interacts_with DB00674?
DB06589 inhibits the activation of P09619 β-expressing astrocytes in the brain metastatic microenvironment of breast cancer cells . Brain metastases occur in more than one-third of metastatic breast cancer patients whose tumors overexpress P04626 or are triple negative . Brain colonization of cancer cells occurs in a unique environment , containing microglia , oligodendrocytes , astrocytes , and neurons . Although a neuroinflammatory response has been documented in brain metastasis , its contribution to cancer progression and therapy remains poorly understood . Using an experimental brain metastasis model , we characterized the brain metastatic microenvironment of brain tropic , P04626 -transfected MDA-MB-231 human breast carcinoma cells ( 231-BR- P04626 ) . A previously unidentified subpopulation of metastasis-associated astrocytes expressing phosphorylated platelet-derived growth factor receptor β ( at tyrosine 751 ; p751- P09619 β ) was identified around perivascular brain micrometastases . p751- P09619 β(+) astrocytes were also identified in human brain metastases from eight craniotomy specimens and in primary cultures of astrocyte-enriched glial cells . Previously , we reported that pazopanib , a multispecific tyrosine kinase inhibitor , prevented the outgrowth of 231-BR- P04626 large brain metastases by 73 % . Here , we evaluated the effect of pazopanib on the brain neuroinflammatory microenvironment . DB06589 treatment resulted in 70 % ( P = 0.023 ) decrease of the p751- P09619 β(+) astrocyte population , at the lowest dose of 30 mg/kg , twice daily . Collectively , the data identify a subpopulation of activated astrocytes in the subclinical perivascular stage of brain metastases and show that they are inhibitable by pazopanib , suggesting its potential to prevent the development of brain micrometastases in breast cancer patients . DB00674 ameliorates the impairment of recognition memory in mice repeatedly treated with methamphetamine : involvement of allosteric potentiation of nicotinic acetylcholine receptors and dopaminergic- P27361 /2 systems . DB00674 , a drug used to treat Alzheimer 's disease , inhibits acetylcholinesterase ( P22303 ) and allosterically modulates nicotinic acetylcholine receptors ( nAChRs ) resulting in stimulation of catecholamine neurotransmission . In this study , we investigated whether galantamine exerts cognitive-improving effects through the allosteric modulation of nAChRs in an animal model of methamphetamine ( Meth ) psychosis . The mice treated with Meth ( 1 mg/kg.d ) for 7 d showed memory impairment in a novel object recognition test . DB00674 ( 3 mg/kg ) ameliorated the memory impairment , and it increased the extracellular dopamine release in the prefrontal cortex ( P27918 ) of Meth-treated mice . Donepezil , an P22303 inhibitor ( 1 mg/kg ) increased the extracellular ACh release in the P27918 , whereas it had no effect on the memory impairment in Meth-treated mice . The nAChR antagonist , mecamylamine , and dopamine D1 receptor antagonist , P35240 23390 , blocked the ameliorating effect of galantamine on Meth-induced memory impairment , whereas the muscarinic AChR antagonist , scopolamine , had no effect . The effects of galantamine on extracellular dopamine release were also antagonized by mecamylamine . DB00674 attenuated the defect of the novelty-induced activation of extracellular signal-regulated kinase 1/2 ( P27361 /2 ) . The ameliorating effect of galantamine on recognition memory in Meth-treated mice was negated by microinjection of an P29323 inhibitor , PD98059 , into the P27918 . These results suggest that the ameliorating effect of galantamine on Meth-induced memory impairment is associated with indirect activation of dopamine D1 receptor- P27361 /2 following augmentation with dopaminergic neurotransmission in the P27918 through the allosteric activation of nAChRs . DB00674 could be a useful therapeutic agent for treating cognitive deficits in schizophrenia/Meth psychosis , as well as Alzheimer 's disease . In vivo selection for human and murine hematopoietic cells transduced with a therapeutic P16455 lentiviral vector that inhibits HIV replication . We have developed an HIV-based lentiviral vector , DB05251 , which efficiently transduces human P28906 + progenitors and P01730 + T lymphocytes . DB05251 contains an antisense sequence against the HIV envelope and is currently being evaluated for safety in a clinical trial for treatment of HIV . Selective outgrowth of transduced hematopoietic cells in vivo is anticipated to increase the therapeutic efficacy of this treatment by maximizing the persistence of virus-resistant cells in the body . Although HIV resistance is selective , additional selection may aid in treatment efficacy due to the vast quantity of target cells . Therefore , we engineered DB05251 to express the P140K P16455 gene to drive potent drug-mediated in vivo selection for transduced hematopoietic long-term repopulating cells . Suboptimally transduced T cell cultures treated with O6-benzylguanine and DB00262 were selected from 3 to 100 % , and after selection cultures did not support HIV replication . Primary P28906 + progenitors derived from G- P04141 -mobilized peripheral blood were transduced at 27 to 35 % efficiency . Approximate sixfold selection was observed for transduced P28906 + progenitors , colony-forming units , and long-term culture-initiating