MH_dev_133

Pharmacogenetic tests in cancer chemotherapy : what physicians should know for clinical application . Significant efforts to develop pharmacogenomic predictors have been made to guide more effective and safer chemotherapy . Although a considerable amount of data has been generated from numerous experimental or clinical studies , there is a large gap between pharmacogenomic knowledge and clinical application . This review will focus on eight pharmacogenetic tests including P04818 , Q12882 , P22309 , P10635 , P00533 , P01116 , P08637 , and P38398 / 2 to predict toxicity or response to commonly used chemotherapeutic agents . We will discuss the current level of evidence , if the current pharmacogenetic tests are appropriate for clinical application , and how to integrate the pharmacogenomic information into routine clinical practice .

P35372 mutant , T394A , abolishes opioid-mediated adenylyl cyclase superactivation . This study was to characterize the effects of a point-mutant at C-terminal of mu opioid receptor ( MOR ) , namely MOR T394A , in chronic opioid-induced cellular responses . After 18 h of exposure to [ D-Ala , N-Me - DB00120 , DB00145 - ol ] enkephalin ( DAMGO ) , adenylyl cyclase ( AC ) superactivation , a hallmark for the cellular adaptive response after chronic opioid stimulation , was observed in the cells expressing wild-type receptor , but was totally abolished in the cells expressing MOR T394A . Receptor phosphorylation was also attenuated in cells with MOR T394A after prolonged preexposure to agonist . Furthermore , Q96HU1 kinase kinase - 1 ( Q02750 ) overexpression was able to rescue AC superactivation in cells with MOR T394A , but showed no effect in the wild-type MOR-expressing cells . These results indicated that the amino acid T394 at C-terminus of MOR played a critical role in chronic agonist-induced AC superactivation and receptor phosphorylation .

Altered P25942 and P12830 expression - - putative role in oral lichen planus . BACKGROUND : Oral lichen planus ( OLP ) is characterized among other features by apoptosis of basal keratinocytes . To identify potential regulatory mechanisms associated with basal cell apoptosis in OLP , we investigated the expression of P25942 , P29965 ( P29965 ) , P16070 and epithelial ( E ) - cadherin . METHODS : Biopsies from 22 patients with OLP were investigated by immunohistochemistry for detection of P25942 , P29965 , P12830 , P16070 , Laminin - 5 and Collagen IV , double-labelling for P25942 and CD3 , and in situ mRNA hybridization for P25942 and P29965 . RESULTS : In actively diseased areas of OLP lesions , basal keratinocytes did not express P25942 and were focally P12830 - negative , in contrast to non-diseased areas and normal oral mucosa . Demonstration of intraepithelial T cells expressing P25942 and P29965 , indicates a potential role in inflammatory cell responses involved in the disease process of OLP . CONCLUSION : T cells may orchestrate inflammatory cell responses in OLP via P25942 - P29965 interactions . As basal keratinocytes downregulate P25942 , they may escape P25942 - P29965 - induced apoptosis in OLP . On the other hand , loss of P12830 expression may contribute to epithelial basal cell destruction and T-cell migration into the epithelial compartment in OLP .

OSU - 03012 and Viagra Treatment Inhibits the Activity of Multiple Chaperone Proteins and Disrupts the Blood-Brain Barrier : Implications for Anti-Cancer Therapies . We examined the interaction between OSU - 03012 ( also called AR - 12 ) with phosphodiesterase 5 ( O76074 ) inhibitors to determine the role of the chaperone glucose-regulated protein ( P11021 ) / P11021 / P11021 in the cellular response . DB00203 MEN ( Viagra ) interacted in a greater than additive fashion with OSU - 03012 to kill stem-like GBM cells . Treatment of cells with OSU - 03012 / sildenafil : abolished the expression of multiple oncogenic growth factor receptors and plasma membrane drug efflux pumps and caused a rapid degradation of P11021 and other HSP 70 and HSP 90 family chaperone proteins . Decreased expression of plasma membrane receptors and drug efflux pumps was dependent upon enhanced Q9NZJ5 - eIF 2α - P18848 - P35638 signaling and was blocked by P11021 over-expression . In vivo OSU - 03012 / sildenafil was more efficacious than treatment with celecoxib and sildenafil at killing tumor cells without damaging normal tissues and in parallel reduced expression of P08183 and Q9UNQ0 in the normal brain . The combination of OSU - 03012 / sildenafil synergized with low concentrations of sorafenib to kill tumor cells , and with lapatinib to kill P00533 over-expressing tumor cells . In multiplex assays on plasma and human tumor tissue from an OSU - 03012 / sildenafil treated mouse , we noted a profound reduction in uPA signaling and identified FGF and P23458 / 2 as response biomarkers for potentially suppressing the killing response . Inhibition of FGFR signaling and to a lesser extent P23458 / 2 signaling profoundly enhanced OSU - 03012 / sildenafil lethality .

