interacts_with DB08877?
Target genes discovery through copy number alteration analysis in human hepatocellular carcinoma . High-throughput short-read sequencing of exomes and whole cancer genomes in multiple human hepatocellular carcinoma ( HCC ) cohorts confirmed previously identified frequently mutated somatic genes , such as P04637 , P35222 and O15169 , and identified several novel genes with moderate mutation frequencies , including O14497 , Q68CP9 , Q03164 , MLL2 , Q8NEZ4 , MLL4 , P14316 , Q13315 , CDKN2A , O95750 , P42336 , P51812 , P23458 , Q14145 , Q16236 , Q7Z3J2 , LEPR , P15153 , and P40189 . Functional classification of these mutated genes suggested that alterations in pathways participating in chromatin remodeling , Wnt/β-catenin signaling , JAK/ P35610 signaling , and oxidative stress play critical roles in HCC tumorigenesis . Nevertheless , because there are few druggable genes used in HCC therapy , the identification of new therapeutic targets through integrated genomic approaches remains an important task . Because a large amount of HCC genomic data genotyped by high density single nucleotide polymorphism arrays is deposited in the public domain , copy number alteration ( Q08209 ) analyses of these arrays is a cost-effective way to reveal target genes through profiling of recurrent and overlapping amplicons , homozygous deletions and potentially unbalanced chromosomal translocations accumulated during HCC progression . Moreover , integration of CNAs with other high-throughput genomic data , such as aberrantly coding transcriptomes and non-coding gene expression in human HCC tissues and rodent HCC models , provides lines of evidence that can be used to facilitate the identification of novel HCC target genes with the potential of improving the survival of HCC patients . beta-Carotene induces apoptosis and up-regulates peroxisome proliferator-activated receptor gamma expression and reactive oxygen species production in MCF-7 cancer cells . Although the pharmacological role of beta-carotene in the prevention and treatment of many cancer cells has received increasing attention , the molecular mechanisms underlying such chemopreventive activity are not clear . Since peroxisome proliferator-activated receptor gamma ( P37231 ) has been implicated in regulating breast cancer cell differentiation and apoptosis , the effects of beta-carotene on the P37231 -mediated pathway and its association with reactive oxygen species production in MCF-7 cells were investigated in the present study . The results demonstrated that beta-carotene significantly increased P37231 mRNA and protein levels in time-dependent manner . In addition , beta-carotene increased the cyclin-dependent kinase inhibitor P38936 ( P38936 /CIP1) expression and decreased the prostanoid synthesis rate-limiting enzyme cyclooxygenase-2 expression . DB07863 ( GW9662 ) , an irreversible P37231 antagonist , partly attenuated the cell death caused by beta-carotene . Further , reactive oxygen species ( ROS ) production was induced by beta-carotene , resulting in mitochondrial dysfunction and cytochrome C release . DB00143 ( DB00143 ) treatment decreases the intracellular ROS and prevents cytochrome C release and cell apoptosis induced by beta-carotene . In total , these observations suggest that the synergistic effect of P37231 expression and ROS production may account for beta-carotene-mediated anticancer activities . Glucocorticoids enhance regeneration of murine olfactory epithelium . CONCLUSION : Glucocorticoid ( GC ) administration enhanced apoptotic changes in mature olfactory receptor neurons ( ORNs ) . GC administration may enhance regeneration of olfactory epithelium ( OE ) . OBJECTIVES : The mechanism underlying olfactory epithelial cells turnover involves apoptosis replaced by new ORNs . On regeneration of OE , we evaluated the apoptotic changes in OE . Our aim was to corroborate the enhancement of apoptosis of ORNs induced by GCs that are generally administered locally or systemically to patients with olfactory dysfunction . MATERIALS AND METHODS : For the in vitro study , we established cultured murine ORNs . DB00620 acetonide was added to culture supernatants . ORNs were then cultured for another 2 weeks . In the in vivo study , triamcinolone acetonide was administered to mice 5 or 10 times . The mice were dissected 3 days after the final injection , and the olfactory regions were removed and embedded in paraffin . All samples were examined by immunohistochemical staining and the TdT-mediated dUTP-biotin nick-end labeling ( TUNEL ) method . RESULTS : P04150 ( GR ) expression of cultured murine ORNs was observed among ORNs at the mature stage . Expression of GRs by murine OE was localized on mature ORNs and supporting cells . Administration of GC to both cultured ORNs and mice resulted in proportions of apoptotic cells that were significantly higher than those in the control groups . Poly(ADP-ribose) polymerase-1 : a novel therapeutic target in necrotizing enterocolitis . Necrotizing enterocolitis ( NEC ) is the most common gastrointestinal disease of infancy , afflicting 11 % of infants born 22-28 wk GA . Both inflammation and oxidation may be involved in NEC pathogenesis through reactive nitrogen species production , protein oxidation , and DNA damage . Poly(ADP-ribose) polymerase-1 ( P09874 ) is a critical enzyme activated to facilitate DNA repair using nicotinamide adenine dinucleotide ( NAD+ ) as a substrate . However , in the presence of severe oxidative stress and DNA damage , P09874 overactivation may ensue , depleting cells of NAD+ and DB00171 , killing them by metabolic catastrophe . Here , we tested the hypothesis that NO dysregulation in intestinal epithelial cells during NEC leads to marked P09874 expression and that administration of a P09874 inhibitor ( nicotinamide ) attenuates intestinal injury in a newborn rat model of NEC . In this model , 56 % of control pups developed NEC ( any stage ) versus 14 % of pups receiving nicotinamide . Forty-four percent of control pups developed high-grade NEC ( grades 3-4 ) , whereas only 7 % of pups receiving nicotinamide developed high-grade NEC . DB02701 treatment protects pups against intestinal injury incurred in the newborn rat NEC model . We speculate that P09874 overactivation in NEC may drive mucosal cell death in this disease and that P09874 may be a novel therapeutic target in NEC . Effects of inhaled prostacyclin analogue on chronic hypoxic pulmonary hypertension . Inhaled DB01240 has been reported to elicit pulmonary vasodilation , but whether it is also effective in treating chronic hypoxic pulmonary hypertension is still uncertain . We designed this study to address the in vivo effectiveness of inhaled DB05229 , a stable DB01240 analogue , on pulmonary vascular tone during hypoxic exposure in normoxic ( N ) and chronically hypoxic ( CH ) rats . Pulmonary vasodilation was observed by low-dose inhaled DB05229 in N rats , but not in CH rats . It was not until higher doses of DB05229 were given that pulmonary vasodilation was obtained in CH rats . When the agent was continuously administered by an intravascular route at the inhaled dose , it elicited no vasodilation in N rats . On the contrary , it elicited profound vasodilation in CH rats , although a concomitant systemic hypotension was observed . The P43119 mRNA expression was unchanged in the lungs of CH rats compared with that of N rats . We conclude that low doses of aerosolized DB05229 may reduce pulmonary vascular tone in rats without preexisting lung diseases . In contrast , when hypoxic pulmonary hypertension is present , the threshold of DB05229 inhalation was elevated to provoke pulmonary vasodilation . 15d-PGJ2 and rosiglitazone suppress Janus kinase- P35610 inflammatory signaling through induction of suppressor of cytokine signaling 1 ( O15524 ) and O14543 in glia . Peroxisome proliferator-activated receptor ( Q07869 ) -gamma agonists are now emerging as therapeutic drugs for various inflammatory diseases . However , their molecular mechanism of action remains to be elucidated . Here we report a novel mechanism that underlies the P37231 agonist-mediated suppression of brain inflammation . We show that 15-deoxy-Delta12,14-prostaglandin J(2) ( 15d-PGJ(2) ) and rosiglitazone reduce the phosphorylation of P42224 and P40763 as well as P23458 ( P23458 ) and O60674 in activated astrocytes and microglia . The P37231 agonist-mediated reduction in phosphorylation leads to the suppression of JAK- P35610 -dependent inflammatory responses . The effects of 15d-PGJ(2) and rosiglitazone are not mediated by activation of P37231 . 