interacts_with DB01101?
Association and interactions between DNA repair gene polymorphisms and adult glioma . It is generally accepted that glioma develops through accumulation of genetic alterations . We hypothesized that polymorphisms of candidate genes involved in the DNA repair pathways may contribute to susceptibility to glioma . To address this possibility , we conducted a study on 373 Caucasian glioma cases and 365 cancer-free Caucasian controls to assess associations between glioma risk and 18 functional single-nucleotide polymorphisms in DNA repair genes . We evaluated potential gene-gene and gene-environment interactions using a multianalytic strategy combining logistic regression , multifactor dimensionality reduction and classification and regression tree approaches . In the single-locus analysis , six single-nucleotide polymorphisms [ P07992 3' untranslated region ( UTR ) , P18887 R399Q , P27695 E148D , P09874 A762V , P16455 F84L , and LIG1 5'UTR ] showed a significant association with glioma risk . In the analysis of cumulative genetic risk of multiple single-nucleotide polymorphisms , a significant gene-dosage effect was found for increased glioma risk with increasing numbers of adverse genotypes involving the aforementioned six single-nucleotide polymorphisms ( P(trend) = 0.0004 ) . Furthermore , the multifactor dimensionality reduction and classification and regression tree analyses identified P16455 F84L as the predominant risk factor for glioma and revealed strong interactions among ionizing radiation exposure , P09874 A762V , P16455 F84L , and P27695 E148D . Interestingly , the risk for glioma was dramatically increased in ionizing radiation exposure individuals who had the wild-type genotypes of P16455 F84L and P09874 A762V ( adjusted odds ratios , 5.95 ; 95 % confidence intervals , 2.21-16.65 ) . Taken together , these results suggest that polymorphisms in DNA repair genes may act individually or together to contribute to glioma risk . Analysis of over 10,000 Cases finds no association between previously reported candidate polymorphisms and ovarian cancer outcome . BACKGROUND : Ovarian cancer is a leading cause of cancer-related death among women . In an effort to understand contributors to disease outcome , we evaluated single-nucleotide polymorphisms ( SNP ) previously associated with ovarian cancer recurrence or survival , specifically in angiogenesis , inflammation , mitosis , and drug disposition genes . METHODS : Twenty-seven SNPs in P40337 , P14210 , Q14116 , P22694 , P08183 , P10632 , P18074 , and P07992 previously associated with ovarian cancer outcome were genotyped in 10,084 invasive cases from 28 studies from the Ovarian Cancer Association Consortium with over 37,000-observed person-years and 4,478 deaths . Cox proportional hazards models were used to examine the association between candidate SNPs and ovarian cancer recurrence or survival with and without adjustment for key covariates . RESULTS : We observed no association between genotype and ovarian cancer recurrence or survival for any of the SNPs examined . CONCLUSIONS : These results refute prior associations between these SNPs and ovarian cancer outcome and underscore the importance of maximally powered genetic association studies . Q9P2X3 : These variants should not be used in prognostic models . Alternate approaches to uncovering inherited prognostic factors , if they exist , are needed . Poly( DB02059 )polymerase-1 signalling of the DNA damage induced by P11387 poison in D54(p53wt) and U251(p53mut) glioblastoma cell lines . Glioblastomas are widely characterised by the mutation of the p53 gene and p53 disruption sensitizes glioblastoma cells to P11387 ( TOPO I ) inhibitor-mediated apoptosis . We investigated the effects of combined treatments with the P11387 inhibitor DB01030 and the poly( DB02059 )polymerase-1 inhibitor DB02690 in D54(p53wt) and U251(p53mut) glioblastoma cell lines . Analysis of cell growth and cell cycle kinetics showed a synergistic anti-proliferative effect of 10 nM TPT and 10 microM DB02690 and a G2/M block of the cell cycle . We also evaluated , the