interacts_with DB00712?
P10275 promotes the migration and invasion of upper urinary tract urothelial carcinoma cells through the upregulation of P14780 and P35354 . Dysregulated androgen receptor ( AR ) signaling is implicated in several types of tumor , including carcinomas of the prostate , breast , liver and bladder . However , the contribution of AR to the progression of upper urinary tract urothelial carcinomas ( UUTUC ) has not been fully investigated . In the present study , we demonstrated that the AR is involved in the metastasis and invasiveness of UUTUC cells . We investigated the role of the AR in UUTUC by using UUTUC-derived BFTC 909 cells . The overexpression of AR promotes the migration and invasion of BFTC 909 cells . Expression of migration/invasion-related genes was increased in BFTC 909 cells overexpressing AR determined by qPCR and western blot analyses . The results showed that AR-enhanced migration and invasion of UUTUC cells are linked to the upregulation of the matrix-degrading enzyme P14780 and cyclooxygenase ( P36551 ) -2 . Subsequently , the blocking of P14780 and P35354 signaling by inhibitors suppressed AR-enhanced cell migration and invasion . The results of the present study provide evidence for the first time of the role of AR in the motility and invasion of UUT cancer cells and support the hypothesis that the AR may play a critical role in the establishment of the invasive phenotype in urothelial neoplasia of UUT . Thus , the AR may also serve as a novel biomarker and potential therapeutic target for UUT cancer . Correcting human mitochondrial mutations with targeted RNA import . Mutations in the human mitochondrial genome are implicated in neuromuscular diseases , metabolic defects , and aging . An efficient and simple mechanism for neutralizing deleterious mitochondrial DNA ( mtDNA ) alterations has unfortunately remained elusive . Here , we report that a 20-ribonucleotide stem-loop sequence from the H1 RNA , the RNA component of the human RNase P enzyme , appended to a nonimported RNA directs the import of the resultant RNA fusion transcript into human mitochondria . The methodology is effective for both noncoding RNAs , such as tRNAs , and mRNAs . The RNA import component , polynucleotide phosphorylase ( Q8TCS8 ) , facilitates transfer of this hybrid RNA into the mitochondrial matrix . In addition , nucleus-encoded mRNAs for mitochondrial proteins , such as the mRNA of human mitochondrial ribosomal protein P28222 ( O15235 ) , contain regulatory sequences in their 3'-untranslated region ( UTR ) that confers localization to the mitochondrial outer membrane , which is postulated to aid in protein translocation after translation . We show that for some mitochondrial-encoded transcripts , such as P35354 , a 3'-UTR localization sequence is not required for mRNA import , whereas for corrective mitochondrial-encoded tRNAs , appending the 3'-UTR localization sequence was essential for efficient fusion-transcript translocation into mitochondria . In vivo , functional defects in mitochondrial RNA ( mtRNA ) translation and cell respiration were reversed in two human disease lines . Thus , this study indicates that a wide range of RNAs can be targeted to mitochondria by appending a targeting sequence that interacts with Q8TCS8 , with or without a mitochondrial localization sequence , providing an exciting , general approach for overcoming mitochondrial genetic disorders . Genetic markers in the EET metabolic pathway are associated with outcomes in patients with aneurysmal subarachnoid hemorrhage . Preclinical studies show that epoxyeicosatrienoic acids ( EETs ) regulate cerebrovascular tone and protect against cerebral ischemia . We investigated the relationship between polymorphic genes involved in EET biosynthesis/metabolism , cytochrome P450 ( CYP ) eicosanoid levels , and outcomes in 363 patients with aneurysmal subarachnoid hemorrhage ( aSAH ) . Epoxyeicosatrienoic acids and dihydroxyeicosatetraenoic acid ( DHET ) cerebrospinal fluid ( P04141 ) levels , as well as acute outcomes defined by delayed cerebral ischemia ( P42126 ) or clinical neurologic deterioration ( CND ) , were assessed over 14 days . Long-term outcomes were defined by Modified Rankin Scale ( P59665 ) at 3 and 12 months . P10632 *4 allele carriers had 44 % and 36 % lower mean EET and DHET P04141 levels ( P=0.003 and P=0.007 ) and were 2.2- and 2.5-fold more likely to develop P42126 and CND ( P=0.039 and