interacts_with DB08870?
3,4-Dimethoxyphenyl bis-benzimidazole derivative , mitigates radiation-induced DNA damage . Radiation-induced DNA damage initiates a series of overlapping responses that include DNA damage recognition and repair , induction of cell cycle checkpoints , senescence and/or apoptosis . This study assessed the DNA damage response and whole genome expression profile in two mammalian cell lines ( P29320 and U87 ) in response to ( 5-{4-methylpiperazin-1-yl}-2-[2'-(3,4-dimethoxyphenyl)-5'-benzimidazolyl] benzimidazole ) P28067 and ionizing radiation . P28067 has been shown to act as a potent radiation protector , yielding significant levels of protection , i.e. , 20.9 % in P29320 cells and 21.2 % in U87 cells . Our findings revealed treatment with P28067 significantly reduced γ- P16104 , Q12888 and Rad51 foci formation after irradiation . Q96HU1 kinase , WNT signaling and p53 pathways were found to be activated in P28067 -treated cells . In addition , the DNA damage response genes , HSP70 , P10809 , Q06830 , Q9BXM0 , P27797 , P06748 , P0CG48 , and Q01105 showed differential regulation in P28067 , P28067 + radiation and radiation-treated cells . The data suggest that P28067 -influenced repertoire of repair proteins , which are an indispensable part of the cell , interplay with each other to reduce DNA damage and maintain the genomic integrity of the cell . DB00559 , an endothelin receptor antagonist , ameliorates collagen-induced arthritis : the role of P01375 -α in the induction of endothelin system genes . OBJECTIVE : Endothelins ( ETs ) are involved in several inflammatory events . The present study investigated the efficacy of DB00559 , a dual P25101 /ETB receptor antagonist , in collagen-induced arthritis ( CIA ) in mice . TREATMENT : CIA was induced in DBA/1J mice . Arthritic mice were treated with DB00559 ( 100 mg/kg ) once a day , starting from the day when arthritis was clinically detectable . METHODS : CIA progression was assessed by measurements of visual clinical score , paw swelling and hypernociception . Histological changes , neutrophil infiltration and pro-inflammatory cytokines were evaluated in the joints . Gene expression in the lymph nodes of arthritic mice was evaluated by microarray technology . PreproET-1 mRNA expression in the lymph nodes of mice and in peripheral blood mononuclear cells ( PBMCs ) was evaluated by real-time PCR . The differences were evaluated by one-way Q9UNW9 or Student 's t test . RESULTS : Oral treatment with DB00559 markedly ameliorated the clinical aspects of CIA ( visual clinical score , paw swelling and hyperalgesia ) . DB00559 treatment also reduced joint damage , leukocyte infiltration and pro-inflammatory cytokine levels ( IL-1β , TNFα and Q16552 ) in the joint tissues . Changes in gene expression in the lymph nodes of arthritic mice returned to the levels of the control mice after DB00559 treatment . PreproET mRNA expression increased in PBMCs from rheumatoid arthritis ( RA ) patients but returned to basal level in PBMCs from patients under anti- P01375 therapy . In-vitro treatment of PBMCs with TNFα upregulated ET system genes . CONCLUSION : These findings indicate that ET receptor antagonists , such as DB00559 , might be useful in controlling RA . Moreover , it seems that ET mediation of arthritis is triggered by TNFα . The unexpected effect of cyclosporin A on CD56+CD16- and CD56+CD16+ natural killer cell subpopulations . DB00091 ( Q13216 ) is commonly used to prevent graft-versus-host disease . The influence of Q13216 on T-cell function has been extensively investigated ; however , the effect of Q13216 on natural killer ( NK ) cells is less understood . NK cells were cultured with P60568 and P40933 with and without Q13216 for 1 week . Compared with controls , Q13216 -treated cultures showed fewer CD56(+)CD16(+) P55040 (+) NK cells and a reciprocal increase in CD56(+)CD16(-) P55040 (-) cells . These changes were due mainly to a reduced proliferation of the CD56(dim) NK-cell subpopulation and a relative resistance of CD56(bright) NK cells to Q13216 . Following coculture with K562 targets , Q13216 -exposed NK cells differed from controls and lacked Ca(2+) oscillations , nuclear factor of activated T cells ( NFAT ) dephosphorylation , and NFAT nuclear translocation . NK cells cultured in Q13216 retained cytotoxicity against K562 , Raji , and P55040 ligand-expressing lymphoblastoid cells . NK cells cultured in Q13216 showed increases in O14931 and reductions in O95944 and P26718 . Following IL-12 and Q14116 stimulation , Q13216 -treated NK cells showed more P01579 -producing cells . Using in vitro NK-cell differentiation , progenitor cells gave rise to more CD56(+) P55040 (-) NK cells in the presence of Q13216 than controls . Collectively , these studies show that Q13216 influences NK-cell function and phenotype , which may have important implications for graft-versus-leukemia effects . Intracellular capture of P33681 