysteine hydrolase and hypocholesterolemic agents . d- DB03769 ( DEA ) is a potent inhibitor of S-adenosyl-l-homocysteine hydrolase ( P23526 ) and has hypocholesterolemic activity . We have hypothesized that 3-deaza-DEA ( P01024 -DEA ) and its analogues retain high level of P23526 inhibitory activity and have resistance to deamination and glycosidic bond hydrolysis in vivo . Such P01024 -DEA analogues would have much higher hypocholesterolemic activity . P01024 -DEA , and its methyl ester ( P01024 -OMeDEA ) and its methyl amido ( P01024 -NMeDEA ) were synthesized to examine their P23526 inhibitory and hypocholesterolemic activities . A crystal structure of P23526 containing P01024 -DEA was determined and confirmed that DEA and P01024 -DEA bound to the same site of P23526 with the same binding mode . The P23526 inhibitory activities of P01024 -DEA ( K(I)=1.5 microM ) and P01024 -OMeDEA ( K(I)=1.5 microM ) are significantly lower than that of DEA ( K(I)=30 nM ) , while rats fed by P01024 -DEA and P01024 -OMeDEA decrease the total plasma cholesterol and phospholipids by 36-40 % and 23 % , respectively , which is similar to the level of reductions ( 42 % and 27 % ) by DEA . P01024 -NMeDEA lost most of the P23526 inhibitory activity ( K(I)=30 microM ) and dietary P01024 -NMeDEA does not decrease cholesterol and phospholipid in plasma but decreases the triacylglycerol level by 16 % . DEA and P01024 -DEA analogues are neither substrates nor inhibitors of adenosine deaminase . P22303 antagonist potentiated insulin action in fed but not fasted state . The glucose disposal effect of insulin is doubled in response to a meal . This meal-induced insulin sensitization results from insulin acting on the liver , in the presence of a permissive hepatic parasympathetic feeding signal and elevated hepatic glutathione ( DB00143 ) , to release hepatic insulin-sensitizing substance ( HISS ) , a hormone that acts selectively on skeletal muscle to stimulate insulin-mediated glucose uptake . Blockade of the parasympathetic feeding signal to the liver , either through surgical denervation or atropine-mediated antagonism of hepatic muscarinic receptors , eliminates the HISS response , resulting in HISS-dependent insulin resistance ( HDIR ) and decreasing the response to insulin by approximately 55 % in the fed state . P01308 action in Sprague-Dawley rats , as determined with a rapidly sampled , transient euglycemic clamp in response to insulin ( 50 mU/kg ) , is decreased in a dose-dependent manner by atropine . In this study , we have used the ED75 atropine-induced model of HDIR . After a submaximal dose of atropine , potentiation of the remaining parasympathetic effect with the acetylcholinesterase antagonist neostigmine significantly restored postprandial insulin sensitization in a dose-dependent manner with peak effect at 0.1 microg/kg/min . DB01400 reversed the insulin resistance induced by partial fasting and partial muscarinic inhibition ( hepatic DB00143 levels are at fed levels ) , but not that induced by surgical hepatic denervation ( DB00143 normal , no nerve signal ) or 24-h fasting ( low DB00143 ) . No potentiation of the response to insulin by neostigmine occurred in normal , fed rats . The data suggest the use of either direct or indirectly acting cholinergic agonists for the treatment of impaired postprandial insulin sensitization . P42345 mediates RhoA-dependent leptin-induced cardiomyocyte hypertrophy . Obesity is associated with increased leptin production which may contribute to cardiac hypertrophy . However , the mechanism of leptin-induced cardiac hypertrophy remains incompletely understood . The Rho family ( RhoA , Rac1 , and Cdc42 ) and mammalian target of rapamycin ( P42345 ) have recently emerged as important regulators of cell growth . We therefore explored the roles and interrelationships of phosphatidylinositol 3-kinase ( PI3K ) , P42345 , and the Rho family in the regulation of actin polymerization and leptin-induced hypertrophy in cultured neonatal rat ventricular myocytes . Five minutes treatment with leptin ( 3.1 nM ) resulted in activation of RhoA and Rac1 ( by 330 and 160 % , respectively , P < 0.05 ) which was significantly attenuated by AG-490 ( 50 μM ) and LY294002 ( 10 μM ) , specific inhibitors of O60674 and PI3K , respectively . However , Cdc42 activity was unaffected by leptin . The hypertrophic effect of leptin was associated with an increase in phosphorylation of P08133 (S6K) , the major target of P42345 , by 110 % ( P < 0.05 ) . The specific P42345 inhibitor rapamycin ( 10 nM ) attenuated leptin-induced RhoA and Rac1 activation . Furthermore , the leptin-induced decrease in the G/F-actin ratio , a measure of actin polymerization , was blunted by rapamycin . Leptin produced activation of the transcriptional factor P43694 which was attenuated by the RhoA inhibitor P01024 , the p38 MAPK inhibitor SB203580 ( 10 μM ) as well as rapamycin . Our results demonstrate a critical role for PI3K/ P42345 / P08133 (S6K) in leptin-induced RhoA activation resulting in cardiomyocyte hypertrophy associated with P43694 stimulation . Stem cell quiescence . Adult stem cells are maintained in a quiescent state but are able to exit quiescence and rapidly expand and differentiate in response to stress . The quiescent state appears to be necessary for preserving the self-renewal of stem cells and is a critical factor in the resistance of cancer stem cells ( CSCs ) to chemotherapy and targeted therapies . Limited knowledge about quiescence mechanisms has prevented significant advances in targeting of drug-resistant quiescent CSCs populations in the clinic . Thus , an improved understanding of the molecular mechanisms of quiescence in adult stem cells is critical for the development of molecularly targeted therapies against quiescent CSCs in different cancers . Recent studies have provided a better understanding of the intrinsic and extrinsic regulatory mechanisms that control stem cell quiescence . It is now appreciated that the p53 gene plays a critical role in regulating stem cell quiescence . Other intrinsic regulatory mechanisms include the FoxO , HIF-1α , and O95644 transcription factors and signaling through Q13315 and P42345 . Extrinsic microenvironmental regulatory mechanisms include angiopoietin-1 , TGF-β , bone morphogenic protein , thrombopoietin , P19022 , and integrin adhesion receptors ; Wnt/β-catenin signaling ; and osteopontin . In this article , we review current advances in understanding normal stem cell quiescence , their significance for CSC quiescence and drug resistance , and the potential clinical applications of these findings . Whole blood lead concentration and erythrocyte delta-aminolevulinic acid dehydratase ( P13716 ) activity in selected canine populations in Greece . In a total number of 275 dogs of various ages , sex and breed , blood lead concentrations ( O43927 ) and erythrocyte P13716 activity were measured . Sixty-six of the dogs were living in lead mining areas ( Group A ) , 157 in urban areas ( Group B ) and 52 in rural areas ( Group C ) of Greece . Mean O43927 differed significantly ( P < 0.05 ) between locations and were 326,97 and 68 micrograms/L , respectively . Mean P13716 activity was significantly different ( P < 0.05 ) only between Groups A and B as between groups A and C . A significant ( P < 0.05 ) negative correlation existed between O43927 and P13716 activity . A normal range of erythrocyte P13716 activity of 807-992 mumol/ DB02272 /LRBC/h was established for dogs . None of the 33 Group A dogs and 2 of the Group B dogs that had a O43927 of 350 micrograms/L presented clinical signs indicating acute or chronic lead intoxication . No erythrocyte basophilic stippling or large number of nucleated red blood cells were seen in the 30 dogs of Group A with O43927 > 350 micrograms/L . Pathways targeted by antidiabetes drugs are enriched for multiple genes associated with type 2 diabetes risk . Genome-wide association studies ( GWAS ) have uncovered > 65 common variants associated with type 2 diabetes ( T2D ) ; however , their relevance for drug development is not yet clear . Of note , the first two T2D-associated loci ( P37231 and Q14654 / Q09428 ) encode known targets of antidiabetes medications . We therefore tested whether other genes/pathways targeted by antidiabetes drugs are associated with T2D . We compiled a list of 102 genes in pathways targeted by marketed antidiabetic medications and applied Gene Set