P=0.041 ) , respectively . P34913 55Arg , P51589 *7 , P10632 *1B , and P10632 g.36785A allele carriers had lower EET and DHET P04141 levels . P10632 g.25369T and P10632 g.36755A allele carriers had higher EET levels . Patients with P10632 *2C and P34913 404del variants had worse long-term outcomes while those with P34913 287Gln , P51589 *7 , and P11712 g.816G variants had favorable outcomes . Epoxyeicosatrienoic acid levels were associated with Fisher grade and unfavorable 3-month outcomes . Dihydroxyeicosatetraenoic acids were not associated with outcomes . No associations passed Bonferroni multiple testing correction . These are the first clinical data demonstrating the association between the EET biosynthesis/metabolic pathway and the pathophysiology of aSAH . DB00313 n-3 , DB00313 n-6 and DB01708 improve lipoprotein profiles and aortic function in hamsters fed a high cholesterol diet . The present study examined the cholesterol-lowering activity of omega-3 docosapentaenoic acid ( DB00313 n-3 ) , omega-6 docosapentaenoic acid ( DB00313 n-6 ) and docosahexaenoic acid ( DB01708 ) , and their interaction with gene expression of transporters , receptors and enzymes involved in cholesterol absorption and metabolism as well as their effect on aortic function . Forty hamsters were fed either the control diet containing 0.4 % stearic acid or one of the three experimental diets containing 0.4 % DB00313 n-3 , 0.4 % DB00313 n-6 and 0.4 % DB01708 . Results showed that supplementation of these three fatty acids reduced plasma total cholesterol ( TC ) and non high-density-lipoprotein cholesterol ( non-HDL-C ) by 29-33 % and 29-50 % , respectively , compared with the control . The reduction in TC and non-HDL-C was accompanied by down-regulation of hepatic Q12772 and P04035 . Aorta from DB00313 n-3 and DB01708 groups was found to have significantly lesser tension and relax better than that from the control and DB00313 n-6 hamsters , largely mediated by their inhibition on the gene expression of cycloxygense-2 ( P35354 ) . It was concluded that all three fatty acids were beneficial in improving lipoprotein profile with DB00313 n-3 and DB01708 having better effect on aortic function . 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 . Non-phosphorylated FTY720 induces apoptosis of human microglia by activating Q12772 . A synthetic analog of sphingosine named FTY720 ( DB08868 ) , phosphorylated by sphingosine kinase-2 , interacts with sphingosine-1-phosphate ( Q14703 ) receptors expressed on various cells . FTY720 suppresses the disease activity of multiple sclerosis ( MS ) chiefly by inhibiting Q14703 -dependent egress of autoreactive T lymphocytes from secondary lymphoid organs , and possibly by exerting anti-inflammatory and neuroprotective effects directly on brain cells . However , at present , biological effects of FTY720 on human microglia are largely unknown . We studied FTY720-mediated apoptosis of a human microglia cell line HMO6 . The exposure of HMO6 cells to non-phosphorylated FTY720 ( FTY720-non-P ) induced apoptosis in a dose-dependent manner with IC50 of 10.6 ± 2.0 μM , accompanied by the cleavage of caspase-7 and caspase-3 but not of caspase-9 . The apoptosis was inhibited by Z-DQMD-FMK , a caspase-3 inhibitor , but not by Pertussis toxin , a Gi protein inhibitor , suramin , a Q99500 / Q9H228 inhibitor , or W123 , a P21453 competitive antagonist , although HMO6 expressed P21453 , O95136 , and Q99500 . Furthermore , both phosphorylated FTY720 ( FTY720-P ) and SEW2871 , P21453 selective agonists , did not induce apoptosis of HMO6 . Genome-wide gene expression profiling and molecular network analysis indicated activation of transcriptional regulation by sterol regulatory element-binding protein ( SREBP ) in FTY720-non-P-treated HMO6 cells . Western blot verified activation of Q12772 in these cells , and apoptosis was enhanced by pretreatment with simvastatin , an activator of Q12772 , and by overexpression of the N-terminal fragment of Q12772 . These observations suggest that FTY720-non-P-induced apoptosis of HMO6 human microglia is independent of Q14703 receptor binding , and positively regulated by the Q12772 -dependent proapoptotic signaling pathway . Enhanced fracture repair by leukotriene antagonism is characterized by increased chondrocyte proliferation and early bone formation : a novel role of the cysteinyl LT-1 receptor . Inflammatory mediators and drugs which affect inflammation can