cells . Multilineage in vivo selection was demonstrated for transduced murine hematopoietic cells in human P28906 (+)-derived hematopoietic cells in NOD-SCID mice . These results establish efficient ex vivo and in vivo selection for hematopoietic cells transduced with lentiviral vectors and support the potential therapeutic benefit of this strategy in human gene therapy . Expression of adhesion molecules and c-kit on P28906 + hematopoietic progenitor cells : comparison of cytokine-mobilized blood stem cells with normal bone marrow and peripheral blood . We assessed the expression of the adhesion molecules leukocyte function antigen-1 ( LFA-1 , CD11a ) , intercellular adhesion molecule-1 ( P05362 , CD54 ) , homing-associated cell adhesion molecule ( H- P62158 , P16070 ) , and c-kit ( stem cell factor receptor ) on the P28906 + progenitor population from the leukapheresis products of 23 patients ( LP P28906 + ) . For blood stem cell collection granulocyte colony-stimulating factor ( DB00099 ) or interleukin-3/granulocyte-macrophage colony-stimulating factor ( P08700 /GM- P04141 ) was administered after cytotoxic chemotherapy . Furthermore , bone marrow- and blood-derived P28906 + progenitor cells from 6 normal volunteers ( BM and PB P28906 + ) were analyzed . LFA-1 expression was higher on PB P28906 + ( 88.2 +/- 2.5 % , mean +/- SEM ) than on BM P28906 + ( 75.3 +/- 4.3 % ) . Following cytokine administration , LFA-1 was expressed on only 59.7 +/- 3.7 % of LP P28906 + at a low fluorescence intensity , suggesting that down-regulation of LFA-1 may facilitate the egress of cells from the bone marrow and prolong their circulation . In contrast , P05362 was weakly positive on P28906 + cells from all sources . P16070 was expressed on the vast majority of P28906 + cells ( > 95 % ) in all samples studied . The highest proportion of P28906 + cells costaining for c-kit was found in normal bone marrow ( 32.2 +/- 3.3 % ) . In normal peripheral blood and after cytokine mobilization , fewer of the P28906 + cells weakly expressed c-kit ( < 15 % ) . The low percentage and level of c-kit expression may indicate that the majority of cytokine-mobilized P28906 + cells are lineage-committed progenitor cells , as reflected by the coexpression pattern for P28907 , HLA-DR , and P20138 . Novel MEK inhibitor trametinib and other retinoblastoma gene ( RB ) -reactivating agents enhance efficacy of 5-fluorouracil on human colon cancer cells . Chemotherapy for colorectal cancer has become more complicated and diversified with the appearance of molecular-targeting agents . DB00544 ( DB00544 ) has been a mainstay of chemotherapy for colorectal cancer , but it is still unknown whether the combining of DB00544 with novel molecular-targeting agents is effective . P04818 ( TS ) is a direct target of DB00544 , and the low TS level has been generally supposed to sensitize DB00544 's efficacy . We therefore hypothesized that RB-reactivating agents could enhance the efficacy of DB00544 , because the RB-reactivating agents could suppress the function of transcription factor E2F of TS gene promoter . We used three RB-reactivating agents , trametinib/GSK1120212 ( MEK inhibitor ) , fenofibrate ( Q07869 α agonist ) , and LY294002 ( PI3K inhibitor ) , with DB00544 against human colon cancer HT-29 and HCT15 cells . DB08911 induced p15 and p27 expression and reduced cyclin D1 levels in HT-29 cells . Fenofibrate also dephosphorlated P27361 /2 and reduced cyclin D1 levels in HT-29 cells . LY294002 induced p27 expression in HCT15 cells . All three agents caused dephosphorylation of RB protein and P55008 -phase arrest with a reduction of TS expression . As a consequence , the combination of DB00544 with each of the agents resulted in a significant decrease of colony numbers in HT-29 or HCT15 cells . These results suggest " RB-reactivation therapy " using molecular-targeting agents to be a new strategy for DB00544 -based chemotherapy . In particular , we strongly expect trametinib , which was discovered in Japan and was recently submitted to FDA for approval , to be used together with established regimens for colorectal cancer . Coexpression of P49771 and GM- P04141 genes modulates immune responses induced by P04626 /neu DNA vaccine . DNA vaccine and dendritic cells ( DCs ) -based vaccine have emerged as promising strategies for cancer immunotherapy . P36888 -ligand ( P49771 ) and granulocyte-macrophage-colony-stimulating factor ( GM- P04141 ) have been exploited for the expansion of DC . It was reported previously that combination of plasmid encoding GM- P04141 with P04626 /neu DNA vaccine induced predominantly P01730 (+) T-cell-mediated antitumor immune response . In this study , we investigated the modulation of immune responses by murine P49771 and GM- P04141 , which acted as genetic adjuvants in the forms of bicistronic ( pFLAG ) and monocistronic ( pFL and pGM ) plasmids for P04626 /neu DNA vaccine ( pN-neu ) . Coexpression of P49771 and GM- P04141 significantly enhanced maturation and antigen-presentation abilities of splenic DC . Increased numbers of infiltrating DC at the immunization site , higher interferon-gamma production , and enhanced cytolytic activities by splenocytes were prominent in mice vaccinated with pN-neu in conjunction with pFLAG . Importantly , a potent CD8(+) T-cell-mediated antitumor immunity against bladder tumors naturally overexpressing P04626 /neu was induced