Enrichment Analysis ( MAGENTA [ Meta-Analysis Gene-set Enrichment of variaNT Associations ] ) to this gene set , using available GWAS meta-analyses for T2D and seven quantitative glycemic traits . We detected a strong enrichment of drug target genes associated with T2D ( P = 2 × 10(-5) ; 14 potential new associations ) , primarily driven by insulin and thiazolidinedione ( TZD ) targets , which was replicated in an independent meta-analysis ( Metabochip ) . The glycemic traits yielded no enrichment . The T2D enrichment signal was largely due to multiple genes of modest effects ( P = 4 × 10(-4) , after removing known loci ) , highlighting new associations for follow-up ( P33121 , P19838 , P11168 , incretin targets ) . Furthermore , we found that TZD targets were enriched for LDL cholesterol associations , illustrating the utility of this approach in identifying potential side effects . These results highlight the potential biomedical relevance of genes revealed by GWAS and may provide new avenues for tailored therapy and T2D treatment design . A new 12-gene diagnostic biomarker signature of melanoma revealed by integrated microarray analysis . Genome-wide microarray technology has facilitated the systematic discovery of diagnostic biomarkers of cancers and other pathologies . However , meta-analyses of published arrays often uncover significant inconsistencies that hinder advances in clinical practice . Here we present an integrated microarray analysis framework , based on a genome-wide relative significance ( GWRS ) and genome-wide global significance ( GWGS ) model . When applied to five microarray datasets on melanoma published between 2000 and 2011 , this method revealed a new signature of 200 genes . When these were linked to so-called ' melanoma driver ' genes involved in MAPK , Ca(2+) , and WNT signaling pathways we were able to produce a new 12-gene diagnostic biomarker signature for melanoma ( i.e., P00533 , P21802 , P22607 , P10145 , P10586 , P24821 , O43927 , P12107 , O43745 , Q6S5L8 , Q9Y2T4 , and P56705 ) . We have begun to experimentally validate a subset of these genes involved in MAPK signaling at the protein level , including O43927 , P12107 , P10586 and Q6S5L8 and found these to be over-expressed in metastatic and primary melanoma cells in vitro and in situ compared to melanocytes cultured from healthy skin epidermis and normal healthy human skin . While Q6S5L8 has been reported previously to be associated to melanoma , this is the first time O43927 , P12107 , and P10586 have been associated with melanoma on experimental validation . Our computational evaluation indicates that this 12-gene biomarker signature achieves excellent diagnostic power in distinguishing metastatic melanoma from normal skin and benign nevus . Further experimental validation of the role of these 12 genes in a new signaling network may provide new insights into the underlying biological mechanisms driving the progression of melanoma . Targeting tumorigenesis : development and use of P42345 inhibitors in cancer therapy . The mammalian target of rapamycin ( P42345 ) is an intracellular serine/threonine protein kinase positioned at a central point in a variety of cellular signaling cascades . The established involvement of P42345 activity in the cellular processes that contribute to the development and progression of cancer has identified P42345 as a major link in tumorigenesis . Consequently , inhibitors of P42345 , including temsirolimus , everolimus , and ridaforolimus ( formerly deforolimus ) have been developed and assessed for their safety and efficacy in patients with cancer . DB06287 is an intravenously administered agent approved by the US Food and Drug Administration ( FDA ) and the European Medicines Agency ( EMEA ) for the treatment of advanced renal cell carcinoma ( RCC ) . DB01590 is an oral agent that has recently obtained US FDA and EMEA approval for the treatment of advanced RCC after failure of treatment with sunitinib or sorafenib . Ridaforolimus is not yet approved for any indication . The use of P42345 inhibitors , either alone or in combination with other anticancer agents , has the potential to provide anticancer activity in numerous tumor types . Cancer types in