influence the healing of injured tissues . Leukotrienes are potent inflammatory mediators , and similar to prostaglandins , are metabolites of arachidonic acid which can have positive or negative effects on bone and cartilage tissues . Here we tested the hypothesis that blocking the negative regulation of leukotrienes , would lead to enhanced endochondral bone formation during fracture repair . A closed femoral fracture was created in mice . Animals were divided into three groups for treatment with either montelukast sodium , a cysteinyl leukotriene type 1 receptor antagonist ( trade name Singulair ) , zileuton , a P09917 enzyme inhibitor ( trade name DB00744 ) , or carrier alone . The fractures were analyzed using radiographs , quantitative gene expression , histology and histomorphometry , and immunohistochemistry . Both the montelukast sodium group and the zileuton group exhibited enhanced fracture repair when compared with controls . Both treatment groups exhibited increased callous size and earlier bone formation when compared to controls as early as day 7 . Gene expression analysis of treatment groups showed increased markers of chondrocyte proliferation and differentiation , and increased early bone formation markers when compared with controls . Treatment with montelukast sodium directly targeted the cysteinyl leukotriene type 1 receptor , leading to increased chondrocyte proliferation at early time points . These novel findings suggests a potential mechanism by which the cysteinyl leukotriene type 1 receptor acts as a negative regulator of chondrocyte proliferation , with important and previously unrecognized implications for both fracture repair , and in a broader context , systemic chondrocyte growth and differentiation . P10275 repression of gonadotropin-releasing hormone gene transcription via enhancer 1 . DB00644 ( DB00644 ) plays a major role in the hypothalamic-pituitary-gonadal ( HPG ) axis , and synthesis and secretion of DB00644 are regulated by gonadal steroid hormones . Disruptions in androgen levels are involved in a number of reproductive defects , including hypogonadotropic hypogonadism and polycystic ovarian syndrome . Androgens down-regulate DB00644 mRNA synthesis in vivo and in vitro via an androgen receptor ( AR ) -dependent mechanism . DB02998 ( R1881 ) , a synthetic AR agonist , represses DB00644 expression through multiple sites in the proximal promoter . In this study , we show AR also represses DB00644 transcription via the major enhancer ( DB00644 -E1 ) . A multimer of the -1800/-1766 region was repressed by R1881 treatment . Mutation of two bases , -1792 and -1791 , resulted in decreased basal activity and a loss of AR-mediated repression . AR bound to the -1796/-1791 sequence in electrophoretic mobility shift assays , indicating a direct interaction with DNA or other transcription factors in this region . We conclude that AR repression of DB00644 -E1 acts via multiple AR-responsive regions , including the site at -1792/-1791 . DB00216 Pfizer . Pfizer has developed and launched eletriptan , a P28222 /1D agonist , for the potential treatment of migraine with and without aura . DB00216 has 6-fold greater affinity for the P28221 receptor than sumatriptan , and a 3-fold greater affinity for the P28222 receptor [ 249570 ] . DB00216 pharmacology has also been evaluated in vitro in comparison with zolmitriptan ( AstraZeneca plc ) and naratriptan ( GlaxoSmithKline plc ) [ 290116 ] . Activation of c-Jun-N-terminal-kinase is crucial for the induction of a cell cycle arrest in human colon carcinoma cells caused by flurbiprofen enantiomers . The unselective cyclooxygenase ( P36551 ) inhibitor DB00712 and its-in terms of P36551 -inhibition- " inactive " enantiomer R-flurbiprofen have been previously found to inhibit tumor development and growth in various animal models . The underlying mechanisms are unknown . Here , we show that both R- and DB00712 reduce survival of three colon cancer cell lines , which differ in the expression of P35354 ( HCT-15 , no P35354 ; Caco-2 , inducible P35354 ; and HT-29 , constitutive P35354 ) . The IC50 for S- and R-flurbiprofen ranged from 250 to 450 microM . Both flurbiprofen enantiomers induced apoptosis in all three cell lines as indicated by DNA- and PARP-cleavage . In addition , R- and DB00712 caused a P55008 -cell cycle block . The latter was associated with an activation of c-Jun N-terminal kinase ( JNK ) , an increase of the DNA binding