influence of TPT+/- DB02690 treatment on P09874 and p53 activity . We got evidences of a TPT-dependent increase of P09874 auto-modification level in both the cells . Moreover , in the D54(p53wt) cells we found that in co-treatments DB02690 incremented the TPT-dependent stimulation of p53 transcriptional activity and increased the P38936 nuclear amount . Conversely , in U251(p53mut) cells we found that DB02690 incremented the TPT-dependent apoptosis characterised by P09874 proteolysis . Our findings suggest that the modulation of P09874 can be considered a strategy in the potentiation of the chemotherapeutic action of TOPO I poisons in glioblastoma cells apart from their p53 status . Celecoxib with chemotherapy in colorectal cancer . P35354 ( P35354 ) is the enzyme that normally synthesizes prostaglandins during an inflammatory response . Many primary and metastatic cancers express P35354 , and its presence is correlated with tumor angiogenesis , more invasive tumor phenotype , resistance to apoptosis , and systemic immunosuppression . The expression of P35354 is associated with a worse prognosis . Inhibition of prostaglandin synthesis may be beneficial in human malignancy . Regular consumption of nonsteroidal anti-inflammatory drugs ( NSAIDs ) decreases the incidence of , and mortality rate resulting from , a number of types of gastrointestinal cancers . Premalignant colonic lesions regress following the administration of nonspecific P36551 inhibitors , such as sulindac ( DB00605 ) . Advanced solid tumor patients treated with indomethacin ( DB00328 ) survive twice as long as do such patients who receive supportive care alone . The U.S . Food and Drug Administration has approved specific P35354 inhibitors for the treatment of arthritis , pain , and familial adenomatous polyposis . Preclinical studies show that these drugs block angiogenesis , suppress solid tumor metastases , and slow the growth of implanted gastrointestinal cancer cell lines . The P35354 inhibitors have safely and effectively been combined with chemotherapeutic agents in experimental studies . Ongoing clinical trials are currently assessing the potential therapeutic role of P35354 inhibitors in both prevention and treatment of a diverse range of human cancers . Kinin-B2 receptor exerted neuroprotection after diisopropylfluorophosphate-induced neuronal damage . The kinin-B2 receptor ( B2BKR ) activated by its endogenous ligand bradykinin participates in various metabolic processes including the control of arterial pressure and inflammation . Recently , functions for this receptor in brain development and protection against glutamate-provoked excitotoxicity have been proposed . Here , we report neuroprotective properties for bradykinin against organophosphate poisoning using acute hippocampal slices as an in vitro model . Following slice perfusion for 10min with diisopropylfluorophosphate ( DB00677 ) to initiate the noxious stimulus , responses of pyramidal neurons upon an electric impulse were reduced to less than 30 % of control amplitudes . Effects on synaptic-elicited population spikes were reverted when preparations had been exposed to bradykinin 30min after challenging with DB00677 . Accordingly , bradykinin-induced population spike recovery was abolished by HOE-140 , a B2BKR antagonist . However , the kinin-B1 receptor ( B1BKR ) agonist Lys-des- DB00125 (9)-bradykinin , inducing the phosphorylation of mitogen-activated protein kinase ( MEK/MAPK ) and cell death , abolished bradykinin-mediated neuroprotection , an effect , which was reverted by the P29323 inhibitor PD98059 . In agreement with pivotal B1BKR functions in this process , antagonism of endogenous B1BKR activity alone was enough for restoring population spike activity . On the other hand pralidoxime , an oxime , reactivating acetylcholinesterase ( P22303 ) after organophosphate poisoning , induced population spike recovery after DB00677 exposure in the presence of bradykinin and Lys-des- DB00125 (9)-bradykinin . Lys-des- DB00125 (9)-bradykinin did not revert protection exerted by pralidoxime , however when instead bradykinin and Ly-des- DB00125 (9)-bradykinin were superfused together , recovery of population spikes diminished . These findings again confirm the neuroprotective feature of bradykinin , which is , diminished by its endogenous metabolites , stimulating the B1BKR , providing a novel understanding of the physiological roles of these receptors . Role of Q14116 in overt pain-like behaviour in mice . There are evidences that targeting Q14116 might be beneficial to inhibit inflammatory symptoms , including hypernociception ( decrease in nociceptive threshold ) . The mechanism of Q14116 mechanical hypernociception depends on endothelin in rats and mice . However , the role of Q14116 in overt pain-like behaviour remains undetermined . Therefore , we addressed the role of Q14116 in writhing response induced by intraperitoneal ( i.p. ) injection of phenyl-p-benzoquinone ( PBQ ) and acetic acid in mice . Firstly , it was detected that PBQ and acetic acid i.p. injection induced a dose-dependent number of writhes in Balb/c mice . Subsequently , it was observed that the PBQ - but not the acetic acid-induced writhes were diminished in Q14116 deficient ( ( -/- ) ) mice . Therefore , considering that P01579 , endothelin and prostanoids mediate Q14116 -induced mechanical hypernociception , we also investigated the role of these mediators in the same model of writhing response in which Q14116 participates . It was noticed that PBQ-induced writhes were diminished in P01579 (-/-) mice and by the treatment with DB00559 ( mixed endothelin P25101 /ETB receptor antagonist ) , BQ 123 ( cyclo[DTrp-DAsp-Pro-DVal- DB00149 ] , selective endothelin P25101 receptor antagonist ) , BQ 788 ( N-cys-2,6 dimethylpiperidinocarbonyl-l-methylleucyl-d-1-methoxycarboyl-d-norleucine , selective endothelin ETB receptor antagonist ) or indomethacin ( cycloxigenase inhibitor ) . Thus , Q14116 , P01579 , endothelin acting on endothelin P25101 and ETB receptors , and prostanoids mediate PBQ-induced writhing response in mice . To conclude , these results further advance the understanding of the physiopathology of overt pain-like behaviour , and suggest for the first time a role for Q14116 in writhing response in mice . Evaluation of a microarray for genotyping polymorphisms related to xenobiotic metabolism and DNA repair . We present an oligonucleotide microarray ( " MetaboChip " ) based on the arrayed primer extension ( P27695 ) technique , allowing genotyping of single nucleotide polymorphisms ( SNPs ) in genes of interest for cancer susceptibility and pharmacogenetics . P27695 consists of a sequencing reaction primed by an oligonucleotide anchored with its 5' end to a glass slide and terminating one nucleotide before the polymorphic site . The extension with one fluorescently labeled dideoxynucleotide complementary to the template reveals the polymorphism . Ninety-three SNPs in 42 genes were selected among those resequenced in the context of the SNP500 project , using a set of 102 reference DNA samples from the Coriell Biorepository . Selected SNPs belong to the following genes : P00325 , P05091 , P27695 , CDKN2A , P21964 , P04798 , P05177 , Q16678 , P11509 , P33261 , P11712 , P05181 , P08684 , P14416 , P21917 , P07099 , P07992 , P18074 , Q92889 , P28715 , P30550 , O15217 , P21266 , P09211 , GSTT2 , LIG3 , Q00987 , P16455 , P05164 , NAT1 , NAT2 , P15559 , O15527 , P12004 , P06746 , Q01959 , P04179 , P04637 , P18887 , O43543 , O43542 , and O15287 . We assessed the performance of P27695 by comparing the results obtained with MetaboChip against those reported by the SNP500 . Among 88 SNPs that yielded signals , 6 showed less than 99 % of concordance , whereas 82 performed accurately , showing that P27695 is a reliable and sensitive genotyping method . Determination of fenofibric acid concentrations by HPLC after anion exchange solid-phase extraction from human serum . Triglycerides are increasingly being recognized as a risk factor for cardiovascular disease . Research efforts to identify sources of variability in triglyceride-lowering response to the lipid-lowering drug fenofibrate require quantification of the active acidic form of this Q07869 