interacts_with DB00242?
Predictive molecular markers : has the time come for routine use in lung cancer ? Although some evidence exists to support the use of clinical factors such as performance status and weight loss to predict response and toxicity to therapy in non-small cell lung cancer ( NSCLC ) patients , researchers have shown little prospective data on the use of molecular markers to facilitate selection of specific chemotherapy or new molecularly targeted agents in this patient population . Breast cancer exemplifies the growing role that molecular markers are playing , not only as prognostic factors , but also in predicting response to targeted treatments such as hormonal therapy , and more recently , trastuzumab ( Herceptin ) . Although several studies have examined molecular markers in lung cancer and have shown promising potential value , these studies were retrospective and require prospective validation . To identify molecular markers that reliably predict response and to be able to individualize cytotoxic and targeted therapy for NSCLC patients are the ultimate goals of future trials . This article focuses on a selected number of promising markers under study in lung cancer , including those thought to play roles in response to DNA damaging chemotherapy ( excision repair cross-complementing [ P07992 ] , xeroderma pigmentosum group D [ P18074 ] ) , taxane resistance ( beta-tubulin III ) , antimetabolite therapy ( P23921 ) , irinotecan metabolism ( P22309 ) and epidermal growth factor receptor ( P00533 ) pathway inhibition . To date , none of these markers can be recommended for routine use in clinical practice . DB01098 , a new P04035 inhibitor , reduces the colonic inflammatory response in dextran sulfate sodium-induced colitis in mice . The aim of the present study was to elucidate the beneficial effects of rosuvastatin , a new P04035 inhibitor , on colonic mucosal damage and on the inflammatory response in a dextran sulfate sodium ( DSS ) colitis model . Acute colitis was induced using 8 % DSS in female BALB/c mice . Colonic mucosal inflammation was evaluated clinically , biochemically , and histologically . Mucosal protein contents and mRNA levels of tumor necrosis factor ( P01375 ) -alpha were determined by immunoassay and real time-PCR . The mRNA levels of endothelial nitric oxide synthase ( P29474 ) were determined by real-time PCR . Disease activity scores in DSS-induced colitis model mice , as determined by weight loss , stool consistency , and blood in stool , were significantly lower in the rosuvastatin-treated mice than in control mice . Shortening of the colon was significantly reversed by rosuvastatin . Increases in tissue-associated myeloperoxidase activity and thiobarbituric acid-reactive substances after DSS administration were both significantly inhibited by treatment with rosuvastatin . DB01098 also inhibited increases in intestinal P01375 protein and mRNA expression after DSS administration , respectively . The mucosal mRNA levels of P29474 were decreased after DSS administration , but preserved in mice treated with rosuvastatin . These results suggest that rosuvastatin prevents the development of DSS-induced colitis in mice via the inhibition of mucosal inflammatory responses associated with the preservation of P29474 transcription . Allele frequencies of single nucleotide polymorphisms ( SNPs ) in 40 candidate genes for gene-environment studies on cancer : data from population-based Japanese random samples . Knowledge of genetic polymorphisms in gene-environment studies may contribute to more accurate identification of avoidable risks and to developing tailor-made preventative measures . The aim of this study was to describe the allele frequencies of single nucleotide polymorphisms ( SNPs ) of select genes , which may be included in future gene-environment studies on cancer in Japan . SNP typing was performed on middle-aged Japanese men randomly selected from the general population in five areas of Japan . We genotyped and calculated allele frequencies of 153 SNPs located on 40 genes : P04798 , Q16678 , P11712 , P33261 , P05181 , P05093 , P11511 , P35869 , P03372 , Q92731 , ERRRG , P06401 , P07099 , P34913 , P37059 , P37058 , P28161 , P21266 , GSTT2 , P09211 , NAT1 , NAT2 , P21964 , P07327 , P00325 , P00326 , P05091 , P35228 , NOS3 , P01583 , P01584 , O15527 , P36639 [ P36639 ] , P14416 , P35462 , P21917 , P31645 , P04150 [ GCCR ] , P42898 , and P15559 . In the present