AM2389 , a high-affinity , in vivo potent P21554 - receptor-selective cannabinergic ligand as evidenced by drug discrimination in rats and hypothermia testing in mice . RATIONALE : The endocannabinoid signaling system ( ECS ) has been targeted for developing novel therapeutics since ECS dysfunction has been implicated in various pathologies . Current focus is on chemical modifications of the hexahydrocannabinol ( HHC ) nabilone ( DB00486 MEN ( ® ) ) . OBJECTIVE : To characterize the novel , high-affinity cannabinoid receptor 1 ( CB ( 1 ) R ) HHC-ligand AM2389 [ 9β - hydroxy - 3 - ( 1 - hexyl-cyclobut - 1 - yl ) - hexahydrocannabinol in two rodent pre-clinical assays . MATERIALS AND METHODS : CB ( 1 ) R mediation of AM2389 - induced hypothermia in mice was evaluated with AM251 , a CB ( 1 ) R-selective antagonist / inverse agonist . Additionally , two groups of rats discriminated the full cannabinergic aminoalkylindole AM5983 ( 0.18 and 0.56 mg / kg ) from vehicle 20 min post-injection in a two-choice operant conditioning task motivated by 0.1 % saccharin / water . Generalization / substitution tests were conducted with AM2389 , AM5983 , and Δ ( 9 ) - tetrahydrocannabinol ( Δ ( 9 ) - THC ) . RESULTS : Δ ( 9 ) - THC ( 30 mg / kg ) - induced hypothermia exhibited a faster onset and shorter duration of action compared with AM2389 ( 0.1 and 0.3 mg / kg ) . AM251 ( 3 and 10 mg / kg ) attenuated / blocked hypothermia induced by 0.3 mg / kg AM2389 . In drug discrimination , the order of potency was AM2389 > AM5983 > Δ ( 9 ) - THC with ED ( 50 ) values of 0.0025 , 0.0571 , and 0.2635 mg / kg , respectively , in the low-dose condition . The corresponding ED ( 50 ) values in the high-dose condition were 0.0069 , 0.1246 , and 0.8438 mg / kg , respectively . Onset of the effects of AM2389 was slow with a protracted time-course ; the functional , perceptual in vivo half-life was approximately 17 h . CONCLUSIONS : This potent cannabinergic HHC exhibited a slow onset of action with a protracted time-course . The AM2389 chemotype appears well suited for further drug development , and AM2389 currently is used to probe behavioral consequences of sustained ECS activation .

Receptor cross-talk spatially restricts p - P29323 during O00206 stimulation of autoreactive B cells . To maintain tolerance , autoreactive B cells must regulate signal transduction from the P11274 and TLRs . We recently identified that dendritic cells and macrophages regulate autoreactive cells during O00206 activation by releasing P05231 and soluble P29965 ( sCD 40L ) . These cytokines selectively repress Ab secretion from autoreactive , but not antigenically naive , B cells . How P05231 and sCD 40L repress autoantibody production is unknown . In this work , we show that P05231 and sCD 40L are required for low-affinity / avidity autoreactive B cells to maintain tolerance through a mechanism involving receptor cross-talk between the P11274 , O00206 , and the IL - 6R or P25942 . We show that acute signaling through IL - 6R or P25942 integrates with chronic P11274 - mediated P29323 activation to restrict p - P29323 from the nucleus and represses O00206 - induced Blimp - 1 and P17861 expression . Tolerance is disrupted in 2-12 H / MRL / lpr mice where P05231 and sCD 40L fail to spatially restrict p - P29323 and fail to repress O00206 - induced Ig secretion . In the case of P25942 , acute signaling in B cells from 2-12 H / MRL / lpr mice is intact , but the chronic activation of p - P29323 emanating from the P11274 is attenuated . Re-establishing chronically active P29323 through retroviral expression of constitutively active Q02750 restores tolerance upon sCD 40L , but not P05231 , stimulation , indicating that regulation by P05231 requires another signaling effector . These data define the molecular basis for the regulation of low-affinity autoreactive B cells during O00206 stimulation ; they explain how autoreactive but not naive B cells are repressed by P05231 and sCD 40L ; and they identify B cell defects in lupus-prone mice that lead to O00206 - induced autoantibody production .