15d-PGJ(2) and rosiglitazone rapidly induce the transcription of suppressor of cytokine signaling ( Q9NSE2 ) 1 and 3 , which in turn inhibit JAK activity in activated glial cells . In addition , Src homology 2 domain-containing protein phosphatase 2 ( SHP2 ) , another negative regulator of JAK activity , is also involved in their anti-inflammatory action . Our data suggest that 15d-PGJ(2) and rosiglitazone suppress the initiation of JAK- P35610 inflammatory signaling independently of P37231 , thus attenuating brain inflammation . P09874 deficiency blocks P05113 expression through calpain-dependent degradation of P35610 -6 in a murine asthma model . BACKGROUND : We recently showed that poly(ADP-ribose)polymerase-1 ( P09874 ) may play a role in allergen (ovalbumin)-induced airway eosinophilia , potentially through a specific effect on P05113 production . We also reported that while P05113 replenishment promotes reversal of eosinophilia in lungs of P09874 (-/-) mice , P05112 or Immunoglobulin E replenishment do not , suggesting a potentially significant regulatory relationship between P09874 and P05113 . OBJECTIVE : To explore the mechanism by which P09874 regulates P05113 production and to determine how P09874 inhibition blocks allergen-induced eosinophilia . METHODS : This study was conducted using a murine model of allergic airway inflammation and primary splenocytes . RESULTS : P09874 knockout-associated reduction in P05113 upon allergen exposure occurs at the mRNA level . Such an effect appears to take place after P05112 receptor activation as P09874 inhibition exerted no effect on P23458 / P52333 activation . Signal transducer and activator of transcription-6 ( P35610 -6 ) protein was severely downregulated in spleens of P09874 (-/-) mice without any effect on mRNA levels , suggesting an effect on protein integrity rather than gene transcription . Interestingly , the degradation of P35610 -6 in P09874 (-/-) mice required allergen stimulation . Additionally , P09874 enzymatic activity appears to be required for P35610 -6 integrity . The downregulation of P35610 -6 coincided with mRNA and protein reduction of GATA-binding protein-3 and occupancy of its binding site on the P05113 gene promoter . P05112 was sufficient to induce P35610 -6 downregulation in both P09874 (-/-) mice and isolated splenocytes . Such degradation may be mediated by calpain , but not by proteasomes . CONCLUSION : These results demonstrate a novel function of P09874 in regulating P05113 expression during allergen-induced inflammation and explain the underlying mechanism by which P09874 inhibition results in P05113 reduction . The polymorphisms S503P and Q576R in the interleukin-4 receptor alpha gene are associated with atopy and influence the signal transduction . P05112 ( P05112 ) plays a major role in immunoglobulin E ( IgE ) production . Its signal is conferred to effector cells through binding to the alpha chain of the P05112 receptor ( IL-4Ralpha ) . We present further evidence for polymorphisms in the IL-4Ralpha gene having an effect on IgE regulation . For two of four common polymorphisms , S503P and Q576R , we found an association with lowered total IgE concentrations ( P=0.0008 if occurring together ) . The polymorphism S503P has not yet been described and is located within the I4R motif of the receptor . In vitro analyses using synthetic peptides of this region showed that the tyrosine kinase P23458 ( P23458 ) , as well as P35568 and Q9Y4H2 bind to the I4R motif irrespective of the polymorphism or a tyrosine phosphorylation . In vivo immunoassays using T cells of four different groups of individuals ( S503/Q576 ; P503/Q576 ; S503/R576 ; P503/R576 ) revealed that only in case of both polymorphisms the phosphorylation of P35568 and Q9Y4H2 , but not P23458 was increased . We found no binding of P42226 to the I4R synthetic peptides ; however , the phosphorylation was reduced in the presence of any of the two polymorphisms , including P503 alone . We discuss possible conformational changes of the receptor leading to the observed effects on the phosphorylation status of P35568 , Q9Y4H2 and P42226 , in addition to previous findings that Q576R alters P42226 binding . We conclude that P503 and R576 influence the signal transduction pathways through the IL-4Ralpha , an effect that is magnified by