in the vaccinated mice . Collectively , our results indicate that murine P49771 and GM- P04141 genes coexpressed by a bicistronic plasmid modulate the class of immune responses and may be superior to those codelivered by two separate monocistronic plasmids as the genetic adjuvants for P04626 /neu DNA vaccine . Different cholinesterase inhibitor effects on P04141 cholinesterases in Alzheimer patients . BACKGROUND : The current study aimed to compare the effects of different cholinesterase inhibitors on acetylcholinesterase ( P22303 ) and butyrylcholinesterase ( BuChE ) activities and protein levels , in the cerebrospinal fluid ( P04141 ) of Alzheimer disease ( AD ) patients . METHODS AND FINDINGS : AD patients aged 50-85 years were randomized to open-label treatment with oral rivastigmine , donepezil or galantamine for 13 weeks . P22303 and BuChE activities were assayed by Ellman 's colorimetric method . Protein levels were assessed by enzyme-linked immunosorbent assay ( ELISA ) . Primary analyses were based on the Completer population ( randomized patients who completed Week 13 assessments ) . 63 patients were randomized to treatment . DB00989 was associated with decreased P22303 activity by 42.6 % and decreased P22303 protein levels by 9.3 % , and decreased BuChE activity by 45.6 % and decreased BuChE protein levels by 21.8 % . DB00674 decreased P22303 activity by 2.1 % and BuChE activity by 0.5 % , but increased P22303 protein levels by 51.2 % and BuChE protein levels by 10.5 % . Donepezil increased P22303 and BuChE activities by 11.8 % and 2.8 % , respectively . Donepezil caused a 215.2 % increase in P22303 and 0.4 % increase in BuChE protein levels . Changes in mean P22303 -Readthrough/Synaptic ratios , which might reflect underlying neurodegenerative processes , were 1.4 , 0.6 , and 0.4 for rivastigmine , donepezil and galantamine , respectively . CONCLUSION : The findings suggest pharmacologically-induced differences between rivastigmine , donepezil and galantamine . DB00989 provides sustained inhibition of P22303 and BuChE , while donepezil and galantamine do not inhibit BuChE and are associated with increases in P04141 P22303 protein levels . The clinical implications require evaluation . How I treat patients who mobilize hematopoietic stem cells poorly . Transplantation with 2-5 × 10(6) mobilized P28906 (+)cells/kg body weight lowers transplantation costs and mortality . Mobilization is most commonly performed with recombinant human G- P04141 with or without chemotherapy , but a proportion of patients/donors fail to mobilize sufficient cells . BM disease , prior treatment , and age are factors influencing mobilization , but genetics also contributes . Mobilization may fail because of the changes affecting the P19526 /progenitor cell/BM niche integrity and chemotaxis . Poor mobilization affects patient outcome and increases resource use . Until recently increasing G- P04141 dose and adding P21583 have been used in poor mobilizers with limited success . However , plerixafor through its rapid direct blockage of the P61073 / P48061 chemotaxis pathway and synergy with G- P04141 and chemotherapy has become a new and important agent for mobilization . Its efficacy in upfront and failed mobilizers is well established . To maximize P19526 harvest in poor mobilizers the clinician needs to optimize current mobilization protocols and to integrate novel agents such as plerixafor . These include when to mobilize in relation to chemotherapy , how to schedule and perform apheresis , how to identify poor mobilizers , and what are the criteria for preemptive and immediate salvage use of plerixafor . P10275 is expressed in murine choroid plexus and downregulated by 5alpha-dihydrotestosterone in male and female mice . The choroid plexuses ( CPs ) of the brain form a unique interface between the peripheral blood and the cerebrospinal fluid ( P04141 ) . CPs produce several neuroprotective peptides , which are secreted into the P04141 . Despite their importance in neuroprotection , the mechanisms underlying the regulation of most of these peptides in CPs remain unknown . Androgens regulate the expression of neuroprotective peptides in several tissues where the androgen receptor ( AR ) is coexpressed , including the brain . The presence of AR in CPs has never been investigated , but recent studies in our laboratory show that the CP is an androgen-responsive tissue . In order to fulfill this gap , we investigated and characterized AR distribution and expression in male and female rat CPs and in primary cultures from rat CP epithelial cells . In addition , the response of AR to 5alpha-dihydrotestosterone ( DB02901 ) in castrated male and female mice subjected to DB02901 replacement was analyzed . We show that rat CP epithelial cells contain AR mRNA and protein . Moreover , we demonstrate that AR is downregulated by DB02901 in mice CPs . Effects of external calcium on the biotransformation of DB06749 to ginsenoside Rd by Paecilomyces bainier 229-7 . DB01373 is a known signalling molecule in eukaryotic cells and plays a central role in the regulation of many cellular processes . In the following study , we report on the effect of external calcium treatments on the biotransformation of DB06749 to ginsenoside Rd by Paecilomyces bainier 229-7 . We observed that the intracellular calcium content of P. bainier 229-7 mycelia was increased in response to exposure to