Amelioration of scopolamine induced cognitive dysfunction and oxidative stress by Inonotus obliquus - a medicinal mushroom . The present study was aimed to investigate the cognitive enhancing and anti-oxidant activities of Inonotus obliquus ( Chaga ) against scopolamine-induced experimental amnesia . Methanolic extract of Chaga ( Q9NRJ3 ) at 50 and 100 mg kg ( - 1 ) doses were administered orally for 7 days to amnesic mice . Learning and memory was assessed by passive avoidance task ( PAT ) and Morris water maze ( MWM ) test . Tacrine ( DB00382 MEN , 10 mg kg ( - 1 ) , orally ( p . o ) ) used as a reference drug . To elucidate the mechanism of the cognitive enhancing activity of Q9NRJ3 , the activities of acetylcholinesterase ( P22303 ) , anti-oxidant enzymes , the levels of acetylcholine ( ACh ) and nitrite of mice brain homogenates were evaluated . Q9NRJ3 treatment for 7 days significantly improved the learning and memory as measured by PAT and MWM paradigms . Further , Q9NRJ3 significantly reduced the oxidative-nitritive stress , as evidenced by a decrease in malondialdehyde and nitrite levels and restored the glutathione and superoxide dismutase levels in a dose dependent manner . In addition , Q9NRJ3 treatment significantly decreased the P22303 activity in both the salt and detergent-soluble fraction of brain homogenates . Further , treatment with Q9NRJ3 restored the levels of ACh as did DB00382 MEN . Thus , the significant cognitive enhancement observed in mice after Q9NRJ3 administration is closely related to higher brain anti-oxidant properties and inhibition of P22303 activity . These findings stress the critical impact of Chaga , a medicinal mushroom , on the higher brain functions like learning and memory .

P06401 level as a predictor of response to megestrol acetate in advanced breast cancer : a retrospective study . DB00351 MEN ( 160 mg / day ) produced a response rate of 44 % in a retrospective series of 39 evaluable patients with advanced breast cancer . The estrogen-receptor ( ER ) level was greater than 10 fmols / mg of protein in 28 patients , and the progesterone-receptor ( PR ) level was greater than 10 fmols / mg of protein in 26 patients . ER and PR levels , age , and disease-free interval were analyzed for their relationship to response . The PR was the single best predictor of response to megestrol acetate ; the addition of ER added 2 % to the predictive accuracy rate of PR alone .

Platelet-associated antibodies , cellular immunity and FCGR 3a genotype influence the response to rituximab in immune thrombocytopenia . DB00073 SUB is widely used in autoimmune diseases including immune thrombocytopenia ( ITP ) , although the mechanism of effect remains unclear . This study describes the effects of rituximab on platelet-associated antibodies ( PA-APAs ) , B and T cell counts and clonality ( IGHV and TRG @ gene rearrangements ) , P08637 ( FcγRIIIa ) and P12318 ( FcγRIIa ) polymorphisms and correlation to anti - P29965 ( P29965 ) response . PA-APA levels fell more frequently in responders ( 6/8 ) than in non-responders ( 2/10 : P = 0 · 08-0 · 15 ) . Two responders had no PA-APAs . Two non-responders with a fall in PA-APAs had very high CD8 levels . One non-responder had a B cell clone , one responder and one non-responder had a T cell clone . 15/16 patients had the same responses to rituximab and antiCD 40L . Patients with P08637 V / V polymorphisms were more likely to respond to rituximab ( P = 0 · 03 ) . In summary , the fall in PA-APAs in responders confirms the humoural effect of rituximab . Failure to respond in patients with very high CD8 levels , despite PA-APA fall indicates a role for T cell-mediated platelet / megakaryocyte destruction . Concordance of response to anti - P29965 suggests autoantibody-producing cells are under T cell control . Finally , the effect of FCGR polymorphisms on response confirms the importance of FCGR-mediated depletion of B cells in autoimmunity . This has implications on the pathology of ITP as well as the immunological effect of B cell depletion .