which these agents are under evaluation include neuroendocrine tumors , breast cancer , leukemia , lymphoma , hepatocellular carcinoma , gastric cancer , pancreatic cancer , sarcoma , endometrial cancer , and non-small-cell lung cancer . The results of ongoing clinical trials with P42345 inhibitors , as single agents and in combination regimens , will better define their activity in cancer . DB06287 induces surfactant lipid accumulation and lung inflammation in mice . Interstitial lung disease ( ILD ) is a well-known adverse effect of mammalian target of rapamycin ( P42345 ) inhibitors . However , it remains unknown how lung toxicities are induced by P42345 inhibitors . Here , we constructed a mouse model of P42345 inhibitor-induced ILD using temsirolimus and examined the pathogenesis of the disease . Male ICR mice were treated with an intraperitoneal injection of different doses of temsirolimus ( 3 or 30 mg·kg(-1)·wk(-1) ) or vehicle . DB06287 treatment increased capillary-alveolar permeability and induced neutrophil infiltration and fibrinous exudate into the alveolar space , indicating alveolar epithelial and/or endothelial injury . It also induced macrophage depletion and the accumulation of excessive surfactant phospholipids and cholesterols . Alveolar macrophage depletion is thought to cause surfactant lipid accumulation . To further examine whether temsirolimus has cytotoxic and/or cytostatic effects on alveolar macrophages and alveolar epithelial cells , we performed in vitro experiments . DB06287 inhibited cell proliferation and viability in both alveolar macrophage and alveolar epithelial cells . DB06287 treatment caused some signs of pulmonary inflammation , including upregulated expression of several proinflammatory cytokines in both bronchoalveolar lavage cells and lung homogenates , and an increase in lymphocytes in the bronchoalveolar lavage fluid . These findings indicate that temsirolimus has the potential to induce alveolar epithelial injury and to deplete alveolar macrophages followed by surfactant lipid accumulation , resulting in pulmonary inflammation . This is the first study to focus on the pathogenesis of P42345 inhibitor-induced ILD using an animal model . Prolonged DB01221 -mediated responses , altered ifenprodil sensitivity , and epileptiform-like events in the malformed hippocampus of methylazoxymethanol exposed rats . Cortical malformations are often associated with refractory epilepsy and cognitive deficit . Clinical and experimental studies have demonstrated an important role for glutamate-mediated synaptic transmission in these conditions . Using whole cell voltage-clamp techniques , we examined evoked glutamate-mediated excitatory postsynaptic currents ( eEPSCs ) and responses to exogenously applied glutamate on hippocampal heterotopic cells in an animal model of malformation i.e. , rats exposed to methylazoxymethanol ( MAM ) in utero . Analysis revealed that the late N-methyl-D-aspartate ( DB01221 ) receptor-mediated eEPSC component was significantly increased on heterotopic cells compared with age-matched normotopic pyramidal cells . At a holding potential of +40 mV , heterotopic cells also exhibited eEPSCs with a slower decay-time constant . No differences in the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid ( AMPA ) component of eEPSCs were detected . In 23 % of heterotopic pyramidal cells , electrical stimulation evoked prolonged burst-like responses . Focal application of glutamate ( 10 mM ) targeted to different sites near the heterotopia also evoked epileptiform-like bursts on heterotopic cells . DB08954 ( 10 microM ) , an Q13224 subunit antagonist , only slightly reduced the DB01221 receptor ( NMDAR ) -mediated component and amplitude of eEPSCs on heterotopic cells ( MAM ) but significantly decreased the late component and peak amplitude of eEPSCs in normotopic cells ( control ) . Our data demonstrate a functional alteration in the DB01221 -mediated component of excitatory synaptic transmission in heterotopic cells and suggest that this alteration may be attributable , at least in part , to changes in composition and function of the NMDAR subunit . Changes in NMDAR function may directly contribute to the hyperexcitability