high external Ca(2+) concentrations . Both ginsenoside Rd biotransformation and β-glucosidase activity were both found to be dependent on the external calcium concentration . At an optimal Ca(2+) concentration of 45 mM , maximal ginsenoside Rd bioconversion rate of 92.44 % was observed and maximal β-glucosidase activity of 0.1778 U was reached in a 72-h biotransformation . The Ca(2+) channel blocker Verapamil blocked the trans-membrane influx of calcium and decreased ginsenoside Rd biotransformatiom . In addition , β-glucosidase activity and ginsenoside Rd content decreased by 36.0 and 29.2 % respectively after a 72-h incubation in the presence of 0.05 mM P62158 ( P62158 ) antagonist DB00850 . These results suggest that both Ca(2+) channels and P62158 are involved in ginsenoside Rd biotransformation via regulation of β-glucosidase activity . This is the first report regarding the effects of calcium signal transduction on biotransformation and enzyme activity in fungi . DB00203 inhibits calcineurin/ Q13469 -mediated cyclin A expression in pulmonary artery smooth muscle cells . AIMS : To examine whether calcineurin/NFAT signaling pathway leads to proliferation of pulmonary artery smooth muscle cells ( PASMCs ) by regulating cell cycle proteins and whether the phosphodiesterase-5 ( O76074 ) inhibitor sildenafil affects calcineurin/NFAT-induced cell proliferation . MAIN METHODS : A [(3)H]thymidine incorporation assay was used to examine DNA synthesis ( cell proliferation ) ; cyclin A and Q13469 expressions were determined by Western blot . P24941 ( P24941 ) activity was measured with an in vitro kinase activity assay , and calcineurin and NFAT activity were evaluated using a calcineurin assay kit and a luciferase activity assay , respectively . A chemical inhibitor or siRNA transfection was used to inhibit calcineurin/NFAT signaling pathway . KEY FINDINGS : Serotonin dose-dependently stimulated cyclin A expression in PASMCs . This effect was accompanied by dose-dependent increases in P24941 activity and the rate of DNA synthesis . At the same time , PASMCs treated with serotonin showed dose-dependent activation of calcineurin/NFAT signaling pathway . Inhibition of calcineurin activity by cyclosporine A or loss of Q13469 protein by siRNA transfection abolished serotonin-induced cyclin A expression and consequent P24941 activation and DNA synthesis . We further found that pretreatment of cells with sildenafil suppressed serotonin-triggered activation of calcineurin/ Q13469 signaling pathway and resultant cyclin A expression , P24941 activation and cell proliferation , while the presence of DT-3 [ a specific protein kinase G ( PKG ) peptide inhibitor ] reversed the effects of sildenafil on PASMCs . SIGNIFICANCE : Our study suggests that enhanced PKG activity suppresses calcineurin/ Q13469 cascade-mediated cyclin A expression , P24941 activation and PASMC proliferation to contribute to the overall effects of sildenafil in the treatment of pulmonary hypertension . Elevation of P13500 and P13500 / P15692 ratio in cerebrospinal fluid of amyotrophic lateral sclerosis patients . Amyotrophic lateral sclerosis ( P35858 ) is a neurodegenerative disease with progressive cell death of upper and lower motor neurons . In this study , we measured monocyte chemotactic protein-1 ( P13500 ) and vascular endothelial growth factor ( P15692 ) levels in cerebrospinal fluid ( P04141 ) and serum by enzyme-linked immunosorbent assay ( ELISA ) in 42 P35858 patients , and compared these levels with those of control subjects with other neurodegenerative disorders or with those of normal controls . P13500 levels in P04141 were significantly higher in P35858 patients than in the control group . P15692 levels in P04141 tended to be lower in P35858 patients than in the control group , but not significantly . A positive correlation was found between P13500 levels in P04141 of P35858 patients and the total Norris scale . The elevation of P13500 / P15692 ratio in P04141 was more specific to P35858 patients compared to other neurological diseases such as Parkinson 's disease ( PD ) and spinocerebellar ataxia ( SCA ) and to controls . Our data suggested that both P13500 levels and P13500 / P15692 ratio in P04141 may be useful markers for the clinical diagnosis of P35858 . 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 , DB06822 . 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 . Stress-induced alterations in P08908 receptor transcriptional modulators O75398 and Q6P1N0 . The effect of stress on the mRNA and protein level of the P08908 receptor and two of its key transcriptional modulators , O75398 and Q6P1N0 , was examined in the prefrontal cortex ( P27918 ) and hippocampus ( Hp ) using rodent models : olfactory bulbectomy ( OB ) and prenatal stress ( PS ) in male and female rats ; chronic mild stress in male rats ( CMS ) and pregnancy stress . In P27918 , CMS induced the most widespread changes , with significant reduction in both mRNA and protein levels of O75398 , P08908 receptor and in Q6P1N0 mRNA ; while in Hp P08908 receptor and Q6P1N0 protein levels were also decreased . In male , but not female OB rats P27918 Q6P1N0 and P08908 receptor protein levels were reduced , while in Hp P08908 receptor , Q6P1N0 and O75398 mRNA 's but not protein were reduced . In PS rats P27918 P08908 receptor protein was reduced more in females than males ; while in Hp Q6P1N0 protein was