DB00073 SUB - dependent cytotoxicity by natural killer cells : influence of P08637 polymorphism on the concentration-effect relationship . The P08637 gene dimorphism generates two allotypes : FcgammaRIIIa - 158V and FcgammaRIIIa - 158F . The genotype homozygous for FcgammaRIIIa - 158V ( VV ) is associated with higher clinical response to rituximab , a chimeric anti - P11836 REA IgG 1 used in the treatment of B lymphoproliferative malignancies . Our objective was to determine whether this genetic association relates to rituximab-dependent cytotoxicity mediated by FcgammaRIIIa / CD16a + cells . The number of CD16 + circulating monocytes , T cells , and natural killer ( NK ) cells in 54 donors was first shown to be unrelated to P08637 polymorphism . We then demonstrated that FcgammaRIIIa - 158V displays higher affinity for rituximab than FcgammaRIIIa - 158F by comparing rituximab concentrations inhibiting the binding of 3G8 mAb ( anti-CD 16 ) with VV NK cells and NK cells homozygous for FcgammaRIIIa - 158F ( FF ) . VV and FF NK cells killed Daudi cells similarly after FcgammaRIIIa engagement by saturating concentrations of rituximab or 3G8 . However , the rituximab concentration resulting in 50 % lysis ( EC ( 50 ) ) observed with NK cells from VV donors was 4.2 times lower than that observed with NK cells from FF donors ( on average 0.00096 and 0.00402 microg / ml , respectively , P = 0.0043 ) . Finally , the functional difference between VV and FF NK cells was restricted to rituximab concentrations weakly sensitizing P11836 REA . This study supports the conclusion that P08637 genotype is associated with response to rituximab because it affects the relationship between rituximab concentration and NK cell-mediated lysis of P11836 REA + cells . DB00073 SUB administration could therefore be adjusted according to P08637 genotype .

DB00588 MEN - induced regulation of the balance within macrophage subpopulations . In asthma , treatment with inhaled corticosteroids reduces chronic peribronchial inflammation and restores the balance within macrophage subpopulations . This study investigates whether corticosteroids can regulate monocyte differentiation in vitro and thereby influence the balance of functionally distinct macrophages . Graded doses of fluticasone propionate ( FP ) were added to cultures of normal peripheral blood monocytes in the presence or absence of P05112 . Cells were harvested after 7 days ' culture . Double immunofluorescence studies were performed on cytospins of differentiated macrophages using the MoAbs RFD 1 and RFD 7 to distinguish inductive and suppressive macrophages by their respective phenotypes . Macrophage function was determined by quantifying allostimulation in a mixed leucocyte reaction and by measuring tumour necrosis factor-alpha ( P01375 ) production . FP reduced the number of mature cells with a D1 + antigen-presenting phenotype and up-regulated the development of cells with the D1 / D7 + and D7 + phenotypes . Functionally , this was associated with reduced stimulation of T cell proliferation in a mixed leucocyte reaction ( P08235 ) . DB00588 MEN also reversed the increase in both D1 + expression and P01375 production induced by P05112 . The effect of FP persisted for 24 h after removal of FP from the culture medium . These results suggest that FP treatment of asthmatics may have a direct beneficial effect by normalizing the macrophage subset imbalance that contributes to the chronic peribronchial inflammation present in this condition .

M2 macrophages phagocytose rituximab-opsonized leukemic targets more efficiently than m1 cells in vitro . Because macrophages have been implicated as major players in the mechanism of action of rituximab , we have investigated the factors that modulate their tumor cell killing potential . Human macrophages , differentiated in vitro from peripheral blood monocytes , were used in binding and phagocytosis assays using B-chronic lymphocytic leukemia or lymphoma target cells opsonized with rituximab . Phagocytosis was maximal at 0.1 microg / ml rituximab and was not significantly affected by P11836 REA expression levels or by P08637 polymorphism at position 158 ( DB00161 / DB00120 ) . The role of FcgammaRs was demonstrated by complete inhibition of phagocytosis by excess human Igs . Because macrophages can be differentiated to M1 - or M2 - type cells with either GM - P04141 or P09603 , respectively , and can be classically activated by proinflammatory stimuli ( P01579 / LPS ) or undergo alternative activation with cytokines such as P05112 or P22301 , we have analyzed the effect of these different polarization programs on the phagocytosis mediated by rituximab . Macrophages differentiated in presence of P09603 showed a 2 - to 3 - fold greater phagocytic capacity compared with GM - P04141 - induced cells . Furthermore , addition of P22301 significantly increased , whereas P05112 decreased phagocytosis by both P09603 - and GM - P04141 - differentiated macrophages . LPS / P01579 had little effect . Expression of CD16 , CD32 , and CD64 in different macrophage populations correlated with phagocytic activity . Interestingly , several B lymphoma cell lines were observed to secrete 400-1300 pg / ml P22301 in vitro , and coculture of human macrophages with lymphoma conditioned medium increased significantly their phagocytic capacity . Our data suggest that cytokines secreted by lymphoma cells can favor alternate activation of macrophages with a high phagocytic capacity toward rituximab-opsonized targets .