the presence of both polymorphisms . This could explain the observed association effects with lowered total IgE concentrations . Differential role of two P11473 coactivators , Q15648 and Q9Y6Q9 , in keratinocyte proliferation and differentiation . Cell programs such as proliferation and differentiation involve the selective activation and repression of gene expression . The vitamin D receptor ( P11473 ) , through 1,25(OH)(2)D(3) , controls the proliferation and differentiation of keratinocytes . Previously , we have identified two P11473 binding coactivator complexes . In proliferating keratinocytes P11473 bound preferentially to the DRIP complex , whereas in differentiated keratinocytes the P12931 complex was preferred . We proposed that different coactivators are required for sequential gene regulation in the transition from proliferation to differentiation . Here we examined the roles of Q15648 and Q9Y6Q9 in this transition . Silencing of Q15648 and P11473 caused hyperproliferation of keratinocytes , demonstrated by increased XTT and BrdU incorporation . Q9Y6Q9 silencing , on the other hand , did not have an effect on proliferation . In contrast , Q9Y6Q9 as well as Q15648 and P11473 silencing blocked keratinocyte differentiation as shown by decreased expression of keratin 1 and filaggrin . These results are consistent with the differential localization of Q15648 and Q9Y6Q9 in skin . These results indicate that Q15648 is required for keratinocyte proliferation . Both Q15648 and Q9Y6Q9 are required for the keratinocyte differentiation . These results support the concept that the selective use of coactivators by P11473 underlies the selective regulation of gene expression in keratinocyte proliferation and differentiation . DB08877 for the treatment of primary myelofibrosis . PURPOSE : The pharmacology , pharmacokinetics , pharmacogenomics , clinical efficacy , and safety profile of ruxolitinib for the treatment of primary myelofibrosis are reviewed . SUMMARY : DB08877 , an oral tyrosine kinase inhibitor that targets the Janus-associated kinases ( JAKs ) 1 and 2 , has been recently approved for the treatment of patients with intermediate- or high-risk myelofibrosis . Unlike previous treatment options for patients with myelofibrosis , ruxolitinib offers a targeted therapy option for these patients who often suffer with severe and debilitating symptoms associated with the disease process . After oral administration , ruxolitinib is rapidly absorbed and can be given without regard to meals . DB08877 is primarily metabolized by the cytochrome P-450 ( CYP ) 3A4 isoenzyme system ; therefore , if concomitant use with a strong P08684 inhibitor is unavoidable , an initial dosage reduction is warranted . Two Phase III randomized trials comparing ruxolitinib to either placebo or best available therapy found a rapid and sustained response in the reduction of spleen size and improvements in constitutional symptoms and quality of life , with one study demonstrating an improvement in overall survival . The most commonly reported serious adverse effects of ruxolitinib are anemia and thrombocytopenia . DB08877 is administered as an oral tablet given twice daily , with the initial starting dosage based on the baseline platelet count . Dosage reductions are based on the development of thrombocytopenia . CONCLUSION : By directly targeting both P23458 and O60674 through small-molecule inhibition , ruxolitinib elicits a reduction in splenomegaly and disease-related symptoms in patients with intermediate- or high-risk myelofibrosis while maintaining an acceptable toxicity profile and a low treatment-discontinuation rate . P43119 -induced P40763 phosphorylation in human erythroleukemia cells is mediated via Galpha(s) and Galpha(16) hybrid signaling . Human prostacyclin receptor ( hIP ) stimulates P40763 via pertussis toxin-insensitive G proteins in human erythroleukemia ( HEL ) cells . Since hIP can utilize G(s) and G(q) proteins for signal transduction and that both G proteins can induce P40763 phosphorylation and activation via complex signaling networks , we sought to determine if one of them is predominant in mediating the hIP signal . Stimulation of P40763 DB00135 (705) and DB00133 (727) phosphorylations by the IP-specific agonist , cicaprost , was sensitive to inhibition of protein