and cognitive deficits reported in animal models and patients with brain malformations . P01308 growth factor-receptor ( IGF-1R ) antibody cixutumumab combined with the P42345 inhibitor temsirolimus in patients with refractory Ewing 's sarcoma family tumors . PURPOSE : DB06287 was combined with cixutumumab , a fully human IgG1 monoclonal antibody directed at the insulin growth factor-1 receptor ( IGF-1R ) . EXPERIMENTAL DESIGN : Patients received cixutumumab , 6 mg/kg i.v. weekly , and temsirolimus , 25 to 37.5 mg i.v. weekly ( 4-week cycles ) , with restaging after 8 weeks . Median follow-up was 8.9 months . RESULTS : Twenty patients [ 17 with Ewing 's sarcoma ( Q01844 ) , 3 with desmoplastic small-round cell tumor ( DSRCT ) ] were enrolled . Twelve patients ( 60 % ) were men with a median age of 24 years and six median prior systemic therapies in a metastatic setting . The most frequent toxicities were thrombocytopenia ( 85 % ) , mucositis ( 80 % ) , hypercholesterolemia ( 75 % ) , hypertriglyceridemia ( 70 % ) , and hyperglycemia ( 65 % ; mostly grade I-II ) . Seven of 20 patients ( 35 % ) achieved stable disease ( SD ) for more than 5 months or complete/partial ( CR/PR ) responses . Tumor regression of more than 20 % ( 23 % , 23 % , 27 % , 100 % , 100 % ) occurred in five of 17 ( 29 % ) patients with Q01844 , and they remained on study for 8 to 27 months . One of six patients with Q01844 who previously developed resistance to a different IGF-1R inhibitor antibody achieved a CR . Four of the seven best responders developed grade III mucositis , myelosuppression , or hyperglycemia , which were controlled while maintaining drug dose . CONCLUSION : Cixutumumab combined with temsirolimus was well-tolerated and showed preliminary evidence of durable antitumor activity in heavily pretreated Q01844 family tumors . Developmental programming : effect of prenatal steroid excess on intraovarian components of insulin signaling pathway and related proteins in sheep . Prenatal testosterone ( T ) excess increases ovarian follicular recruitment , follicular persistence , insulin resistance , and compensatory hyperinsulinemia . Considering the importance of insulin in ovarian physiology , in this study , using prenatal T- and dihydrotestosterone ( DB02901 , a nonaromatizable androgen ) -treated female sheep , we tested the hypothesis that prenatal androgen excess alters the intraovarian insulin signaling cascade and metabolic mediators that have an impact on insulin signaling . Changes in ovarian insulin receptor ( INSRB ) , insulin receptor substrate 1 ( P35568 ) , mammalian target of rapamycin ( P42345 ) , phosphatidylinositol 3-kinase ( PIK3 ) , peroxisome proliferator-activated receptor-gamma ( P37231 ) , and adiponectin proteins were determined at fetal ( Days 90 and 140 ) , postpubertal ( 10 mo ) , and adult ( 21 mo ) ages by immunohistochemistry . Results indicated that these proteins were expressed in granulosa , theca , and stromal compartments , with INSRB , P35568 , P37231 , and adiponectin increasing in parallel with advanced follicular differentiation . Importantly , prenatal T excess induced age-specific changes in P37231 and adiponectin expression , with increased P37231 expression evident during fetal life and decreased antral follicular adiponectin expression during adult life . Comparison of developmental changes in prenatal T and DB02901 -treated females found that the effects on P37231 were programmed by androgenic actions of T , whereas the effects on adiponectin were likely by its estrogenic action . These results suggest a role for P37231 in the programming of ovarian disruptions by prenatal T excess , including a decrease in antral follicular adiponectin expression and a contributory role for adiponectin in follicular persistence and ovulatory failure . Dual P00533 and P42345 targeting in squamous cell carcinoma models , and development of early markers of efficacy . The epidermal growth factor receptor ( P00533 ) is a validated target in squamous cell carcinoma ( SCC ) of the head and neck . Most patients , however , do not respond or develop resistance to this agent . P42345 ( P42345 ) is involved in the pathogenesis of SCC of the head and neck ( SCCHN ) . This