T lymphocytes expressing a CD16 signaling receptor exert antibody-dependent cancer cell killing . To expand applications for T-cell-based immunotherapy in cancer , we designed a receptor that binds the Fc portion of human immunoglobulins and delivers activation signals . The construct included the high-affinity CD16 ( P08637 ) V158 variant , CD8α hinge , and transmembrane domains , along with signaling domains from CD3ζ and 4-1 BB ( Q07011 ) , forming a chimeric receptor termed CD16V - BB-ζ . After retrovirus-mediated expression in human T cells , CD16V - BB-ζ bound humanized antibodies with higher affinity than a control receptor containing the more common F158 variant . Engagement of CD16V - BB-ζ provoked T-cell activation , exocytosis of lytic granules , and sustained proliferation , with a mean cell recovery after 4 - week coculture with Daudi lymphoma cells and rituximab of nearly 70 - fold relative to input cells . In contrast , unbound antibody alone produced no effect . CD16V - BB-ζ T cells specifically killed lymphoma cells and primary chronic lymphocytic leukemia cells in combination with rituximab at a low effector : target ratio , even when assayed on mesenchymal cells . DB00072 MENMAX DB00072 MEN triggered CD16V - BB-ζ-mediated killing of P04626 ( P04626 ) ( + ) breast and gastric cancer cells ; similar results were obtained with an anti-GD 2 antibody in neuroblastoma and osteosarcoma cells . Furthermore , coadministration of CD16V - BB-ζ T cells with immunotherapeutic antibodies exerted considerable antitumor activity in vivo . Signaling mediated by 4-1 BB-CD 3ζ induced higher T-cell activation , proliferation , and cytotoxicity than CD3ζ or FcεRIγ , and the receptor was expressed effectively after mRNA electroporation without viral vectors , facilitating clinical translation . Our results offer preclinical proof of concept for CD16V - BB-ζ as a universal , next-generation chimeric receptor with the potential to augment the efficacy of antibody therapies for cancer .

Activation of tumor-promoting type 2 macrophages by P00533 - targeting antibody cetuximab . PURPOSE : In a recent randomized phase III clinical trial in metastatic colorectal cancer patients , the addition of the anti-epidermal growth factor receptor ( P00533 ) monoclonal antibody ( mAb ) cetuximab to bevacizumab and chemotherapy resulted in decreased progression-free survival , in particular for patients with the high-affinity FcγRIIIA . EXPERIMENTAL DESIGN : The presence of natural killer ( NK ) cells and type 2 ( M2 ) macrophages in colorectal cancer was determined by immunohistochemistry , using antibodies to lineage-specific markers O76036 and P34810 with Q86VB7 , respectively . Influence of tumor-bound cetuximab on M2 macrophages was carried out in vitro with P00533 - expressing tumor cells and short-term differentiated monocytes from blood donors , who were typed for the FcγRIIIA polymorphism ( CD16 ) . RESULTS : Antibody-dependent cellular cytotoxicity by NK cells is generally proposed as one of the antitumor mechanisms of mAbs . We found that Q86VB7 - positive M2 macrophages are much more abundant in colorectal carcinomas . In vitro analysis of M2 macrophages revealed high levels of Fc-gamma receptors ( FcγR ) and Q9NZQ7 and production of P22301 and P15692 but not IL - 12 . These anti-inflammatory and tumor-promoting mediators were released upon coculture with P00533 - positive tumor cells loaded with low concentrations of cetuximab . Macrophage activation depended on P00533 expression on the tumor cells , FcγRs , target specificity of the mAb and mobility of antibody complexes . Cetuximab-induced macrophage responses were more pronounced for P08637 158 - DB00161 ( high-affinity ) carriers . CONCLUSION : These results suggest that tumor-promoting M2 macrophages are activated by the therapeutic mAb cetuximab in the local tumor microenvironment and argue that this immune mechanism should be taken into account for the application of therapeutic antibodies .