activity of the transcription factor AP-1 and down-regulation of cyclin D1 expression . Western blot analysis , as well as supershift experiments , revealed that the AP-1 activation was associated with a change of AP-1 composition toward an increase of JunB . The JNK inhibitor SP600125 antagonized R- and DB00712 -induced AP-1 DNA binding , suppression of cyclin D1 expression , and the P55008 -cell cycle block . However , JNK inhibition had no effect on flurbiprofen-induced apoptosis . Hence , the cell cycle arrest is obviously mediated , at least in part , through JNK-activation , whereas R- and DB00712 -induced apoptosis is largely independent of JNK . Although in vitro effects of R- and DB00712 were indistinguishable , only R-flurbiprofen inhibited HCT-15 tumor growth in nude mice , suggesting the involvement of additional in vivo targets , which are differently affected by R- and DB00712 . Patients with severe sepsis vary markedly in their ability to generate activated protein C . DB00055 ( P25054 ) supplementation significantly reduces mortality in patients with severe sepsis , presumably by down-regulating coagulation , inflammation , and apoptosis . In vivo , endogenous P25054 is generated from protein C ( PC ) " on demand " in response to elevated thrombin levels . P07204 and endothelial cell protein C receptor are endothelial receptors required to generate P25054 endogenously . Since these receptors may be down-regulated in sepsis , we measured plasma markers of P25054 generation in 32 patients with severe sepsis to determine whether P25054 generation is impaired and whether markers of P25054 generation correlate with 28-day mortality . Relative to normals , all patients had elevated F1 + 2 and thrombin-antithrombin complex ( TAT ) levels ( markers of thrombin generation and inhibition , respectively ) , and 28 of 32 patients had reduced PC levels . In 20 patients , P25054 levels paralleled elevated F1 + 2 levels , whereas 12 patients had low P25054 levels despite elevated F1 + 2 levels , suggesting that P25054 generation is impaired in the latter . No significant differences exist between survivors and nonsurvivors with respect to baseline PC levels , F1 + 2 levels , and APACHE II ( acute physiology and chronic health evaluation ) scores . Baseline P25054 levels were higher in survivors ( P = .024 ) , and baseline F1 + 2/ P25054 ratios were lower in survivors ( P = .047 ) . Larger studies are warranted to establish whether P25054 generation profiles aid in managing sepsis . Inhibition of Akt/ P31749 by a P35354 inhibitor induces apoptosis in gastric cancer cells . BACKGROUND/AIM : Inhibition of cyclooxygenase-2 has been proposed to be a potential mechanism for the chemoprevention of gastrointestinal tumors by nonsteroidal anti-inflammatory drugs . This study investigates the mechanisms by which the cyclooxygenase-2 inhibitor SC236 induces apoptosis of gastric cancer cell lines and its downstream signaling pathway . METHODS : Two gastric cancer cell lines , AGS and MKN28 , were treated with SC236 and assessed for cell growth and apoptosis . The involvement of mitogen-activated protein kinase and Akt kinase/protein kinase B ( Akt/ P31749 ) pathways and their downstream signalings were studied in the AGS cell line . RESULTS : SC236 treatment induced apoptosis in gastric cancer cells and caused activation of p38 and stress-activated protein kinase/jun kinase , but down-regulated Akt/ P31749 . The specific p38 inhibitor SB203580 and the dominant-negative stress-activated protein kinase/jun kinase both failed , while the constitutively active form of Akt/ P31749 was able to block SC236-induced apoptosis . SC236-induced apoptosis was coupled with release of cytochrome c and activation of caspases . CONCLUSION : One of the pathways involved in SC-236-induced apoptosis in gastric cancer cells is through downregulation of Akt and then release of cytochrome c . Growth factors expression in patients with erosive esophagitis . Although the pathogenesis and treatment of erosive esophagitis ( EE ) is well recognized , little is known about the cellular and molecular mechanisms of mucosal healing in EE patients . In this pilot study , we enrolled typical EE patients to evaluate what kinds of growth factors and their receptors were activated in their injured esophageal mucosa . Forty endoscopically proved EE patients were consecutively enrolled . Messenger RNA expressions , which includes keratinocyte