agonist . Anion-exchange solid-phase extraction , in combination with reverse-phase high-performance liquid chromatography ( HPLC ) , rapidly and accurately determines steady-state fenofibric acid serum concentrations . Chromatographic separation under isocratic conditions , with use of ultraviolet detection at 285 nm , provides clean baseline and sharp peaks for clofibric acid , 1-napthyl acetic acid ( internal standards ) , and fenofibric acid . Commonly prescribed and over-the-counter nonsteroidal anti-inflammatory drugs ( NSAIDs ) were screened for assay interference , and the assay was employed to quantify fenofibric acid in more than 800 human subject specimens . DB01039 analysis was found to be linear over the range of 0.5 to 40 mg/L and was validated with either internal standard . Accuracies ranged from 98.65 % to 102.4 % , whereas the within- and between-day precisions ranged from 1.0 % to 2.2 % and 2.0 % to 6.2 % , respectively . NSAIDs had minimal interference with the assay , which succeeded in quantifying fenofibric acid in more than 843 of 846 serum samples from human subjects , many taking a variety of coadministered medications . Anion-exchange solid-phase extraction in combination with reverse-phase HPLC accurately determines steady-state fenofibric acid serum concentrations in humans without interference from NSAIDs or commonly administered medications . This method is suitable for quantification of fenofibric acid for clinical pharmacokinetic studies in patients with dyslipidemia . Fucoxanthin enhances cisplatin-induced cytotoxicity via NFκB-mediated pathway and downregulates DNA repair gene expression in human hepatoma HepG2 cells . Cisplain , a platinum-containing anticancer drug , has been shown to enhance DNA repair and to inhibit cell apoptosis , leading to drug resistance . Thus , the combination of anticancer drugs with nutritional factors is a potential strategy for improving the efficacy of cisplatin chemotherapy . In this study , we investigated the anti-proliferative effects of a combination of fucoxanthin , the major non-provitamin A carotenoid found in Undaria Pinnatifida , and cisplatin in human hepatoma HepG2 cells . We found that fucoxanthin ( 1-10 μΜ ) pretreatment for 24 h followed by cisplatin ( 10 μΜ ) for 24 h significantly decreased cell proliferation , as compared with cisplatin treatment alone . Mechanistically , we showed that fucoxanthin attenuated cisplatin-induced NFκB expression and enhanced the NFκB-regulated Bax/Bcl-2 mRNA ratio . DB00515 alone induced mRNA expression of excision repair cross complementation 1 ( P07992 ) and thymidine phosphorylase ( TP ) through phosphorylation of P29323 , p38 and PI3K/AKT pathways . However , fucoxanthin pretreatment significantly attenuated cisplatin-induced P07992 and TP mRNA expression , leading to improvement of chemotherapeutic efficacy of cisplatin . The results suggest that a combined treatment with fucoxanthin and cisplatin could lead to a potentially important new therapeutic strategy against human hepatoma cells . 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 . Molecular characterisation of a panel of human ovarian carcinoma xenografts . In a panel of 16 human ovarian tumours transplanted in nude mice , the expression of genes involved in cell cycle regulation and in response to drug treatment were characterised . In the 16 tumours analysed we could not detect overexpression of Erb-B2 oncogene while expression of P08183 mRNA was not detected in 11/15 samples and was low in 4/15 tumours . Only three tumours had mutations in the p53 gene exons 5-8 and one of these mutations did not result in any amino acid alteration . The levels of mRNA for cyclins A , D1 and E were heterogeneous with some tumours expressing high levels and others not expressing them at all . The same was found for the cyclin dependent kinases ( CDK ) P24941 and P11802 and for CDK inhibitors P38936 / P38936 , p27/ P46527 and p16/CDKN2 . Two genes belonging to the nucleotide excision repair , P07992 and P19447 were detectable in all the samples examined , as were the genes P16455 and P20916 , also