Intracellular signaling mechanisms associated with Q08722 modified surfaces . We have previously established that recombinant Q08722 can ameliorate the inflammatory response to synthetic polymeric surfaces . Here , we begin to profile , at the transcriptional , translational and cell signaling level , the inflammatory cell response when blood interacts with Q08722 modified polyvinyl chloride ( PVC ) ( Q08722 - PVC ) . We used qPCR arrays to compare transcriptional changes between human whole blood exposed to Q08722 - PVC or PVC . Transcription of Q9UBH0 , Q8WWZ1 , Q96PD4 , P10147 , P8 0075 , Q9NRJ3 , P48061 , and O43927 was upregulated in blood exposed to PVC , compared to Q08722 - PVC . The increase in P10147 and P8 0075 transcription correlated with an increase in the chemokines ' presence in the plasma . Exposure of blood to Q08722 - PVC resulted in an increase , compared to PVC , in transcription of P13500 , P13236 , P78556 , P09341 , TGFβ 3 , Q9NR23 , P55107 , P29965 , and P50591 . Q08722 - PVC exposure resulted in an increase of the following matrix metalloproteinase related genes : P03956 , P09237 , P45452 , and P51512 . Phosflow cytometry , and assays examining transcription factor binding , cell attachment , and genome-wide chromatin association indicated that members of the JAK - P35610 signaling pathway , particularly O60674 and P42229 , mediate inflammatory cell interactions with Q08722 - PVC . Our data demonstrate that differential molecular responses to Q08722 involve downregulation of cytokines , upregulation of MMPs , and JAK / P35610 signaling mechanisms .

Pharmacogenetics in cancer treatment . Interindividual variability in the efficacy and toxicity of drug therapy is associated with polymorphisms in genes encoding drug-metabolizing enzymes , transporters , or drug targets . Pharmacogenetics aims to identify individuals predisposed to high risk of toxicity from conventional doses of cancer chemotherapeutic agents . We review the role of genetic polymorphisms in P22309 and P51580 , as well as mutations in Q12882 , in influencing drug disposition and toxicity . Recent studies show that pharmacogenetic determinants may also influence treatment outcomes . We discuss the clinical significance of polymorphisms in TS , P42898 , and P08637 , as well as the polymorphic DNA repair genes P18074 and P18887 , in influencing response to chemotherapy and survival outcomes . Finally , the potential implications of transporter pharmacogenetics in influencing drug bioavailability are addressed .

Dynamic coregulatory complex containing P38398 , Q01094 and Q99708 controls Q13315 transcription . Chromosomal instability is a key feature in cancer progression . Recently we have reported that P38398 regulates the transcription of several genes in prostate cancer , including Q13315 ( ataxia telangiectasia mutated ) . Although it is well accepted that Q13315 is a pivotal mediator in genotoxic stress , it is unknown whether Q13315 transcription is regulated during the molecular response to DNA damage . Here we investigate Q13315 transcription regulation in human prostate tumor PC3 cell line . We have found that doxorubicin and mitoxantrone repress Q13315 transcription in PC3 cells but etoposide and methotrexate do not affect Q13315 expression . We have demonstrated that P38398 binds to Q13315 promoter and after doxorubicin exposure , it is released . P38398 overexpression increases Q13315 transcription and this enhancement is abolished by P38398 depletion . Moreover , P38398 - BRCT domain loss impairs the ability of P38398 to regulate Q13315 promoter activity , strongly suggesting that BRCT domain is essential for Q13315 regulation by P38398 . P38398 - overexpressing PC3 cells exposed to KU55933 Q13315 kinase inhibitor showed significant decreased Q13315 promoter activity compared to untreated cells , suggesting that Q13315 transcriptional regulation by P38398 is partially mediated by the Q13315 kinase activity . In addition , we have demonstrated Q01094 binding to Q13315 promoter before and after doxorubicin exposure . Q01094 overexpression diminishes Q13315 transcription after doxorubicin exposure which is impaired by Q01094 dominant negative mutants . Finally , the co-regulator of transcription Q99708 increases Q13315 transcription . Q99708 increases Q13315 transcription . Altogether , P38398 / Q01094 / Q99708 binding to Q13315 promoter activates Q13315 transcription . Doxorubicin exposure releases P38398 and Q99708 from Q13315 promoter still keeping Q01094 recruited and , in turn , represses Q13315 expression .