increased in females . In pregnancy stress , P27918 O75398 , Q6P1N0 and P08908 protein receptor levels were reduced , and in HP P08908 receptor protein levels were also reduced ; in HP only O75398 and Q6P1N0 mRNA levels were reduced . Overall , CMS and stress during pregnancy produced the most salient changes in P08908 receptor and transcription factor expression , suggesting a primary role for altered transcription factor expression in chronic regulation of P08908 receptor expression . By contrast , OB ( in males ) and PS ( in females ) produced gender-specific reductions in P27918 P08908 receptor protein levels , suggesting a role for post-transcriptional regulation . These and previous data suggest that chronic stress might be a key regulator of O75398 / Q6P1N0 gene expression . DB06779 , a low-molecular-weight heparin , promotes angiogenesis mediated by heparin-binding P15692 in vivo . Tumors are angiogenesis dependent and vascular endothelial growth factor-A ( P15692 ) , a heparin-binding protein , is a key angiogenic factor . As chemotherapy and co-treatment with anticoagulant low-molecular-weight heparin ( LMWH ) are common in cancer patients , we investigated whether angiogenesis in vivo mediated by P15692 is modulated by metronomic-type treatment with : ( i ) the LMWH dalteparin ; ( ii ) low-dosage cytostatic epirubicin ; or ( iii ) a combination of these two drugs . Using the quantitative rat mesentery angiogenesis assay , in which angiogenesis was induced by intraperitoneal injection of very low doses of P15692 , dalteparin sodium ( Fragmin(®) ) and epirubicin ( Farmorubicin(®) ) were administered separately or in combination by continuous subcutaneous infusion at a constant rate for 14 consecutive days . DB06779 was administered at 27 , 80 , or 240 IU/kg/day , i.e. , doses that reflect the clinical usage of this drug , while epirubicin was given at the well-tolerated dosage of 0.4 mg/kg/day . While dalteparin significantly stimulated angiogenesis in an inversely dose-dependent manner , epirubicin did not significantly affect angiogenesis . However , concurrent treatment with dalteparin and epirubicin significantly inhibited angiogenesis . The effect of dalteparin is the first demonstration of a proangiogenic effect of any LMWH in vivo . The fact that co-treatment with dalteparin and epirubicin significantly inhibited angiogenesis suggests a complex drug effect . [ Effect of the monophase oral contraceptive combination with 20 ug ethinyl estradiol/150 ug desogestrel on haemostasis ] . The authors examined the changes in the haemostasis during the use of the oral contraceptive combination with 20 microg ethynil estradiol/150 microg desogestrel at 35 women , a basic group , who used the oral contraceptive in the duration of 12 months and a control group ( n=35 ) , who do not use the pills . We found statistically significant increase of Antithrombin III ( P01008 ) ( p < 0.011 ) , Cofactor II of DB01109 ( HCII ) ( p < 0.001 ) , the activity of plasminogen ( p < 0.026 ) and beta2-antiplasmin ( 0.026 ) , significant decrease of P02810 ( PrC ) ( p < 0.0001 ) and of total Protein S ( TPrS ) ( p < 0.03 ) in the basic group in comparision with the control one . We do not observe significant changes in the rest of the haemostatic variables between the two groups . During the use of the oral contraceptive combination with 20 microg ethynil estradiol/150 microg desogestrel the changes in the system of the natural inhibitors are balanced by these in the system of fibrinolysis . Concise prediction models of anticancer efficacy of 8 drugs using expression data from 12 selected genes . We developed concise , accurate prediction models of the in vitro activity for 8 anticancer drugs ( DB00544 , DB00515 , DB00305 , DOX , CPT-11 , SN-38 , TXL and TXT ) , along with individual clinical responses to DB00544 using expression data of 12 genes . We first performed cDNA microarray analysis and MTT assay of 19 human cancer cell lines to sort out genes which were correlative in expression levels with cytotoxicities of the 8 drugs ; we selected 13 genes with proven functional significance to drug sensitivity from a huge number of potent prediction marker genes . The correlation significance of each was confirmed using expression data quantified by real-time RT-PCR , and finally 12 genes ( P08183 , Q9UNQ0 , P10632 , P08684 , Q12882 , P09211 , P16455 , P15559 , P16435 , P11388 , P07437 and P04818 ) were selected as more reliable predictors of drug response . Using multiple regression analysis , we fixed 8 prediction formulae which embraced the variable expressions of the 12 genes and arranged them in order , to predict the efficacy of the drugs by referring to the value of Akaike 's information criterion for each sample . These formulae appeared to accurately predict the in vitro efficacy of the drugs . For the first clinical application model , we fixed prediction formulae for individual clinical response to DB00544 in the same way using 41 clinical samples obtained from 30 gastric cancer patients and found to be of predictive value in terms of survival , time to treatment failure and tumor growth . None of the 12 selected genes alone could predict such clinical responses . P48061 and [N33A] P48061 in 5637 and HeLa cells : regulating P00533 phosphorylation via calmodulin/calcineurin . In the human neoplastic cell lines 5637 and HeLa , recombinant P48061 elicited , as expected , downstream signals via both G-protein-dependent and β-arrestin-dependent pathways responsible for inducing a rapid and a late wave , respectively , of P27361 /2 phosphorylation . In contrast , the structural variant [N33A] P48061 triggered no β-arrestin-dependent phosphorylation of P27361 /2 , and signaled via G protein-dependent pathways alone . Both P48061 and [N33A] P48061 , however , generated signals that transinhibited P00533 phosphorylation via intracellular pathways . 