study , the Japanese allele frequencies were verified by using nationwide population samples . Expression of the human concentrative nucleotide transporter 1 ( O00337 ) gene correlates with clinical response in patients affected by Waldenström 's Macroglobulinemia ( WM ) and small lymphocytic lymphoma ( SLL ) undergoing a combination treatment with 2-chloro-2'-deoxyadenosine ( DB00242 ) and DB00073 . PURPOSE : Resistance to nucleoside analogues agents is likely to be multifactorial and could involve a number of mechanisms affecting drug penetration , metabolism and targeting . In vitro studies of resistant human cell lines have confirmed that human concentrative nucleoside transporter 1 ( O00337 ) -deficient cells display resistance . EXPERIMENTAL DESIGN : We applied real-time PCR method to assess the mRNA expression of equilibrative and concentrative nucleoside transporter ( hENT1 , O00337 ) , deoxycytidine and deoxyguanosine kinase ( P27707 , Q16854 ) , 5'-nucleotidase ( 5'-NT ) , ribonucleotide reductase catalytic and regulatory ( P23921 , P31350 ) subunits in bone marrow cells from 32 patients with Waldenström 's Macroglobulinemia ( WM ) and small lymphocytic lymphoma ( SLL ) who received 2CdA-based chemotherapy . Responses to chemotherapy , were then correlated to the expression of these markers . RESULTS : All 32 patients enrolled expressed lower levels of O00337 as compared to healthy donors . In univariate analysis , lower expression level of O00337 ( p=0.0021 ) and P31350 ( p=0.02 ) correlated with response to chemotherapy . In particular , patients with low levels of O00337 achieved inferior clinical response . No significant correlation between these genes expression and age , stage of disease was found . This study suggests that nucleotidase expression levels can be used to identify subgroups of WM and SLL patients who will likely respond differently to a 2CdA-based therapy . Genetic variants associated with the risk of chronic obstructive pulmonary disease with and without lung cancer . Chronic obstructive pulmonary disease ( P48444 ) is a strong risk factor for lung cancer . Published studies about variations of genes encoding glutathione metabolism , DNA repair , and inflammatory response pathways in susceptibility to P48444 were inconclusive . We evaluated 470 single-nucleotide polymorphisms ( SNP ) from 56 genes of these three pathways in 620 cases and 893 controls to identify susceptibility markers for P48444 risk , using existing resources . We assessed SNP- and gene-level effects adjusting for sex , age , and smoking status . Differential genetic effects on disease risk with and without lung cancer were also assessed ; cumulative risk models were established . Twenty-one SNPs were found to be significantly associated with risk of P48444 ( P < 0.01 ) ; gene-based analyses confirmed two genes ( P48506 and P48637 ) and identified three additional genes ( Q9H4Y5 , P07992 , and P23921 ) . Carrying 12 high-risk alleles may increase risk by 2.7-fold ; eight SNPs altered P48444 risk without lung cancer by 3.1-fold and 4 SNPs altered the risk with lung cancer by 2.3-fold . Our findings indicate that multiple genetic variations in the three selected pathways contribute to P48444 risk through P48506 , P48637 , Q9H4Y5 , P07992 , and P23921 genes . Functional studies are needed to elucidate the mechanisms of these genes in the development of P48444 , lung cancer , or both . Cross-talk between PKA-Cβ and p65 mediates synergistic induction of Q07343 by roflumilast and NTHi . Phosphodiesterase 4B ( Q07343 ) plays a key role in regulating inflammation . DB01656 , a phosphodiesterase (PDE)4-selective inhibitor , has recently been approved for treating severe chronic obstructive pulmonary disease ( P48444 ) patients with exacerbation . However , there is also clinical evidence suggesting the development of tachyphylaxis or tolerance on repeated dosing of roflumilast and the possible contribution of Q07343 up-regulation , which could be counterproductive for suppressing inflammation . Thus , understanding how Q07343 is up-regulated in the context of the complex pathogenesis and medications of P48444 may help improve the efficacy and possibly ameliorate the tolerance of roflumilast . Here we show that roflumilast synergizes with nontypeable Haemophilus influenzae ( NTHi ) , a major bacterial cause of P48444 exacerbation , to up-regulate PDE4B2 expression in human airway epithelial cells in vitro and in vivo . Up-regulated PDE4B2 contributes to the induction of certain important chemokines in both enzymatic activity-dependent and activity-independent manners . We also found that protein kinase A catalytic subunit β ( PKA-Cβ ) and nuclear factor-κB ( NF-κB ) p65 subunit were required for the synergistic induction of PDE4B2 . PKA-Cβ phosphorylates p65 in a DB02527 -dependent manner . Moreover , Ser276 of p65 is critical for mediating the PKA-Cβ-induced p65 phosphorylation and the synergistic induction of PDE4B2 . Collectively , our data unveil a previously unidentified mechanism underlying synergistic up-regulation of PDE4B2 via a cross-talk between PKA-Cβ and p65 and may help develop new therapeutic strategies to improve the efficacy of DB05876 inhibitor . Potentiator ivacaftor abrogates pharmacological correction of ΔF508 P13569 in cystic fibrosis . Cystic fibrosis ( CF ) is caused by mutations in the CF transmembrane conductance regulator ( P13569 ) . Newly developed " correctors " such as DB09280 ( VX-809 ) that improve P13569 maturation and trafficking and " potentiators " such as ivacaftor ( VX-770 ) that enhance channel activity may provide important advances in CF therapy . Although VX-770 has demonstrated substantial clinical efficacy in the small subset of patients with a mutation ( G551D ) that affects only channel activity , a single compound is not sufficient to treat patients with the more common P13569 mutation , ΔF508 . Thus , patients with ΔF508 will likely require treatment with both correctors and potentiators to achieve clinical benefit . However , whereas the effectiveness of acute treatment with this drug combination has been demonstrated in vitro , the impact of chronic therapy has not been established . In studies of human primary airway epithelial cells , we found that both acute and chronic treatment with VX-770 improved P13569 function in cells with the G551D mutation , consistent with clinical studies . In contrast , chronic VX-770 administration caused a dose-dependent reversal of VX-809-mediated P13569 correction in ΔF508 homozygous cultures . This result reflected the destabilization of corrected ΔF508 P13569 by VX-770 , markedly increasing its turnover rate . Chronic VX-770 treatment also reduced mature wild-type P13569 levels and function . These findings demonstrate that chronic treatment with P13569 potentiators and correctors may have unexpected effects that can not be predicted from short-term studies . Combining these drugs to maximize rescue of ΔF508 P13569 may require changes in dosing and/or development of new potentiator compounds that do not interfere with P13569 stability . Novel DNA-binding properties of the RNA-binding protein TIAR . P31483 related protein binds avidly to uridine-rich elements in mRNA and pre-mRNAs of a wide range of genes , including interleukin ( IL ) -8 and vascular endothelial growth factor ( P15692 ) . The protein has diverse regulatory roles , which in part depend on the locus of binding within the transcript , including translational control , splicing and apoptosis . Here , we observed selective and potent inhibition of TIAR- Q96LT9 complex formation with P10145 and P15692 3'-untranslated regions ( 3'-UTRs ) using thymidine-rich deoxyoligonucleotide ( ODN ) sequences derived from the VEFG 3'-UTR . We show by ultraviolet crosslinking and electrophoretic mobility shift assays that TIAR can bind directly to single-stranded , thymidine-rich ODNs but not to double-stranded ODNs containing the same sequence . TIAR had a nearly 6-fold greater affinity for DNA than RNA ( K(d)app = 1.6x10(-9) M versus 9.4 x 10(-9) M ) . Truncation of TIAR indicated that the high affinity DNA-binding site overlaps with the RNA-binding site involving RNA recognition motif 2 ( P31350 ) . However , P23921 alone could also bind to DNA . Finally , we show that TIAR can be displaced from single-stranded DNA by active transcription through the binding site . These results provide a potential mechanism by which TIAR can shuttle between RNA and DNA ligands . 