involved in DNA repair . The data indicate a heterogeneity in the expression of genes considered to be involved in the cellular responses to cytotoxic drug treatment and indicate the possibility of using these tumour models to test specifically molecules with a defined mechanism of action . Blood-based P32297 single nucleotide polymorphism and outcome in advanced non-small-cell lung cancer patients . DB00184 acetylcholine receptors ( nAChRs ) are associated with resistance to gemcitabine , cisplatin and paclitaxel in non-small-cell lung cancer ( NSCLC ) cell lines . Three single nucleotide polymorphisms ( SNPs ) of P32297 , P30532 and LOC123688 increase lung cancer risk . These SNPs may have influenced outcome in patients treated in our phase III trial . Stage IV NSCLC patients were treated with customized chemotherapy based on P07992 ( excision repair cross-complementing 1 ) mRNA expression . Patients in the control arm received docetaxel/cisplatin ; patients in the genotypic arm with low levels of P07992 received docetaxel/cisplatin ; patients in the genotypic arm with high levels of P07992 received docetaxel/gemcitabine . DNA was extracted from lymphocytes , and P32297 ( rs1051730 ) , P30532 ( rs16969968 ) and LOC123688 ( rs8034191 ) SNPs were genotyped with the Taqman allele discrimination assay . A significant interaction was found for P32297 and PS ( P=0.02 ) . In patients with PS 0 , CT patients had a better response than both CC ( P=0.01 ) and TT ( P=0.02 ) patients , and patients in the low genotypic group also had a better response ( P=0.01 ) . When the P32297 genotype was added in the multivariate analysis for progression-free survival , an improvement was observed in the low genotypic group in PS 0 patients ( P=0.02 ) . PS 0 patients in the low genotypic group with the CT genotype attained an 84 % response rate , 12.1-month progression-free survival , and 19-month median survival . P32297 ( rs1051730 ) genotyping can improve customized chemotherapy based on tumor assessment of P07992 mRNA in stage IV NSCLC with PS 0 . Phase II study of weekly intravenous oxaliplatin combined with oral daily capecitabine and radiotherapy with biologic correlates in neoadjuvant treatment of rectal adenocarcinoma . PURPOSE : To evaluate the efficacy of a combination of capecitabine , oxaliplatin , and radiotherapy ( RT ) in the neoadjuvant treatment of Stage II and III rectal cancers . METHODS : DB01101 was given at 725 mg/m(2) orally twice daily Monday through Friday concurrently with RT . DB00526 was given intravenously at 50 mg/m(2) once weekly five times starting the first day of RT . The radiation dose was 50.4 Gy in 28 fractions ( 1.8 Gy/fraction ) , five fractions weekly . Endorectal tumor biopsies were obtained before treatment and on the third day of treatment to explore the effects of treatment on thymidine phosphorylase , thymidylate synthase , excision repair cross-complementing rodent repair deficiency complementation group 1 ( P07992 ) , and apoptosis . RESULTS : A total of 25 patients were enrolled in this study ; 6 patients ( 24 % ) had a complete pathologic response . T-downstaging occurred in 52 % of patients , and N-downstaging occurred in 53 % . Grade 3 diarrhea was the most common Grade 3-4 toxicity , occurring in 20 % of patients . Only 2 patients experienced disease recurrence , with a median of 20 months of follow-up . P04818 , thymidine phosphorylase , P07992 , and apoptosis did not vary significantly between the pretreatment and Day 3 tumor biopsies , nor did they predict for T-downstaging or a complete pathologic response . CONCLUSION : DB01101 at 725 mg/m(2) orally twice daily , oxaliplatin 50 mg/m(2)/wk , and RT at 50.4 Gy is an effective neoadjuvant combination for Stage II and III rectal cancer and results in a greater rate of complete pathologic responses than historically shown in fluoropyrimidine plus RT controls . The potential role of PD0332991 ( DB09073 ) in the treatment of multiple myeloma . INTRODUCTION : Multiple myeloma ( MM ) remains an incurable malignancy indicating a need for continued investigation of novel therapies . Recent studies