Characterization of plant P18887 and its interaction with proliferating cell nuclear antigen . In plants , there are no P06746 ( Pol beta ) and P49916 ( Lig 3 ) genes . Thus , the plant short-patch base excision repair ( short-patch BER ) pathway must differ considerably from that in mammals . We characterized the rice ( Oryza Sativa L . cv . Nipponbare ) homologue of the mammalian X-ray repair cross complementing 1 ( P18887 ) , a well-known BER protein . The plant P18887 lacks the N-terminal domain ( NTD ) which is required for Pol beta binding and is essential for mammalian cell survival . The recombinant rice P18887 ( OsXRCC 1 ) protein binds single-stranded DNA ( ssDNA ) as well as double-stranded DNA ( dsDNA ) and also interacts with rice proliferating cell nuclear antigen ( OsPCNA ) in a pull-down assay . Through immunoprecipitation , we demonstrated that OsXRCC 1 forms a complex with P12004 in vivo . OsXRCC 1 mRNA was expressed in all rice organs and was induced by application of bleomycin , but not of MMS , H ( 2 ) O ( 2 ) or UV-B . DB00290 MEN also increased the fraction of OsXRCC 1 associated with chromatin . These results suggest that OsXRCC 1 contributes to DNA repair pathways that differ from the mammalian BER system .

P35372 and P20813 gene variants as risk factors in methadone-related deaths . DB00333 MEN is a medication valued for its effectiveness in the treatment of heroin addiction ; however , many fatal poisonings associated with its use have been reported over the years . We have examined the association between P20813 and micro-opioid receptor ( P35372 ) gene variations and apparent susceptibility to methadone poisoning . Genomic DNA was extracted from postmortem whole blood of 40 individuals whose deaths were attributed to methadone poisoning . The presence of P20813 * 4 , * 9 , and * 6 alleles and the P35372 A118G variant was determined by SNP genotyping . P20813 * 4 , * 9 , and * 6 alleles were found to be associated with higher postmortem methadone concentrations in blood ( P < or = 0.05 ) . P35372 A118G was also associated with higher postmortem methadone concentrations in blood but not to a level of statistical significance ( P = 0.39 ) . In these methadone-related deaths , P35372 118GA was associated with higher postmortem benzodiazepine concentrations ( P = 0.04 ) , a finding not associated with morphine-related deaths . The risk of a methadone-related fatality during treatment may be evaluated in part by screening for P20813 * 6 and A118G .

Association of the P08637 - 158F / V gene polymorphism with the response to rituximab treatment in Spanish systemic autoimmune disease patients . DB00073 SUB is being used as treatment for systemic autoimmune diseases . The objective of this study was to determine whether the genetic variant in the Fc gamma-receptor III a ( P08637 ) gene , 158F / V , contributes to the observed variation in response to rituximab in patients with systemic autoimmune diseases . DNA samples from 132 Spanish patients with different systemic autoimmune diseases receiving rituximab were genotyped for P08637 - 158F / V ( rs396991 ) gene polymorphism using the TaqMan ( ® ) allelic discrimination technology . Six months after infusion with rituximab we evaluated the response to the drug : 61 % of the patients showed a complete response , partial 27 % and 12 % did not respond to the treatment . A statistically significant difference was observed in V allele frequency between responder ( 38 % ) and nonresponder ( 16 % ) patients ( p= 0.01 ; odds ratio [ OR ]= 3.24 , 95 % confidence interval [ CI ] 1.17- 11.1 ) . DB00073 SUB was also more effective in V allele carriers ( 94 % ) than in homozygous FF patients ( 81 % ) : p= 0.02 ; OR = 3.96 , 95 % CI 1.10- 17.68 . These results suggest that P08637 - 158F / V ( rs396991 ) gene polymorphism play a role in the response to rituximab in autoimmune diseases . Validation of these findings in independent cohorts is warranted .

17 DB00783 MEN - mediated growth inhibition of MDA-MB - 468 cells stably transfected with the estrogen receptor : cell cycle effects . P03372 ( ER ) - negative MDA-MB - 468 human breast cancer cells were stably transfected with wild-type human ER and utilized as a model for investigating estrogen - and aryl hydrocarbon ( Ah ) - responsiveness . Treatment of the stably transfected cells with 10 nM 17 beta-estradiol ( E2 ) resulted in a significant inhibition ( > 60 % ) of cell proliferation and DNA synthesis , which was blocked by 10 ( - 7 ) M ICI 182 780 . Analysis by flow cytometry indicated that treatment with E2 increased the percentage of cells in G0 / P55008 ( from 68.8 to 89.4 ) and decreased cells in S ( from 18.4 to 3.4 ) and G2 / M ( from 12.8 to 7.2 ) phases of the cell cycle . The effects of E2 on the major cyclins , cyclin-dependent kinases and cyclin-dependent kinase inhibitors , retinoblastoma protein ( RB ) , Q01094 , and cyclin-dependent kinase activities were also investigated in the stably transfected MDA-MB - 468 cells . The results demonstrated that the growth inhibitory effects of 10 (-8 ) M E2 in ER stably transfected MDA-MB - 468 cells were associated with modulation of several factors required for cell cycle progression and DNA synthesis , including significant induction of the cyclin-dependent kinase inhibitor p21cip - 1 ( > 4 - fold increase after 12 h ) and decreased Q01094 and P12004 protein levels . These results show that the growth-inhibitory effects of E2 in the stably transfected cells were due to multiple factors which result in growth arrest in G0 / P55008 and inhibition of DNA synthesis .