growth factor ( KGF ) and its receptor ( P21802 ) , epidermal growth factor ( P01133 ) and its receptor ( P00533 ) , hepatocyte growth factor ( P14210 ) and its receptor ( HGFR ) , basic fibroblast growth factor ( P09038 ) , vascular endothelial growth factor ( P15692 ) , and cyclooxygenase ( P36551 ) -1 and P35354 , were measured using real-time polymerase chain reaction ( PCR ) . Data were compared between the injured EE mucosa and their normal esophageal mucosa above EE . The mRNA expressions of P14210 , HGFR , P01133 , P15692 , and P35354 , but not P00533 , KGF , P21802 , P09038 , and P23219 , were significantly increased in the injured mucosa of EE patients compared with those of normal mucosa ( P < 0.05 ) . The study found that P14210 , HGFR , P01133 , P15692 , and , P35354 are activated in the injured mucosa of EE patients ; their activation might be involved in mucosal repair and ulcer healing of EE . P35372 phosphorylation , desensitization , and ligand efficacy . Mu opioid receptors are subject to phosphorylation and desensitization through actions of at least two distinct biochemical pathways : agonist-dependent mu receptor phosphorylation and desensitization induced by a biochemically distinct second pathway dependent on protein kinase C activation ( 1 ) . To better understand the nature of the agonist-induced mu receptor phosphorylation events , we have investigated the effects of a variety of opiate ligands of varying potencies and intrinsic activities on mu receptor phosphorylation and desensitization . Exposure to the potent full agonists sufentanil , dihydroetorphine , etorphine , etonitazine , and [ D-Ala2 , MePhe4 , Glyol5 ] enkephalin ( DAMGO ) led to strong receptor phosphorylation , while methadone , l-alpha-acetylmethadone ( DB01227 ) , morphine , meperidine , DADL , beta-endorphin(1-31) , enkephalins , and dynorphin A(1-17) produced intermediate effects . The partial agonist buprenorphine minimally enhanced receptor phosphorylation while antagonists failed to alter phosphorylation . DB00921 and full antagonists each antagonized the enhanced mu receptor phosphorylation induced by morphine or DAMGO . The rank order of opiate ligand efficacies in producing mu receptor-mediated functional desensitization generally paralleled their rank order of efficacies in producing receptor phosphorylation . Interestingly , the desensitization and phosphorylation mediated by methadone and DB01227 were disproportionate to their efficacies in two distinct test systems . This generally good fit between the efficacies of opiates in mu receptor activation , phosphorylation , and desensitization supports the idea that activated receptor/agonist/G-protein complexes and/or receptor conformational changes induced by agonists are required for agonist-induced mu receptor phosphorylation . Data for methadone and DB01227 suggest possible contribution from their enhanced desensitizing abilities to their therapeutic efficacies . Novel marine phenazines as potential cancer chemopreventive and anti-inflammatory agents . Two new ( 1 and 2 ) and one known phenazine derivative ( lavanducyanin , 3 ) were isolated and identified from the fermentation broth of a marine-derived Streptomyces sp . ( strain CNS284 ) . In mammalian cell culture studies , compounds 1 , 2 and 3 inhibited P01375 -α-induced NFκB activity ( IC₅₀ values of 4.1 , 24.2 , and 16.3 μM , respectively ) and LPS-induced nitric oxide production ( IC₅₀ values of > 48.6 , 15.1 , and 8.0 μM , respectively ) . PGE₂ production was blocked with greater efficacy ( IC₅₀ values of 7.5 , 0.89 , and 0.63 μM , respectively ) , possibly due to inhibition of cyclooxygenases in addition to the expression of P35354 . Treatment of cultured HL-60 cells led to dose-dependent accumulation in the subG1 compartment of the cell cycle , as a result of apoptosis . These data provide greater insight on the biological potential of phenazine derivatives , and some guidance on how various substituents may alter potential anti-inflammatory and anti-cancer effects . Modulation of cytokine production and enhancement of cell viability by Q9NYK1 and Q9NR96 ligands during anthrax infection of macrophages . Inhalation of Bacillus anthracis , a bioterrorism agent , results in a high mortality rate despite appropriate antibiotic therapy . Macrophages appear to be a key factor in B. anthracis pathogenesis . The burst of pro-inflammatory cytokines from macrophages could be a major cause of