in antigen-presenting cells reduces costimulatory activity . P16410 gene constructs were designed to express P16410 exclusively in the endoplasmic reticulum ( ER ) . Four different P16410 gene constructs were transfected into P29320 293 ( human embryonic kidney ) and A20 ( Balb/c mouse B lymphoma ) cells . All constructs contained an ER retention signal and coded for P16410 expression in the ER . One of the constructs , which contained the membrane part of P16410 , coded for an expression both on the cell surface and in the ER . Three of the expressed P16410 types ( including the ER-membrane-expressed form ) caused a reduced surface expression of P33681 in the A20 cells . Only constructs which allow dimerization of P16410 showed this effect . It is assumed that intracellular P16410 bound P33681 and inhibited therefore the transport of P33681 to the surface . The binding obviously caused also an enhanced degradation of the complexes because both proteins showed a low concentration in the transfected cell lines . P16410 -transfected and P33681 -reduced A20 cells showed a diminished costimulating activity upon T cells . This was demonstrated by a reduced proliferation of T cells from ovalbumin-immunized Balb/c mice , incubated with ovalbumin peptide-primed P16410 -transfected A20 cells . Induction of oral tolerance to oxidized low-density lipoprotein ameliorates atherosclerosis . BACKGROUND : Oxidation of low-density lipoprotein ( LDL ) and the subsequent processing of oxidized LDL ( oxLDL ) by macrophages results in activation of specific T cells , which contributes to the development of atherosclerosis . Oral tolerance induction and the subsequent activation of regulatory T cells may be an adequate therapy for the treatment of atherosclerosis . METHODS AND RESULTS : Tolerance to oxLDL and malondialdehyde-treated LDL ( MDA-LDL ) was induced in P01130 -/- mice fed a Western-type diet by oral administration of oxLDL or MDA-LDL before the induction of atherogenesis . Oral tolerance to oxLDL resulted in a significant attenuation of the initiation ( 30 % to 71 % ; P < 0.05 ) and progression ( 45 % ; P < 0.05 ) of atherogenesis . Tolerance to oxLDL induced a significant increase in P01730 + CD25+ Foxp3+ cells in spleen and mesenteric lymph nodes , and these cells specifically responded to oxLDL with increased transforming growth factor-beta production . Tolerance to oxLDL also increased the mRNA expression of Foxp3 , P16410 , and CD25 in the plaque . In contrast , tolerance to MDA-LDL did not affect atherogenesis . CONCLUSIONS : OxLDL-specific T cells , present in P01130 -/- mice and important contributors in the immune response leading to atherosclerotic plaque , can be counteracted by oxLDL-specific P01730 + CD25+ Foxp3+ regulatory T cells activated via oral tolerance induction to oxLDL . We conclude that the induction of oral tolerance to oxLDL may be a promising strategy to modulate the immune response during atherogenesis and a new way to treat atherosclerosis . Resistance to killing by tumor necrosis factor in an adipocyte cell line caused by a defect in arachidonic acid biosynthesis . We have found that Q96RJ0 -R6 , which are resistant to the cytotoxic effects of tumor necrosis factor ( P01375 ) in the presence of cycloheximide ( Reid , T. R. , Torti , F. , and Ringold , G. M. ( 1989 ) J. Biol. Chem. 264 , 4583-4589 ) , have reduced ability to release arachidonic acid ( 20:4 ) from membrane phospholipids in response to either P01375 or the calcium ionophore A23187 treatment . However , no defect in the activity of phospholipase A2 , the principal enzyme responsible for the release of 20:4 from phospholipids , was observed in these cells . Detailed biochemical characterization of these P01375 -resistant cells has revealed that these cells are unable to synthesize 20:4 endogenously because of a defect in delta 6-desaturase , the rate-limiting enzyme of 20:4 biosynthesis . This deficiency leads to a marked decrease in the steady-state levels of 20:4 present in choline-containing phospholipid ( PC ) and ethanolamine-containing phospholipid ( PE ) . The Q96RJ0 -R6 cells , however , are capable of incorporating exogenous 20:4 into PC and PE , and when loaded in such manner they become significantly more sensitive to the cytotoxic effects of P01375 in the presence of cycloheximide . Therefore , the release of arachidonic acid from phospholipids appears to be a critical element in the signaling pathway utilized by P01375 and is essential to the rapid cytotoxic response elicited by P01375 in the absence of protein synthesis in wild-type Q96RJ0 cells . Immunoregulatory natural killer cells suppress autoimmunity by down-regulating antigen-specific CD8+ T cells in mice . Natural killer ( NK ) cells belong to the innate immune system . Besides their role in antitumor immunity , NK cells also regulate the activity of other cells of the immune system , including dendritic cells , macrophages , and