study aimed to determine if targeting P42345 in combination with P00533 is effective in SCC , and to develop early pharmacodynamic markers of efficacy . Two SCC cell lines , one resistant ( HEP2 ) and one of intermediate susceptibility ( Detroit 562 ) to P00533 inhibitors , were xenografted in vivo and treated with an P42345 inhibitor ( temsirolimus ) , an P00533 inhibitor ( erlotinib ) or a combination of both . DB06287 exerted superior growth arrest in both cell lines than erlotinib . The combined treatment resulted in synergistic antitumor effects in the Detroit 562 cell line . Immunohistochemical assessment of pharmacodynamic effects in fine-needle aspiration ( FNA ) biopsies early after treatment using phospho MAPK , Phospho-P70 and Ki67 as end points demonstrated pathway abrogation in the Detroit 562 tumours treated with the combination , the only group where regressions were seen . In conclusion , an P42345 inhibitor showed antitumor activity in P00533 -resistant SCC cell lines . Marked antitumor effects were associated with dual pathway inhibition , which were detected by early FNA biopsies . Mutational analysis of the mitochondrial P47985 of Saccharomyces cerevisiae . II . Biochemical characterization of temperature-sensitive Q13546 - mutations . Although the function of the P47985 is generally understood , little is known of how the structure of this protein supports its mechanistic role in electron transfer in the cytochrome bc1 complex . To better understand the structural basis of iron-sulfur protein function , we have undertaken a mutational analysis of the gene encoding this protein and initially isolated five temperature-sensitive iron-sulfur protein mutants ( Beckmann , J. D. , Ljungdahl , P. O. , and Trumpower , B. L. ( 1989 ) J. Biol. Chem. 264 , 3713-3722 ) . Each of the five ts-rip1- mutants exhibited pleiotropic effects . Although the mutant iron-sulfur proteins manifest several in vitro phenotypes in common , each exhibited unique characteristics . All of the ts-rip1- mutations resulted in membranes with decreased ubiquinol-cytochrome c oxidoreductase activities and decreased thermostability compared to membranes containing wild type iron-sulfur protein . All of the mutations conferred slight but significant resistance to the respiratory inhibitor myxothiazol , and one mutant was hypersensitive to inhibition by DB04799 , a structural analog of ubiquinone . In addition , one of the mutations completely blocks post-translational processing of the iron-sulfur protein , leading to accumulation of pre-iron-sulfur protein in mitochondrial membranes at nonpermissive temperatures . Finally , a mutation 12-amino acid residues away from the carboxyl terminus ( 203S ) results in an extremely unstable protein . This region of the protein may be essential in blocking degradation of pre-iron-sulfur protein by cytoplasmic proteases as the protein is imported into the mitochondria , or may be a " degradation signal , " which tags the iron-sulfur protein for turnover . DB05311 ( DX-88 ) , a plasma kallikrein inhibitor for the treatment of hereditary angioedema and the prevention of blood loss in on-pump cardiothoracic surgery . BACKGROUND : P03952 plays a major role in the contact ( kallikrein-kinin ) cascade producing bradykinin . Bradykinin is a vasodilator , which increases vascular permeability , activates inflammation and produces pain . P03952 is also crosslinked to the coagulation system and the complement cascade . OBJECTIVE : DB05311 ( DX-88 ) is a potent and specific inhibitor of plasma kallikrein . DB05311 is a recombinantly produced and engineered small protein based on the first Kunitz domain of human tissue factor pathway inhibitor . It was identified through phage display technology . METHODS : The search terms ' ecallantide ' , ' DX-88 ' and ' hereditary angioedema ' were entered into Pubmed/Medline , ClinicalTrials and Google . RESULTS/CONCLUSION : At present , the drug is being studied for two major indications . First , the results for the treatment of hereditary angioedema are promising . Second , a prospective randomised multi-centre trial for the reduction of blood loss during on-pump cardiothoracic surgery will be terminated in October 2008 .