death in anthrax . However , preactivation of Toll-like receptors ( TLRs ) could modify the host response . TLR ligands stimulate the release of activating cytokines but may also down-modulate the subsequent deleterious cytokine response to pathogens . We developed a cell culture model to measure macrophage responses to B. anthracis spores and bacilli . We found that germination from spores to bacilli produced a substantial stimulus for the secretion of the cytokines P05231 , P01375 , P22301 , and IL-12 p40 . Our studies showed that pretreatment of mouse macrophages with the Q9NR96 ligand DB05463 , or the Q9NYK1 ligands R-848 and IT-37 , results in a substantial decrease in the subsequent secretion of P05231 and P01375 in response to B. anthracis infection of macrophages . Furthermore , the Q9NYK1 and Q9NR96 ligands significantly decreased anthrax-induced cytotoxicity in the macrophages . These findings suggest that TLR ligands may contribute to the enhancement of innate immunity in B. anthracis infection by suppressing potentially deleterious pro-inflammatory cytokine responses and by improving macrophage viability . The PEPvIII-KLH ( DB05374 ) vaccine in glioblastoma multiforme patients . Conventional therapies for glioblastoma multiforme ( GBM ) fail to target tumor cells exclusively , resulting in non-specific toxicity . Immune targeting of tumor-specific mutations may allow for more precise eradication of neoplastic cells . P00533 variant III ( EGFRvIII ) is a tumor-specific mutation that is widely expressed in GBM and other neoplasms and its expression enhances tumorigenicity . This in-frame deletion mutation splits a codon , resulting in a novel glycine at the fusion junction producing a tumor-specific epitope target for cellular or humoral immunotherapy . We have previously shown that vaccination with a peptide that spans the EGFRvIII fusion junction ( PEPvIII-KLH/ DB05374 ) is an efficacious immunotherapy in syngeneic murine models . In this review , we summarize our results in GBM patients targeting this mutation in multiple , multi-institutional Phase II immunotherapy trials . These trials demonstrated that a selected population of GBM patients who received vaccines targeting EGFRvIII had an unexpectedly long survival time . Further therapeutic strategies and potential pitfalls of using this approach are discussed . Evidence for colorectal cancer cell specificity of aspirin effects on NF kappa B signalling and apoptosis . Epidemiological evidence indicates that non-steroidal anti-inflammatory drugs ( NSAIDs ) protect against colorectal cancer ( CRC ) to a greater degree than other non-gastrointestinal cancers , but the molecular basis for this difference is unknown . We previously reported that aspirin induces signal-specific I kappa B alpha degradation followed by NF kappa B nuclear translocation in CRC cells , and that this mechanism contributes substantially to aspirin-induced apoptosis . Here , we explored the hypothesis that cell-type specific effects on NF kappa B signalling are responsible for the observed differences in protection by aspirin against CRC compared to breast and gynaecological cancers . We also assessed whether P35354 expression , mutation status of adenomatous polyposis coli ( P25054 ) , beta-catenin , p53 , or DNA mismatch repair ( P22897 ) genes in CRC lines influenced aspirin-induced effects . We found that aspirin induced concentration-dependent I kappa B alpha degradation , NF kappa B nuclear translocation and apoptosis in all CRC lines studied . However , there was no such effect on the other cancer cell types , indicating a considerable degree of cell-type specificity . The lack of effect on NF kappa B signalling , paralleled by absence of an apoptotic response to aspirin in non-CRC lines , strongly suggests a molecular rationale for the particular protective effect of NSAIDs against CRC . Effects on NF kappa B and apoptosis were observed irrespective of P35354 expression , or mutation status in P25054 , beta-catenin , p53 and DNA P22897 genes , underscoring the generality of the aspirin effect on NF kappa B in CRC cells . These findings raise the possibility of cell-type specific targets for the development of novel chemopreventive agents . Epstein-Barr virus Zta-induced immunomodulators from nasopharyngeal carcinoma cells upregulate interleukin-10 production from monocytes . During lytic infection with Epstein-Barr virus ( EBV ) , several viral lytic proteins