have highlighted the role of cyclin-dependent kinases ( CDK ) in the pathogenesis of MM . PD0332991 ( DB09073 ) is an orally bioavailable , highly selective inhibitor of the P11802 /6-cyclin complex and downstream retinoblastoma protein ( Rb ) activation pathway that induces cell cycle arrest in the P55008 phase . AREAS COVERED : In this review , the authors summarize the role of the P11802 /6 signaling pathway in MM . They also summarize the development of PD0332991 as a specific inhibitor of P11802 /6 , and the reported preclinical and clinical data supporting the potential role of PD0332991 in MM . EXPERT OPINION : While PD0332991 is essentially cytostatic , inducing prolonged P55008 arrest , it enhances the cytotoxic effect of other agents effective in MM , including bortezomib and lenalidomide , as confirmed in early phase clinical trials . However , with a plethora of other drugs of different classes being tested in MM , further development of PD0332991 will depend on defining the most efficacious combination with least toxicity . An unexplored opportunity remains the potential protective effect of PD0332991 against lytic bone lesions of MM . The next few years are likely to better define the place of PD0332991 in the treatment of MM . Specific Biomarkers Are Associated with Docetaxeland Gemcitabine-Resistant NSCLC Cell Lines . Five-year survival rate for lung cancer is limited to 10 % to 15 % . Therefore , the identification of novel therapeutic prognostic factors is an urgent requirement . The aim of this study is thus to highlight specific biomarkers in chemoresistant non-small cell lung cancer cell lines . Therefore , we checked-in the control condition as well as after short-term pharmacological treatment with either docetaxel or gemcitabine-the expression of genes such as tumor suppressor genes ( CDKN2A , P53355 , P49789 , P09211 , P16455 , RARβ2 , RASSF1A , and P35625 ) , genes associated with drug resistance ( P38398 , P35354 , P07992 , P17936 , P23921 , and Q13509 ) , and stemness-related genes ( CD133 , Q01860 , and O43623 ) in two cellular models of squamous carcinoma ( CAEP ) and adenocarcinoma ( RAL ) of the lung originally established . Their promoter methylation profile was also evaluated . Drug-related genes were upregulated . DB00515 resistance matched with high levels of P38398 and P07992 in both cell lines ; docetaxel sensitivity of CAEP cells was associated to levels of Q13509 lower than RAL cells . Although CAEP cells were more sensitive to gemcitabine , both cell lines showed high levels of P23921 . Stemness-related genes were downregulated in the control condition but became upregulated in docetaxel-resistant cells , indicating the selection of a population with stemness features . We did not find an unequivocal correspondence between gene expression and respective DNA promoter methylation status , suggesting the involvement of additional mechanisms of gene expression regulation . These results highlight specific biomarkers consistent with the different responses of the two cell lines to standard pharmacological treatments and indicate specific molecular traits for their chemoresistance . Combined effect of rapamycin and cisplatin on survival of Hep-2 cells in vitro . The cytotoxic effects and mechanism of action of cisplatin and the P42345 inhibitor rapamycin on Hep-2 laryngeal cancer cells were investigated . Hep-2 cells were cultured in the presence of different concentrations of rapamycin , cisplatin , or the two combined . Inhibition of cell growth , apoptosis , and AKT , P42345 , S6K , and P07992 protein levels were assessed . All combinations of rapamycin and cisplatin resulted in synergistic inhibition of cell growth ( as indicated by q values determined using Jin 's formula > 1.15 ) . DB00877 inhibited Hep-2 cell growth , induced P55008 arrest , and when combined with cisplatin , enhanced apoptosis . p- P42345 and S6K expressions were significantly downregulated by rapamycin . P07992 expression was significantly upregulated with cisplatin treatment . Combined cisplatin and rapamycin treatment resulted in significant downregulated