kinase A , phospholipase Cbeta , protein kinase C , calmodulin-dependent protein kinase II and O60674 /3 . Unlike Galpha(16)-mediated regulation of P40763 in the same cells , cicaprost-induced P40763 DB00135 (705) phosphorylation was resistant to inhibition of Src and MEK while P40763 DB00133 (727) phosphorylation distinctly required phosphatidylinositol-3 kinase . This unique inhibitor-sensitivity pattern of P40763 phosphorylation was reproduced in HEL cells by stimulating the G(16)-coupled C5a receptor in the presence of dibutyryl- DB02527 , suggesting that the change in inhibitor-sensitivity was due to activation of the G(s) pathway . This postulation was confirmed by expressing constitutively active Galpha(16)QL and Galpha(s)QL in human embryonic kidney 293 cells and the inhibitor-sensitivity of Galpha(16)QL-induced P40763 phosphorylations could be converted by the mere presence of Galpha(s)QL to resemble that obtained with cicaprost in HEL cells . In addition , the restoration of the Galpha(16)-mediated inhibitor-sensitivity upon cicaprost induction in Galpha(s)-knocked down HEL cells again verified the pivotal role of G(s) signal . Taken together , our observations illustrate that co-stimulation of G(s) and G(q) can result in the fine-tuning of P40763 activation status , and this may provide the basis for cell type-specific responses following activation of hIP . Met326Ile aminoacid polymorphism in the human p85 alpha gene has no major impact on early insulin signaling in type 2 diabetes . Class I alpha phosphatidylinositol ( PI ) 3-kinase is an important enzyme in the early insulin signaling cascade , and plays a key role in insulin-mediated glucose transport . Despite extensive investigation , the genes responsible for the development of the common forms of type 2 diabetes remain unknown . This study was performed to identify variants in the coding region of p85 alpha , the regulatory subunit of PI 3-kinase . Fibroblasts from skin biopsies from type 2 diabetics and controls were established to address this issue . P85 alpha cDNA was sequenced , and a single point mutation at codon 326 was found . This mutation resulted in a homozygous missense amino acid change DB00134 --> DB00167 in one subject with type 2 diabetes and heterozygous variant in two other diabetic patients and one with severe insulin resistance . Interestingly , those patients revealed an impaired insulin-mediated insulin receptor substrate ( P41252 ) -1 binding to p85 alpha without any alteration in Q9Y4H2 /p85 alpha association . Furthermore , P35568 , Q9Y4H2 , p85 alpha and MAPK protein contents were not significantly changed , and neither were MAPK or Akt phosphorylation . We conclude from our data that this variant may have only minor impact on signaling events ; however , in combination with variants in other genes encoding signaling proteins , this may have a functional impact on early insulin signaling . Retinoic acid receptors in retinoid responsive ovarian cancer cell lines detected by polymerase chain reaction following reverse transcription . The growth inhibitory effects of all-trans and 13-cis retinoic acid ( RA ) and of the synthetic retinoids DB02877 , DB02877 -ethylester and TTNN were studied on seven human epithelial ovarian cancer cell lines and one ovarian teratocarcinoma cell line . Six of seven ovarian adenocarcinoma cell lines were inhibited in their growth by RA and by synthetic retinoids in a dose dependent manner . No response to these substances was observed for the ovarian teratocarcinoma cell line . The knowledge that RA and retinoids exert their action on the cells via nuclear receptors led us to examine the expression of P10276 , -beta and -gamma mRNA by these cell lines by polymerase chain reaction following reverse transcription . All cell lines expressed P10276 and -gamma mRNA and six of the eight cell lines were found to express additionally P10826 mRNA , among them the ovarian teratocarcinoma cell line . Our data indicate that there was no direct association between the presence of RAR subtype transcripts and the response to retinoids in ovarian cancer cell lines . Interactions Between Ataxia Telangiectasia Mutated Kinase Inhibition , Poly(ADP-ribose) Polymerase-1 Inhibition and P38398 Status in Breast Cancer Cells . BACKGROUND : Cells harboring P38398 / P51587 mutations are hypersensitive to inhibition of poly(ADP-ribose) polymerase-1 ( P09874 ) . We recently showed that interference with P09874 activity by DB02690 is strongly cytotoxic for P38398 -positive BT-20 cells but not P38398 -deficient SKBr-3 cells . These unexpected observations prompted speculation that other P09874 inhibitor(s) may be more cytotoxic towards SKBr-3 cells . In addition , interference with the DNA damage signaling pathway via ( for instance ) Q13315 ( Q13315 ) kinase inhibition may induce synthetic lethality in DNA repair-deficient breast cancer cells and pharmacological interference with Q13315 activity may sensitize breast cancer cells to P09874 inactivation . METHODS : We determined drug cytotoxicity in human MCF-7 and SKBr-3 breast cancer cells using the CellTiterGLO Luminescent cell viability assay and a Tecan multi-label , multitask plate counter to measure generated luminescence . Changes in cell cycle progression were monitored by flow cytometric measurement of DNA content in cells stained with propidium iodide . RESULTS : Unlike DB02690 , AZD2461 , a new P09874 inhibitor , markedly reduced the numbers of living MCF-7 and SKBr-3 cells . Q13315 kinase inhibition ( CP466722 ) was also cytotoxic for both MCF-7 and SKBr-3 cells . Furthermore , AZD2461 enhanced the cytotoxicity of CP466722 in both cell lines by inducing apoptosis , and concurrent inhibition of Q13315 and P09874 reduced cell proliferation more strongly than either single treatment . CONCLUSIONS : Our data show that inhibition of P09874 by AZD2461 is synthetically lethal for DB02690 -resistant MCF-7 and SKBr-3 breast cancer cells . They also indicate that DNA damage signaling is essential for survival of both SKBr-3 and MCF-7 cells , especially after inactivation of P09874 . Inhibition of related JAK/ P35610 pathways with molecular targeted drugs shows strong synergy with ruxolitinib in chronic myeloproliferative neoplasm . This study aimed to assess the antitumour effects , molecular mechanisms of action , and potential synergy of ruxolitinib with sorafenib , KNK437 , dasatinib , and perifosine , in Philadelphia-negative chronic myeloproliferative neoplasms ( Q9BQR3 ) . Cytotoxic and cytostatic effects of the different compounds were determined in the O60674 V617F-positive cell lines , HEL and Ba/ P13726 ( JAK2V617F P19235 ) , and in primary mononuclear and bone marrow P28906 -positive cells from 19 Q9BQR3 patients . DB08877 [ 50 % inhibitory concentration ( IC50 ) (PV) = 15 nmol/l ] , as well as sorafenib ( IC50 PV=8μmol/l ) , KNK437 ( IC50 PV=100μmol/l ) , and perifosine ( IC50 PV=15μmol/l ) , were able to inhibit proliferation in cell line models and in primary cells from Q9BQR3 patients . Dasatinib , KNK437 , and sorafenib showed a strong synergistic effect in combination with ruxolitinib [ combination index ( CI ) (PV) < 0·3 ] . Western blot confirmed that ruxolitinib blocked P29323 , and consequently P42229 activation , sorafenib inhibited P29323 , O75791 and P42229 , dasatinib blocked P12931 and P42229 , and KNK437 decreased the stability of the O60674 protein , reducing its expression . Inhibiting O60674 -related proliferative pathways has the potential to inhibit cell proliferation in MPNs . Furthermore , the combination of ruxolitinib with inhibitors that target these pathways has a strong synergistic effect , which may be due to decreased activation of the common effector , P42229 . Conditional ablation of mediator subunit MED1 ( MED1/ Q15648 ) gene in mouse liver attenuates glucocorticoid receptor agonist dexamethasone-induced hepatic steatosis . P04150 ( GR ) agonist dexamethasone ( DB00514 ) induces hepatic steatosis and enhances constitutive androstane receptor ( CAR ) expression in the liver . CAR is known to worsen hepatic injury in nonalcoholic hepatic steatosis . Because transcription coactivator MED1/ Q15648 gene is required for GR- and CAR-mediated transcriptional activation , we hypothesized that disruption of MED1/ Q15648 gene in liver cells would result in the attenuation of DB00514 -induced hepatic steatosis . Here we show that liver-specific disruption of MED1 gene ( MED1 ( delta Liv ) ) improves DB00514 -induced steatotic phenotype in the liver . In wild-type mice DB00514 induced severe hepatic steatosis and caused reduction in medium- and