function to evade immune recognition or to actively suppress immune cells . An EBV lytic transactivator , Zta , induces an immunosuppressive cytokine interleukin 10 ( P22301 ) in B cells , but whether it regulates P22301 in the context of epithelial cells is unclear . In this study , we tested nasopharyngeal carcinoma ( NPC ) cell lines and found that Zta did not induce P22301 in these epithelial cells . Interestingly , the conditioned medium of Zta-expressing NPC cells enhanced P22301 production from monocytes . We further revealed that the P22301 -inducing effect involved at least two immunomodulators that were upregulated by Zta and secreted from NPC cells : granulocyte-macrophage colony-stimulating factor ( GM- P04141 ) and prostaglandin E(2) ( PGE(2) ) . Zta was recruited to and activated the GM- P04141 promoter , thus upregulating GM- P04141 expression . Zta also activated the promoter of cyclooxygenase-2 ( P35354 ) , and Zta-induced P35354 increased downstream PGE(2) production . Cotreatment with GM- P04141 and PGE(2) synergistically induced P22301 production from monocytes . The P22301 -inducing effect of the Zta-conditioned medium was reduced when GM- P04141 or the P35354 /PGE(2) pathway was blocked . The conditioned medium of NPC cells with EBV lytic infection showed a similar increase of GM- P04141 and PGE(2) levels as well as the P22301 -inducing effect on monocytes , and knockdown of Zta abolished all the effects . Therefore , through Zta-induced immunomodulators , EBV lytic infection in NPC cells can direct bystander monocytes to produce P22301 , which may be a novel way of EBV to promote local immunosuppression . Multifaceted link between cancer and inflammation . Increasing evidence from epidemiological , preclinical and clinical studies suggests that dysregulated inflammatory response plays a pivotal role in a multitude of chronic ailments including cancer . The molecular mechanism(s) by which chronic inflammation drives cancer initiation and promotion include increased production of pro-inflammatory mediators , such as cytokines , chemokines , reactive oxygen intermediates , increased expression of oncogenes , P35354 ( cyclo-oxygenase-2 ) , 5- P28300 ( P09917 ) and MMPs ( matrix metalloproteinases ) , and pro-inflammatory transcription factors such as NF-κB ( nuclear factor κB ) , P40763 ( signal transducer and activator of transcription 3 ) , AP-1 ( activator protein 1 ) and HIF-1α ( hypoxia-inducible factor 1α ) that mediate tumour cell proliferation , transformation , metastasis , survival , invasion , angiogenesis , chemoresistance and radioresistance . These inflammation-associated molecules are activated by a number of environmental and lifestyle-related factors including infectious agents , tobacco , stress , diet , obesity and alcohol , which together are thought to drive as much as 90 % of all cancers . The present review will focus primarily on the role of various inflammatory intermediates responsible for tumour initiation and progression , and discuss in detail the critical link between inflammation and cancer . Preliminary evidence of ethnic divergence in associations of putative genetic variants for methamphetamine dependence . Research into the biological processes that increase susceptibility to methamphetamine dependence has been conducted primarily in Asian populations . Using a case-control design this study 's purpose was to explore , among a population of methamphetamine-dependent Caucasians , six putative single nucleotide polymorphisms previously found to be associated with methamphetamine dependence in Asian populations . A total of 193 non-psychotic males ( 117 methamphetamine-dependent and 76 controls ) were genotyped for variants located in six genes ( P31749 , P32121 , P23560 , P21964 , P09211 , P35372 ) . Genotypic and allelic frequencies , odds ratios , and 95 % confidence intervals were calculated . None of the putative gene associations was significantly replicated in our sample of Caucasian men . Effect size comparisons suggest a trend toward allelic divergence for arrestin beta 2 ( P32121 ) and glutathione S-transferase P1 ( P09211 ) and allelic convergence for brain-derived neurotrophic factor ( P23560 ) . Results provide preliminary support for further exploration and validation of candidate single nucleotide polymorphisms ( SNPs ) for methamphetamine ( METH ) dependence reported among Asian populations across other ethnic/ancestral groups .