Effects of targeted deletion of cannabinoid receptors P21554 and CB2 on immune competence and sensitivity to immune modulation by Delta 9 - tetrahydrocannabinol . The role of cannabinoid receptors , P21554 and CB2 , in immune competence and modulation by Delta 9 - tetrahydrocannabinol ( Delta 9 - THC ) was investigated in P21554 ( - / - ) / CB2 ( - / - ) mice . Immunofluorescence analysis of splenic leukocytes showed no significant differences in the percentage of T cell subsets , B cells , or macrophages between wild-type and P21554 ( - / - ) / CB2 ( - / - ) mice . Lymphoproliferative control responses to PHA , phorbol ester plus ionomycin , or LPS and sensitivity to suppression by Delta 9 - THC showed no profound differences between the two genotypes , although some differences were observed in control baseline responses . Likewise , similar control responses and sensitivity to Delta 9 - THC were observed in mixed lymphocyte responses ( P08235 ) and in P60568 and P01579 production in both genotypes . Conversely , humoral immune responses showed a markedly different profile of activity . Delta 9 - THC suppressed the in vivo T cell-dependent , anti-sheep RBC ( anti-sRBC ) IgM antibody-forming cell ( AFC ) response in wild-type but not in P21554 ( - / - ) / CB2 ( - / - ) mice , and the in vitro anti-sRBC IgM response in P21554 ( - / - ) / CB2 ( - / - ) splenocytes was too low to rigorously assess P21554 / CB2 involvement in modulation by Delta 9 - THC . Conversely , comparable in vitro IgM AFC control responses to LPS and P29965 ( P29965 ) activation were observed in the two genotypes . Interestingly , LPS-induced IgM responses were refractory to suppression by Delta 9 - THC , regardless of genotype , and P29965 - induced IgM responses were only suppressed by Delta 9 - THC in wild-type but not in P21554 ( - / - ) / CB2 ( - / - ) B cells . Collectively , we demonstrate differential involvement of P21554 and / or CB2 in immune modulation by Delta 9 - THC and in some control responses . Moreover , P21554 / CB2 involvement was observed in humoral responses requiring P25942 - initiated signaling for suppression by Delta 9 - THC .

Gender difference in the activity but not expression of estrogen receptors alpha and beta in human lung adenocarcinoma cells . The higher frequency of lung adenocarcinoma in women smokers than in men smokers suggests a role for gender-dependent factors in the etiology of lung cancer . We evaluated estrogen receptor ( ER ) alpha and beta expression and activity in human lung adenocarcinoma cell lines and normal lung fibroblasts . Q8N1N2 - length ERalpha and ERbeta proteins were expressed in all cell lines with higher ERbeta than ERalpha . Although estradiol ( E ( 2 ) ) binding was similar , E ( 2 ) stimulated proliferation only in cells from females , and this response was inhibited by anti-estrogens 4 - hydroxytamoxifen ( DB04468 ) and DB00947 . In contrast , E ( 2 ) did not stimulate replication of lung adenocarcinoma cells from males and DB04468 or ICI did not block cell proliferation . Similarly , transcription of an estrogen response element-driven reporter gene was stimulated by E ( 2 ) in lung adenocarcinoma cells from females , but not males . P06401 ( PR ) expression was increased by E ( 2 ) in two out of five adenocarcinoma cell lines from females , but none from males . E ( 2 ) decreased P12830 protein expression in some of the cell lines from females , as it did in MCF - 7 breast cancer cells , but not in the cell lines from males . Thus , ERalpha and ERbeta expression does not correlate with the effect of ER ligands on cellular activities in lung adenocarcinoma cells . On the other hand , coactivator Q15648 expression was higher in lung adenocarcinoma cells from females versus males and higher in adenocarcinoma cells than in normal human bronchial epithelial cells . Q15648 and other ER coregulators may contribute to differences in estrogen responsiveness between lung adenocarcinoma cells in females and males .