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 . DB00227 -stimulated superinduction of P16581 , P05362 and P19320 in P01375 activated human vascular endothelial cells . Inhibitors of P04035 ( statins ) reveal important pharmacological effects in addition to reducing the plasma LDL cholesterol level . In the pathogenesis of arteriosclerosis , transendothelial migration of various leukocytes including monocytes is a crucial step . We , therefore , investigated the expression of P16581 , intercellular cell adhesion molecule-1 ( P05362 ) and vascular cell adhesion molecule-1 ( P19320 ) in vascular endothelial cells as influenced by lovastatin . Human umbilical vein endothelial cells ( HUVECs ) express significant amounts of selectins and cell adhesion molecules ( CAMs ) within a few hours after stimulation with P01375 . This effect is potentiated by 100-200 % when the cells are pretreated with 0.1-2.5 microM lovastatin . The lovastatin-mediated increase in the cytoplasm and at the cell surface is dose-dependent and significant at lovastatin concentrations comparable to plasma levels in patients under lovastatin treatment . The lovastatin-potentiated increase of P16581 and CAMs is correlated with a corresponding increase of selectin- and P62158 -specific mRNA . We conclude that , in vivo , statin treatment could trigger an enhanced recruitment of macrophages that might support the cholesteryl ester efflux from the arteriosclerotic plaque . An association between P23921 haplotype and gemcitabine-induced neutropenia in breast cancer patients . PURPOSE : We examined the pattern of single-nucleotide polymorphisms ( SNPs ) of gemcitabine metabolism-related and target genes in breast cancer patients and evaluated their association with drug response or toxicity . PATIENTS AND METHODS : SNPs in deoxycytidine kinase ( P27707 ) , deoxycytidine monophosphate deaminase ( P32321 ) , and ribonucleotide reductase M1 polypeptide ( P23921 ) were analyzed with genomic DNA of 10 breast cancer cell lines , 74 peripheral blood mononuclear cell ( PBMC ) samples from advanced breast cancer patients treated with gemcitabine , and 56 PBMC samples from healthy volunteers . RESULTS : The incidences of SNPs of breast cancer patients were 1.4 % in P27707 ( 626 A > G ) , 10.8 % in P32321 ( 315 T > C ) , 40.5 % in the first P23921 ( 1082 C > A ) , 44.6 % in the second P23921 ( 2455 A > G ) , 44.6 % in the third P23921 ( 2464 G > A ) , and 23 % in two P23921 sites ( 2455 A > G and 2464 G > A ) that were similar to those of the normal control group . We found a double SNP of P23921 ( 2455 A > G and 2464 G > A ) to be the novel haplotype that was associated with a lower frequency of chemotherapy-induced toxicity , such as neutropenia ( p < .01 ) and G- P04141 requirement ( p < .005 ) . CONCLUSION : P23921 haplotype showed an association with susceptibility to gemcitabine monotherapy in breast cancer patients . Can a cocktail designed for phenotyping pharmacokinetics and metabolism enzymes in human be used efficiently in rat ? We recently designed the CIME cocktail consisting of 10 drugs to assess the activity of the major human CYPs ( P05177 , P10632 , P11712 , P33261 , P10635 and CYP3A ) , a phase II enzyme ( P22309 /6/9 ) , two drug transporters ( P-gp and Q9Y6L6 ) and a component of the renal function ( Videau et al. 2010 ) . The present work aimed at studying the usefulness of the CIME cocktail in the rat.The CIME cocktail was given per os to three male and three female rats , or incubated with rat liver microsomes . Parent substrates and metabolites were quantified by LC-MS/MS in plasma , urine and hepatic microsomal media , and phenotyping index were subsequently calculated.The CIME cocktail could therefore be used in the rat to phenotype rapidly and simultaneously CYP3A1/2 with omeprazole/omeprazole-sulfone , midazolam/1'-hydroxymidazolam or 4-hydroxymidazolam and/or dextromethorphan/3-methoxymorphinan , CYP2C6/11 with tolbutamide/4-hydroxytolbutamide , CYP2D1/2 with omeprazole/5-hydroxyomeprazole or dextromethorphan/dextrorphan , and P19224 /7 with acetaminophen/acetaminophen-glucuronide . Our results confirmed also several known gender differences and brought new information on the urinary excretion of rosuvastatin . However , the major rat CYPs , CYP2C11 and CYP2C12 , are not specifically assessed . An optimized version of the CIME cocktail should therefore be designed and would be of major importance to more largely phenotype Q09013 enzymes in rats to study Q09013 variability factors such as disease , age , or to exposure to inductors or inhibitors . Metabolism of risperidone to 9-hydroxyrisperidone by human cytochromes P450 2D6 and 3A4 . DB00734 is a relatively new antipsychotic drug that has been reported to improve both the positive and the negative symptoms of schizophrenia and produces relatively few extrapyramidal side effects at low doses . Formation of 9-hydroxyrisperidone , an active metabolite , is the most important metabolic pathway of risperidone in human . In the present study , in vitro metabolism of risperidone ( 100 microM ) was investigated using the recombinant human cytochrome P450 ( CYP ) enzymes P04798 , P05177 , P10632 , P11712 -arg144 , P11712 -cys144 , P33261 , P10635 , P08684 and P20815 supplemented with an NADPH-generating system . DB01267 was determined by a new HPLC method with an Hypersil CN column and a UV detector . Of these enzymes , CYPs 2D6 , 3A4 and 3A5 were found to be the ones capable of metabolising risperidone to 9-hydroxyrisperidone , with activities of 7.5 , 0.4 and 0.2 pmol pmol(-1) CYP min(-1) , respectively . A correlation study using a panel of human liver microsomes showed that the formation of 9-hydroxyrisperidone is highly correlated with P10635 and 3A activities . Thus , both P10635 and 3A4 are involved in the 9-hydroxylation of risperidone at the concentration of risperidone used in this study . This observation is confirmed by the findings that both quinidine ( inhibitor of P10635 ) and ketoconazole ( inhibitor of P08684 ) can inhibit the formation of 9-hydroxyrisperidone . Furthermore , inducers of CYP can significantly increase the formation of 9-hydroxyrisperidone in rat . The formation of 9-hydroxyrisperidone is highly correlated with testosterone 6beta-hydroxylase activities , suggesting that inducible CYP3A contributes significantly to the metabolism of risperidone in rat . Protective effects of metallothionein on isoniazid and rifampicin-induced hepatotoxicity in mice . Isoniazid ( DB00951 ) and DB01045 ( RFP ) are widely used in the world for the treatment of tuberculosis , but the hepatotoxicity is a major concern during clinical therapy . Previous studies showed that these drugs induced oxidative stress in liver , and several antioxidants abated this effect . Metallothionein ( MT ) , a member of cysteine-rich protein , has been proposed as a potent antioxidant . This study attempts to determine whether endogenous expression of MT protects against DB00951 and RFP-induced hepatic oxidative stress in mice . Wild type ( MT+/+ ) and MT-null ( MT-/- ) mice were treated intragastrically with DB00951 ( 150 mg/kg ) , RFP ( 300 mg/kg ) , or the combination ( 150 mg/kg DB00951 +300 mg/kg RFP ) for 21 days . The results showed that MT-/- mice were more sensitive than MT+/+ mice to DB00951 and RFP-induced hepatic injuries as evidenced by hepatic histopathological alterations , increased serum Q9NRA2 levels and liver index , and hepatic oxidative stress as evidenced by the increase of MDA production and the change of liver antioxidant status . Furthermore , DB00951 increased the protein expression of hepatic P05181 and DB00951 /RFP ( alone or in combination ) decreased the expression of hepatic P05177 . These findings clearly demonstrate that basal MT provides protection against DB00951 and RFP-induced toxicity in hepatocytes . The P05181 and P05177 were involved in the pathogenesis of DB00951 and RFP-induced hepatotoxicity . Neurotoxic effects of Q13148 overexpression in C. elegans . RNA-binding protein Q13148 has been associated with multiple neurodegenerative diseases , including amyotrophic lateral sclerosis and frontotemporal lobar dementia . We have engineered pan-neuronal expression of human Q13148 protein in Caenorhabditis elegans , with the goal of generating a convenient in vivo model of Q13148 function and neurotoxicity . Transgenic worms with the neuronal expression of human Q13148 exhibit an ' uncoordinated ' phenotype and have abnormal motorneuron synapses . Caenorhabditis elegans contains a single putative ortholog of Q13148 , designated TDP-1 , which we show can support alternative splicing of P13569 in a cell-based assay . Neuronal overexpression of TDP-1 also results in an uncoordinated phenotype , while genetic deletion of the tdp-1 gene does not affect movement or alter motorneuron synapses . By using the uncoordinated phenotype as a read-out of Q13148 overexpression neurotoxicty , we have investigated the contribution of specific Q13148 domains and subcellular localization to toxicity . Q8N1N2 -length ( wild-type ) human Q13148 expressed in C. elegans is localized to the nucleus . Deletion of either RNA recognition domain ( P23921 or P31350 ) completely blocks neurotoxicity , as does deletion of the C-terminal region . These deleted Q13148 variants still accumulate in the nucleus , although their subnuclear distribution is altered . Interestingly , fusion of TDP-1 C-terminal sequences to Q13148 missing its C-terminal domain restores normal subnuclear localization and toxicity in C. elegans and P13569 splicing in cell-based assays . Overexpression of wild-type , full-length Q13148 in mammalian cells ( differentiated M17 cells ) can also result in cell toxicity . Our results demonstrate that in vivo Q13148 neurotoxicity can result from nuclear activity of overexpressed full-length protein . An ordered NotI fragment map of human chromosome band 11p15 . An ordered NotI fragment map containing over 60 loci and encompassing approximately 17 Mb has been constructed for human chromosome band 11p15 . Forty-two probes , including 11 NotI-linking cosmids , were subregionally mapped to 11p15 using a subset of the J1-deletion hybrids . These and 23 other probes defining loci previously mapped to 11p15 were hybridized to genomic DNA digested with NotI and 5 other infrequently cleaving restriction enzymes and separated by pulsed-field gel electrophoresis . Thirty-nine distinct NotI fragments were detected encompassing approximately 85 % of the estimated length of 11p15 . The predicted order of the gene loci used is cen- P15172 -PTH-CALCA- P78524 - P25800 - P02790 - P68871 - P23921 -TH/ P01308 / P01344 -H19- P07339 - Q02817 - P21917 - P01112 - P13489 -tel . This map will allow higher resolution mapping of new 11p15 markers , facilitate positional cloning of disease genes , and provide a framework for the physical mapping of 11p15 in clone contigs . Stage-dependent inhibition of Plasmodium falciparum by potent Ca2+ and calmodulin modulators . The effects of Ca2+ channel blockers , verapamil , nicardipine and diltiazem , and of potent calmodulin ( P62158 ) inhibitors , trifluoperazine ( Q9HCM9 ) , calmidazolium , W-7 and W-5 , on Plasmodium falciparum in culture were examined . Among Ca2+ blockers , nicardipine was the most potent with the 50 % inhibitory concentration ( IC50 ) of 4.3 microM at 72 h after culture . Parasites were more sensitive to calmidazolium and W-7 with IC50 of 3.4 and 4.5 microM , respectively , than to Q9HCM9 and W-5 . All Ca2+ blockers and P62158 inhibitors suppressed parasite development at later stages . DB00622 , diltiazem , calmidazolium and W-5 also retarded parasite development at earlier stages and/or subsequent growth following pretreatment . Verapamil , nicardipine , Q9HCM9 and calmidazolium reduced erythrocyte invasion by merozoites . Fluorescence microscopy with the cationic fluorescent dye rhodamine 123 revealed that nicardipine , Q9HCM9 and calmidazolium depolarized both the plasma membrane and mitochondrial membrane potentials of the parasite . It is therefore considered that although all Ca2+ and P62158 antagonists tested here influence parasite development at later stages , they are multifunctional , having effects not directly associated with Ca2+ channels or P62158 . Role of adhesion glycoproteins P05107 and intercellular adhesion molecule-1 in complement-mediated reactions of rabbit skin . 1. The role of the adhesion glycoproteins P05107 and intercellular adhesion molecule-1 ( P05362 ) in inflammatory responses produced during a reversed passive Arthus ( RPA ) reaction and induced by zymosan and zymosan-activated plasma ( Q7Z2W4 ) were studied in rabbit skin . 2 . Oedema formation and haemorrhage were quantified by measuring accumulation of 125I-albumin and 111In-labelled red blood cells ( 111In-RBC ) respectively . 3 . Monoclonal antibody ( mAb ) R15.7 ( anti- P05107 ) , administered intravenously , abolished accumulation of 125I-albumin and 111In-RBC in dermal RPA reactions and in response to locally injected zymosan and Q7Z2W4 . 4 . When administered intravenously , the mAb P23921 /1 ( anti- P05362 ) suppressed 125I-albumin and 111In-RBC accumulation in dermal RPA reactions and at sites treated with zymosan and Q7Z2W4 . 5 . Oedema formation in response to platelet-activating factor ( Q15004 ) and bradykinin ( BK ) either in the presence or absence of prostaglandin E2 ( DB00917 ) were not affected by mAb R15.7 or by mAb P23921 /1.1.1 . 