1 ) Prestimulation of P61073 / P00533 -positive 5637 or HeLa cells with P48061 modified the HB- P01133 -dependent activation of P00533 by delaying the peak phosphorylation of tyrosine 1068 or 1173 . 2 ) Prestimulation with the synthetic variant [N33A] P48061 , while preserving P61073 -related chemotaxis and P61073 internalization , abolished P00533 phosphorylation . 3 ) In cells knockdown of β-arrestin 2 , P48061 induced a full inhibition of P00533 like [N33A] P48061 in non-silenced cells . 4 ) P00533 phosphorylation was restored as usual by inhibiting PCK , calmodulin or calcineurin , whereas the inhibition of CaMKII had no discernable effect . We conclude that both recombinant P48061 and its structural variant [N33A] P48061 may transinhibit P00533 via G-proteins/calmodulin/calcineurin , but [N33A] P48061 does not activate β-arrestin-dependent P27361 /2 phosphorylation and retains a stronger inhibitory effect . Therefore , we demonstrated that P48061 may influence the magnitude and the persistence of signaling downstream of P00533 in turn involved in the proliferative potential of numerous epithelial cancer . In addition , we recognized that [N33A] P48061 activates preferentially G-protein-dependent pathways and is an inhibitor of P00533 . Cerebrospinal fluid proteomics in children during induction for acute lymphoblastic leukemia : A pilot study . BACKGROUND : Thrombosis in patients with acute lymphocytic leukemia ( ALL ) can develop after treatment with L-asparaginase ( asp ) and is often localized to the central nervous system ( CNS ) . We hypothesize that changes in the cerebrospinal fluid ( P04141 ) proteome will occur after asp therapy and will anticipate CNS clots . METHODS : Five newly diagnosed patients , ages 1-11 years , with ALL ( n = 4 ) or lymphoblastic lymphoma ( LL ) ( n = 1 ) underwent serial lumbar punctures during induction . P04141 was depleted of abundant plasma proteins and analyzed by gel-free , label-free quantitative proteomics . RESULTS : More than 600 proteins were quantified across all P04141 samples . In four subjects , the expression of proteins involved in coagulation such as protein C Inhibitor ( P05154 ) and heparin cofactor II ( P05546 ) changed over the course of asp therapy . Antithrombin III ( P01008 ) and plasminogen ( PLMN ) levels were shown to have decreased expression over time in one child who developed a CNS thrombosis , compared to other subjects . CONCLUSIONS : P04141 proteomics is feasible and reproducible in ALL and LL . P04141 P01008 and PLMN should be further investigated as predictive markers of CNS thrombosis . Complex regulation of CDKs and P55008 arrest during the granulocytic differentiation of human myeloblastic leukemia Q9NTI2 cells . We previously reported that all-trans retinoic acid ( DB00755 ) and granulocyte-macrophage colony-stimulating factor ( GM- P04141 ) synergistically induced granulocytic differentiation in human myeloblastic leukemia Q9NTI2 cells . The combination of these agents also suppressed DNA-synthesis . In the present study , we investigated the suppression of cyclin dependent kinase ( CDK ) activities resulting in P55008 arrest in differentiated Q9NTI2 cells . We show that treatment of Q9NTI2 cells with DB00755 plus P04141 results in P55008 arrest and suppression of CDK activities . Protein levels of the P55008 CDKs were essentially unchanged during this time . However , we observed an increase in P24941 -bound p27 and P11802 -bound p18 , and a decrease in Q00534 -bound cyclin D3 . These results suggest that complex regulation of CDKs play a key role in P55008 arrest of Q9NTI2 after treatment with DB00755 and GM- P04141 . We also showed that an increase in P24941 -bound p27 and P11802 -bound p18 are caused by treatment with DB00755 and a decrease in Q00534 -bound cyclin D3 is induced synergistically by treatment with both reagents . Furthermore , we propose that the changes in binding of p18 and cyclin D3 to CDKs are due to changes at the protein expression level and that the increase in p27 binding to P24941 is due to a novel mechanism . DB02901 interacts with P00533 /MAPK signalling and modulates P00533 levels in androgen receptor-positive LNCaP prostate cancer cells . P10275 ( AR ) signalling plays a pivotal role in prostate cancer pathogenesis and progression . However , androgen-mediated AR signalling is yet to be fully understood . P00533 and Q96HU1 kinase signalling pathways play predominant roles in AR function . Therefore , we investigated the interaction of P00533 signalling and AR activity in AR-positive LNCaP cells . We found that 5alpha-dihydrotestosterone ( DB02901 ) and P01133 had a synergistic effect on AR activity as detected by a luciferase reporter system , although P01133 alone did not activate AR . Both P27361 /2 and p38 were involved in DB02901 and DB02901 / P01133 -induced AR activation as detected by specific MEK and p38 inhibitors . Furthermore , 24-h