short-chain acyl- DB01992 dehydrogenases that are responsible for mitochondrial beta-oxidation . In contrast , DB00514 did not induce hepatic steatosis in mice conditionally null for hepatic MED1 , as it failed to inhibit fatty acid oxidation enzymes in the liver . MED1 ( delta Liv ) livers had lower levels of GR-regulated CAR mRNA compared to wild-type mouse livers . Microarray gene expression profiling showed that absence of MED1 affects the expression of the GR-regulated genes responsible for energy metabolism in the liver . These results establish that absence of MED1 in the liver diminishes DB00514 -induced hepatic steatosis by altering the GR- and CAR-dependent gene functions . The JAK inhibitor , tofacitinib , reduces the T cell stimulatory capacity of human monocyte-derived dendritic cells . OBJECTIVE : DB08895 , which is a Janus kinase ( JAK ) inhibitor , has shown clinical effects in the treatment of rheumatoid arthritis . JAKs are important kinases in lymphocyte differentiation ; however , their function in dendritic cells ( DCs ) is unknown . In this study , the function of JAKs in DCs was investigated with tofacitinib . METHODS : The effects of tofacitinib on the maturation of human monocyte-derived DCs induced by lipopolysaccharide ( LPS ) stimulation were investigated . In addition , its effects on T cell stimulatory capability was investigated by coculturing with naïve CD45RA-positive T cells . RESULTS : DB08895 decreased expression of P33681 / P42081 in a concentration-dependent manner in LPS-stimulated DCs ; however , it did not affect HLA-DR expression . DB08895 suppressed tumour necrosis factor , interleukin ( IL ) -6 and IL-1β production without affecting transforming growth factor ( TGF ) -β and P22301 production . Meanwhile , P33681 / P42081 expression in DCs was enhanced by type I interferon ( IFN ) stimulation , and the LPS-induced P33681 / P42081 expression was inhibited by an antibody to type I IFN receptor . Furthermore , tofacitinib suppressed production of type I IFN and activation of interferon regulatory factor ( Q969Q1 ) -7 , which is a transcription factor involved in P33681 / P42081 and type I IFN expression . DB08895 also decreased the T cell stimulatory capability of DCs and increased expression of indoleamine 2,3-dioxygenase ( P14902 ) -1 and Q6ZQW0 . CONCLUSIONS : DB08895 , a P23458 / P52333 inhibitor , affected the activities of human DCs . It decreased P33681 / P42081 expression and T cell stimulatory capability through suppression of type I IFN signalling . These results suggest a novel mode of action for tofacitinib and a pivotal role for JAKs in the differentiation of DCs . Sequencing a mouse acute promyelocytic leukemia genome reveals genetic events relevant for disease progression . Acute promyelocytic leukemia ( APL ) is a subtype of acute myeloid leukemia ( AML ) . It is characterized by the t(15;17)(q22;q11.2) chromosomal translocation that creates the promyelocytic leukemia-retinoic acid receptor α ( P29590 - P10276 ) fusion oncogene . Although this fusion oncogene is known to initiate APL in mice , other cooperating mutations , as yet ill defined , are important for disease pathogenesis . To identify these , we used a mouse model of APL , whereby P29590 - P10276 expressed in myeloid cells leads to a myeloproliferative disease that ultimately evolves into APL . Sequencing of a mouse APL genome revealed 3 somatic , nonsynonymous mutations relevant to APL pathogenesis , of which 1 ( Jak1 V657F ) was found to be recurrent in other affected mice . This mutation was identical to the P23458 V658F mutation previously found in human APL and acute lymphoblastic leukemia samples . Further analysis showed that P23458 V658F cooperated in vivo with P29590 - P10276 , causing a rapidly fatal leukemia in mice . We also discovered a somatic 150-kb deletion involving the lysine ( K ) -specific demethylase 6A ( Kdm6a , also known as Utx ) gene , in the mouse APL genome . Similar deletions were observed in 3 out of 14 additional mouse APL samples and 1 out of 150 human AML samples . In conclusion , whole genome sequencing of mouse cancer genomes can provide an unbiased and comprehensive approach for discovering functionally relevant mutations that are also present in human leukemias . The heme oxygenase system rescues hepatic