6 . We conclude that oedema formation and haemorrhage associated with RPA reactions and in responses to zymosan and Q7Z2W4 are completely P05107 -dependent , and are mediated , at least in part , via P05362 . Responses to the neutrophil-independent oedema forming mediators , Q15004 and BK are not dependent upon P05107 or P05362 . Cytokine regulation of intercellular adhesion molecule-1 ( P05362 ) expression on human glioblastoma cells . Intercellular adhesion molecule-1 ( P05362 ) has recently been identified as one of the ligands for lymphocyte function-associated antigen-1 ( LFA-1 ) . Immunohistochemical staining of frozen tissue sections using the P05362 antibody P23921 /1 demonstrated significant levels of P05362 expression on human glioblastoma cells and on intratumoural vascular endothelial cells . P05362 was weakly expressed or absent from low grade gliomas and absent from normal and fetal brain . P05362 expression was similar to that of MHC class II . HLA-DR antigens . Glioblastoma cell lines constitutively expressed P05362 to a minimal or moderate extent . Surface antigen expression of P05362 and P05362 -specific mRNA could be significantly increased by incubating glioblastoma cells with interleukin-1 beta ( P01584 ) , tumour necrosis factor-alpha ( P01375 ) , and interferon-gamma ( P01579 ) . P60568 , P05112 , P05231 and transforming growth factor beta 2 ( TGF-beta 2 ) had no significant effect on surface antigen expression . Significant enhancement of P05362 expression was obtained using P01375 and P01584 at 1-10 U/ml and at 500 U/ml of P01579 . Induction of P05362 specific mRNA was observed 4 h after cytokine treatment and decreased by 24 h . Surface antigen expression of P05362 increased for up to 48 h after treatment . Effect of acetazolamide on aquaporin-1 and fluid flow in cultured choroid plexus . DB00819 ( AZA ) , used in treatment of early or infantile hydrocephalus , is effective in some cases , while its effect on the choroid plexus ( CP ) remains ill-defined . The drug reversibly inhibits aquaporin-4 ( P55087 ) , the most ubiquitous " water pore " in the brain , and perhaps modulation of P29972 ( located apically on CP cells ) by AZA may reduce cerebrospinal fluid ( P04141 ) production . We sought to elucidate the effect of AZA on P29972 and fluid flow in CP cell cultures.CP tissue culture from 10-day Sprague-Dawley rats and a TRCSF-B cell line were grown on Transwell permeable supports and treated with 100 μM AZA . Fluid assays to assess direction and extent of fluid flow , and P29972 expression patterns by immunoblot , Immuncytochemistry ( ICC ) , and quantitative reverse transcriptase polymerase chain reaction ( qRT-PCR ) were performed.Immunoblots and ICC analyses showed a decrease in P29972 protein shortly after AZA treatment ( lowest at 12 h ) , with transient P29972 reduction mediated by mRNA expression ( lowest at 6 h ) . Transwell fluid assays indicated a fluid shift at 2 h , before significant changes in P29972 mRNA or protein levels.Timing of AZA effect on P29972 suggests the drug alters protein transcription , while affecting fluid flow by a concomitant method . It is plausible that other mechanisms account for these phenomena , as the processes may occur independently . DB08879 -- an anti- Q9Y275 human monoclonal antibody for rheumatoid arthritis . INTRODUCTION : Q9Y275 ( Q9Y275 ) is a major regulatory factor that controls the development and survival of B cells . Elevated serum levels of Q9Y275 have been associated with rheumatoid arthritis ( RA ) . DB08879 is a fully human monoclonal antibody that inhibits Q9Y275 and it is being developed for the treatment of RA . This review aims to summarize up-to-date pharmacological and clinical data of belimumab in the treatment of RA . AREAS COVERED : A literature search was performed on PubMed using keywords , including belimumab , LymphoStat-B , benlysta , Q9Y275 inhibitor , rheumatoid arthritis and autoimmune disease . References of relevant studies were searched by hand . Abstracts of international conferences up to October 2012 were also included . DB08879 was well tolerated in the treatment of RA over 24 weeks . It significantly increased American College of Rheumatology ( P10323 )20 responses at week 24 , especially in patients with high disease activity , positive rheumatoid factor , no anti- P01375 treatment experience and those who had failed methotrexate therapy . However , belimumab failed to demonstrate significantly improved ACR50 and ACR70 responses in the single Phase II clinical trial of RA . EXPERT OPINION : These results suggest that the clinical efficacy of belimumab for RA needs to be further investigated in future clinical trials . Careful patient selection may be necessary for belimumab to achieve optimal clinical outcomes in RA .