p- P42345 and S6K expression , but no change in P07992 expression . DB00877 and cisplatin act in a synergistic manner , increasing the cytotoxic effect on Hep-2 cells . DB00877 may facilitate increased Hep-2 cell apoptosis with cisplatin via inhibiting downstream expression of proteins in the AKT- P42345 signaling pathway . Effect of milk hydrolysates on inflammation markers and drug-induced transcriptional alterations in cell-based models . Nonsteroidal anti-inflammatory drugs ( NSAID ) are associated with gastrointestinal inflammation and subsequent damage to the intestinal tissue . Earlier studies in our laboratory have found that specific casein hydrolysates ( CH ) might be useful in the treatment of gastrointestinal wounds . The underlying mechanisms that support inflammation and wound healing are not completely understood , but transcriptional alterations may be used as markers for inflammation and wound healing . The bioactivity of 3 CH prepared by treatment of commercial casein with pepsin ( 60 min ) followed by corolase ( 0 , 10 , or 60 min ) were investigated in intestinal epithelial cells treated with the NSAID indomethacin . The bioactivity was evaluated as transcriptional alterations of transforming growth factor-β1 ( TGF-β1 ) , cyclooxygenase-2 ( P35354 ) , peroxisome proliferator-activated receptor-γ ( Q07869 -γ ) and nuclear factor κB ( NFκB ) by real-time PCR . Furthermore , the effect of CH on lipopolysaccharide-induced inflammation was evaluated in macrophages by measuring PG E(2) levels . Casein hydrolysates treated with corolase for 10 or 60 min after pepsin treatment downregulated transcription of TGF-β1 and NFκB ( P < 0.05 ) compared with the hydrolysate treated with pepsin only . Hydrolysate prepared by corolase treatment for 60 min after pepsin hydrolysis downregulated transcription of P35354 ( P < 0.05 ) compared with hydrolysate treated with corolase for only 10 min whereas transcription of Q07869 -γ was not affected ( P > 0.05 ) . Additionally , the hydrolysate prepared by pepsin treatment only ( 0 min corolase ) had a pro-inflammatory effect on macrophages via PG E(2) stimulation ( P < 0.05 ) . In conclusion , CH produced by a combination of pepsin and corolase treatments downregulated the transcription levels of TGF-β1 , P35354 , and NFκB . A new algorithm for weekly phenprocoumon dose variation in a southern Brazilian population : role for P11712 , P08684 /5 and Q9BQB6 genes polymorphisms . DB00946 is widely used in prophylaxis and treatment of thromboembolic disorders . However , its pharmacokinetics and pharmacodynamics vary according to several genetic and non-genetic factors . DB00946 metabolism is mediated by P11712 and CYP3A enzymes . Moreover , Q9BQB6 is phenprocoumon target of action . Therefore , the aim of this study was to evaluate the association of single nucleotide polymorphisms ( SNPs ) in Q9BQB6 , P11712 , P08684 and P20815 genes with the variance of weekly phenprocoumon dose as well as to develop an algorithm for dose prediction based on genetic and environmental factors . A total of 198 patients with stable phenprocoumon dose , 81 % of European ancestry , were investigated . Genotypes were determined by allelic discrimination with TaqMan assays . Polymorphisms -1639G > A and 1173C > T in Q9BQB6 and the presence of P11712 *2 and/or P11712 *3 are associated with lower doses . On the other hand , 3730G > A in Q9BQB6 gene is associated with higher doses . No association was found between P08684 *1B , P20815 *3 and P20815 *6 polymorphisms . Among non-genetic factors , gender , height , age and use of captopril , omeprazole , simvastatin and β-blockers are associated with dose . Two algorithms were derived : one for the whole sample explained 42 % of dose variation and one for patients of European ancestry only which explained 46 % of phenprocoumon dose . The mean absolute difference between observed and predicted dose was low in both models ( 3.92 mg/week and 3.54 mg/week , for models 1 and 2 , respectively ) . However , more studies with other genes and environmental factors are needed to test and to improve the algorithm .