deterioration in the condition of obesity co-morbid with type-2 diabetes . The prevalence of non-alcoholic fatty-liver disease ( NAFLD ) is increasing globally . NAFLD is a spectrum of related liver diseases that progressive from simple steatosis to serious complications like cirrhosis . The major pathophysiological driving of NAFLD includes elevated hepatic adiposity , increased hepatic triglycerides/cholesterol , excessive hepatic inflammation , and hepatocyte ballooning injury is a common histo-pathological denominator . Although heme-oxygenase ( HO ) is cytoprotective , its effects on hepatocyte ballooning injury have not been reported . We investigated the effects of upregulating HO with hemin or inhibiting it with stannous-mesoporphyrin ( DB04912 ) on hepatocyte ballooning injury , hepatic adiposity and inflammation in Zucker-diabetic-fatty rats ( ZDFs ) , an obese type-2-diabetic model . DB03404 administration to ZDFs abated hepatic/plasma triglycerides and cholesterol , and suppressed several pro-inflammatory cytokines and chemokines including , P01375 -α , P05231 , IL-1β , macrophage-inflammatory-protein-1α ( MIP-1α ) and macrophage-chemoattractant-protein-1 ( P13500 ) , with corresponding reduction of the pro-inflammatory M1-phenotype marker , Q92838 and hepatic macrophage infiltration . Correspondingly , hemin concomitantly potentiated the protein expression of several markers of the anti-inflammatory macrophage-M2-phenotype including ED2 , P22301 and CD-206 , alongside components of the HO-system including P09601 , HO-activity and cGMP , whereas the HO-inhibitor , DB04912 abolished the effects . Furthermore , hemin attenuated liver histo-pathological lesions like hepatocyte ballooning injury and fibrosis , and reduced extracellular-matrix/profibrotic proteins implicated in liver injury such as osteopontin , TGF-β1 , fibronectin and collagen-IV . We conclude that hemin restore hepatic morphology by abating hepatic adiposity , suppressing macrophage infiltration , inflammation and fibrosis . The selective enhancement of anti-inflammatory macrophage-M2-phenotype with parallel reduction of pro-inflammatory macrophage-M1-phenotype and related chemokines/cytokines like P01375 -α , P05231 , IL-1β , MIP-1α and P13500 are among the multifaceted mechanisms by which hemin restore hepatic morphology . Constitutive NF-kappaB activation confers interleukin 6 ( P05231 ) independence and resistance to dexamethasone and Janus kinase inhibitor DB08877 in murine plasmacytoma cells . Myeloma cells are dependent on P05231 for their survival and proliferation during the early stages of disease , and independence from P05231 is associated with disease progression . The role of the NF-κB pathway in the P05231 -independent growth of myeloma cells has not been studied . Because human herpesvirus 8-encoded P13646 selectively activates the NF-κB pathway , we have used it as a molecular tool to examine the ability of the NF-κB pathway to confer P05231 independence on murine plasmacytomas . We demonstrated that ectopic expression of P13646 , but not its NF-κB-defective mutant or a structural homolog , protected plasmacytomas against P05231 withdrawal-induced apoptosis and resulted in emergence of P05231 -independent clones that could proliferate long-term in vitro in the absence of P05231 and form abdominal plasmacytomas with visceral involvement when injected intraperitoneally into syngeneic mice . These P05231 -independent clones were dependent on NF-κB activity for their survival and proliferation but were resistant to dexamethasone and DB08877 , a selective P23458 /2 inhibitor . Ectopic expression of human T cell leukemia virus 1-encoded Tax protein , which resembles P13646 in inducing constitutive NF-κB activation , similarly protected plasmacytoma cells against P05231 withdrawal-induced apoptosis . Although P13646 is known to up-regulate P05231 gene expression , its protective effect was not due to induction of endogenous P05231 production but instead was associated with sustained expression of several antiapoptotic members of the Bcl2 family upon P05231 withdrawal . Collectively , these results demonstrate that NF-κB activation can not only promote the emergence of P05231 independence during myeloma progression but can also confer resistance to dexamethasone and DB08877 .