treatment of the cells with DB02901 resulted in ubiquitination and down-regulation of the P00533 . This effect could be inhibited by the anti-androgen flutamide , suggesting an androgen-dependent mechanism . On the other hand , DB02901 -treatment strongly increased AR levels in LNCaP cells . These data suggest a complex regulatory loop between activated AR and P00533 . In conclusion , activation of AR by both DB02901 and P01133 / DB02901 involves the Q96HU1 kinase pathway . Long-term activation of AR results in increase of AR levels , which through so far unknown regulatory mechanisms results in ubiquitination and degradation of the P00533 . Inhibition of HCV by the serpin antithrombin III . BACKGROUND : Although there have been dramatic strides made recently in the treatment of chronic hepatitis C virus infection , interferon-α based therapy remains challenging for certain populations , including those with unfavorable Q8IZI9 genotypes , psychiatric co-morbidity , HIV co-infection , and decompensated liver disease . We have recently shown that P01008 , a serine protease inhibitor ( serpin ) , has broad antiviral properties . RESULTS : We now show that P01008 is capable of inhibiting HCV in the OR6 replicon model at micromolar concentrations . At a mechanistic level using gene-expression arrays , we found that P01008 treatment down-regulated multiple host cell signal transduction factors involved in the pathogenesis of cirrhosis and hepatocellular carcinoma , including Jun , Myc and P12643 . Using a protein interactive network analysis we found that changes in gene-expression caused by P01008 were dependent on three nodes previously implicated in HCV disease progression or HCV replication : NFκB , O75791 MAPK , and P27361 /2 . CONCLUSIONS : Our findings suggest that P01008 stimulates a novel innate antiviral host cell defense different from current treatment options . Aripiprazole : pharmacodynamics of a dopamine partial agonist for the treatment of schizophrenia . Aripiprazole is the first approved atypical antipsychotic with a mechanism of action that exerts a partial agonism with high affinity at DB00988 D2- and Serotonin- P08908 -receptors as well as an antagonism at Serotonin-5- Q13049 -receptors . Aripiprazole provides good clinical effectiveness and a favorable profile of safety and tolerability . The special pharmacodynamics of aripiprazole are described herein . P35354 predicts adverse effects of tamoxifen : a possible mechanism of role for nuclear P04626 in breast cancer patients . P35354 ( P35354 ) is associated with breast tumour progression . Clinical and molecular studies implicate human epidermal growth factor receptor 2 ( P04626 ) in the regulation of P35354 expression . Recent reports raise the possibility that P04626 could mediate these effects through direct transcriptional mechanisms . The relationship between P04626 and P35354 was investigated in a cohort of breast cancer patients with or without endocrine treatment . A tissue microarray comprising tumours from 560 patients with 10-year follow-up was analysed for P04626 , P27361 /2 , polyoma enhancer activator 3 ( P43268 ) and P35354 expression . Subcellular localisation of P04626 was assessed by immunofluorescence and confocal microscopy . Expression of markers examined was analysed in relation to classic clinicopathological parameters and disease-free survival in the presence and absence of tamoxifen . P35354 expression associated with both membranous and nuclear expression of P04626 ( P=0.0033 and P < 0.00001 respectively ) . No association was detected between P35354 and either P27361 /2 or P43268 ( P=0.7 and P=0.3 respectively ) . None of the markers were found to be independently prognostic . Membrane P04626 , nuclear P04626 and P35354 , however , were all found to predict poor disease-free survival in patients on endocrine treatment ( P=0.0017 , P=0.0003 and P=0.0202 respectively ) . Moreover , patients who were positive for P35354 predicted adverse effects of tamoxifen ( P=0.0427 ) . These clinical ex vivo data are consistent with molecular observations that P04626 can regulate P35354 expression through direct transcriptional mechanisms . P35354 expression correlates with disease progression on endocrine treatment . This study supports a role for P35354 as a predictor of adverse effects of tamoxifen in breast cancer patients . Pretreatment of sildenafil attenuates ischemia-reperfusion renal injury in rats . DB00203 was the first selective inhibitor of phosphodiesterase-5 ( O76074 ) to be widely used for treating erectile dysfunction . Many recent studies have investigated the cardioprotective role of sildenafil in animal models . We evaluated the protective effects of sildenafil in experimental renal ischemia-reperfusion ( IR ) injury in two studies . In study 1 , male Sprague-Dawley rats were divided into four groups : sham , sildenafil-treated sham , vehicle-treated IR , and sildenafil-treated IR groups . In study 2 , we divided the rats into two groups : sildenafil-treated IR rats and PD98059 ( P29323 inhibitor ) +sildenafil-treated IR rats . Functional parameters of the kidney were evaluated at the molecular and structural levels . Blood urea nitrogen ( BUN ) and serum creatinine levels were lower in sildenafil-treated IR rats than in vehicle-treated IR rats . The expression of inducible ( P35228 ) and endothelial nitric oxide synthase ( P29474 ) proteins in sildenafil-treated IR rats was significantly higher than in vehicle-treated IR rats . Pretreatment with sildenafil in IR rats increased P29323 phosphorylation and reduced the renal Bax/Bcl-2 ratio , renal caspase-3 activity , and terminal dUTP nick end-labeling-positive apoptotic cells . In contrast , PD98059 treatment increased BUN and serum creatinine levels and attenuated the sildenafil-induced expression of pERK , P35228 , P29474 , and Bcl-2 . PD98059 also increased caspase-3 activity but did not decrease the sildenafil-induced accumulation of cGMP . In conclusion , this study suggests that sildenafil has antiapoptotic effects in experimental IR renal injury via P29323 phosphorylation , induction of P35228 and P29474 production , and a decrease in the Bax/Bcl-2 ratio . Clinical endocannabinoid deficiency ( CECD ) : can this concept explain therapeutic benefits of cannabis in migraine , fibromyalgia , irritable bowel syndrome and other treatment-resistant conditions ? OBJECTIVES : This study examines the concept of clinical endocannabinoid deficiency ( CECD ) , and the prospect that it could underlie the pathophysiology of migraine , fibromyalgia , irritable bowel syndrome , and other functional conditions alleviated by clinical cannabis . METHODS : Available literature was reviewed , and literature searches pursued via the National Library of Medicine database and other resources . RESULTS : Migraine has numerous relationships to endocannabinoid function . Anandamide ( AEA ) potentiates P08908 and inhibits 5- Q13049 receptors supporting therapeutic efficacy in acute and preventive migraine treatment . Cannabinoids also demonstrate dopamine-blocking and anti-inflammatory effects . AEA is tonically active in the periaqueductal gray matter , a migraine generator . THC modulates glutamatergic neurotransmission via DB01221 receptors . Fibromyalgia is now conceived as a central sensitization state with secondary hyperalgesia . Cannabinoids have similarly demonstrated the ability to block spinal , peripheral and gastrointestinal mechanisms that promote pain in headache , fibromyalgia , IBS and related disorders . The past and potential clinical utility of cannabis-based medicines in their treatment is discussed , as are further suggestions for experimental investigation of CECD via P04141 examination and neuro-imaging . CONCLUSION : Migraine , fibromyalgia , IBS and related conditions display common clinical , biochemical and pathophysiological patterns that suggest an underlying clinical endocannabinoid deficiency that may be suitably treated with cannabinoid medicines . KR-31372 inhibits P35968 /Flk-1 tyrosine phosphorylation via K+( DB00171 ) channel opening in its antiangiogenic effect . The aim of this study was to identify the signaling pathway of the antiangiogenesis by ( 2R,3R,4S ) -N-cyano-N- ( 6-nitro-3,4-dihydro-hydroxy-2-methyl-2-dimethoxymethyl 2H-1-benzopyran-4yl ) -N'-benzylguanidine ( KR-31372 ) . KR-31372 inhibited the in vitro basal tube formation using Matrigel-coated plate and in vivo neovascularizations in mice induced by Matrigel containing vascular endothelial growth factor ( P15692 (165) , 5 ng/ml ) . P15692 (165) markedly increased cell proliferation using 5-bromo-2'-deoxyuridine incorporation and chemotactic migration using transwell chamber in human umbilical vein endothelial cells , those of which were significantly suppressed by pretreatment with KR-31372 and levcromakalim concentration dependently . The suppression of all these variables were strongly antagonized by glibenclamide , DB00171 -sensitive K(+) channel blocker . KR-31372 ( 10(-6)-10(-4) M ) and levcromakalim ( 10(-5) M ) concentration-dependently suppressed the P15692 (165)-induced increases in P35968 /Flk-1 tyrosine phosphorylation as well as the extracellular signal-related kinase 1/2 ( P27361 /2 ) , p38 MAK and p125( Q05397 ) tyrosine phosphorylation . These variables were significantly antagonized by glibenclamide . In conclusion , KR-31372 significantly inhibited the P35968 /Flk-1 tyrosine phosphorylation-linked P27361 /2 , p38 MAPK and p125( Q05397 ) tyrosine phosphorylation via mediation of K(+)( DB00171 ) channel opening , thereby resulting in antiangiogenesis . Gambogic acid inhibits angiogenesis through suppressing vascular endothelial growth factor-induced tyrosine phosphorylation of P35968 /Flk-1 . Previous studies revealed that gambogic acid ( GA ) , the major active ingredient of gamboge , a brownish to orange resin exuded from Garcinia hanburryi tree in Southeast Asia , possessed significant anticancer activity both in vitro and in vivo . In this study , we explored the high antiangiogenic activities of GA for the first time . GA inhibits the P15692 -stimulated proliferation , migration and tube formation of human umbilical vein endothelial cells ( HUVECs ) as well as microvessel sprouting from rat aortic rings in vitro . Moreover , GA inhibits vessel growth in matrigel plugs and P62158 in vivo and transplanted tumor in mice . The results also indicated that GA decreases P15692 production of cultured tumor cells and inhibits P15692 -induced tyrosine phosphorylation of P35968 /Flk-1 . This inhibition of receptor phosphorylation is correlated with a significant decrease in P15692 -triggered phosphorylated forms of P29323 , AKT and p38 . Taken together , these findings strongly suggest that GA might be a structurally novel angiogenesis inhibitor .