T cells , and may , therefore , be involved in autoimmune processes . The aim of the present study was to clarify the role of NK cells within this context . Using two mouse models for type 1 diabetes mellitus , a new subset of NK cells with regulatory function was identified . These cells were generated from conventional NK cells by incubation with Q14116 and are characterized by the expression of the surface markers CD117 ( also known as c-Kit , stem cell factor receptor ) and programmed death ( PD ) -ligand 1 . In vitro analyses demonstrated a direct lysis activity of Q14116 -stimulated NK cells against activated insulin-specific CD8(+) T cells in a P18621 /PD-ligand 1-dependent manner . Flow cytometry analyses revealed a large increase of splenic and lymphatic NK1.1(+)/c-Kit(+) NK cells in nonobese diabetic mice at 8 wk of age , the time point of acceleration of adaptive cytotoxic immunity . Adoptive transfer of unstimulated and Q14116 -stimulated NK cells into streptozotocin-treated mice led to a delayed diabetes development and partial disease prevention in the group treated with Q14116 -stimulated NK cells . Consistent with these data , mild diabetes was associated with increased numbers of NK1.1(+)/c-Kit(+) NK cells within the islets . Our results demonstrate a direct link between innate and adaptive immunity in autoimmunity with newly identified immunoregulatory NK cells displaying a potential role as immunosuppressors . [ Anti-cholesterol agents , new therapeutic approaches ] . Statins and fibrates constitute the two major families of lipid-lowering agents . Statins are widely used for the treatment of pure hypercholesterolaemia while fibrates are used for the treatment of hypertriglyceridemia . Both drugs are also used for the treatment of mixed dyslipidemia . Some fibrates efficiently lower serum LDL-cholesterol . Statins inhibit P04035 and decrease cellular cholesterol synthesis . The resulting lower intracellular cholesterol concentration induces the activation of SREBP thus inducing the over expression and transcription of the P01130 gene . This over expression of the P01130 in the liver increases the clearance of circulating LDL thus decreasing the LDL-cholesterol plasma levels . The effects of fibrates on lipid metabolism are entirely due to their capacity to activate Q07869 and to induce the over expression of genes containing a PPRE in their promoter . Fibrates decrease triglyceride concentrations by increasing the beta-oxidation of fatty acids in the liver and by decreasing triglyceride-VLDL synthesis . Fibrates also decrease triglycerides by increasing the hydolysys of triglycerides in chylomicron and VLDL through their capacity to increase and to decrease the lipoprotein lipase and the apo C-III transcription , respectively . Fibrates could decrease triglycerides partly by inducing apo A-V over-expression . These molecules increase HDL-cholesterol by increasing apo A-I and apo A-II transcription . Therefore the mechanisms of action of statins and fibrates depend on their capacity to modulate the expression of genes controlling lipoprotein metabolism . DB00099 -induced stem cell mobilization in chronic myeloid leukaemia patients during imatinib therapy : safety , feasibility and evidence for an efficient in vivo purging . Therapy with imatinib mesylate is limited by cellular resistance in chronic myeloid leukaemia ( CML ) . Further , the limited availability of matching stem cell donors or an unfavourable risk profile for allogeneic stem cell transplantation ( P09683 ) reduces the number of therapeutic options in a number of patients . To assess the possibility of stem cell mobilization ( DB00919 ) during imatinib therapy we performed granulocyte colony-stimulating factor (filgrastim)-induced DB00919 and subsequent aphaeresis in 15 chronic phase and three accelerated phase CML patients . Aphaeresis was successful in 13 patients ( 72 % ) ( > or =2.0 x 10(6) P28906 + cells/kg body weight ) and five ( 28 % ) harvests could be obtained , which were negative for P11274 / P00519 mRNA as assessed by nested-reverse transcription polymerase chain reaction ( RT-PCR ) . All harvests , except one , were negative after first round RT-PCR , implicating a low level of CML cell contamination . There was no significant change in peripheral P11274 / P00519 transcript load after DB00919 as assessed by quantitative real-time RT-PCR . Fifteen patients remained stable in complete cytogenetic remission ( CCR ) during a median observation period of 9.3 months . One patient achieved a molecular remission shortly after DB00919 . Another patient who exhibited rising P11274 / P00519 mRNA levels before DB00919 achieved CCR after autologous P09683 with the generated harvest . One patient with a Philadelphia chromosome-negative , P11274 / P00519 -positive CML showed a cytogenetic relapse 6 months after DB00919 . We conclude that filgrastim-induced P28906 + cell aphaeresis under simultaneous imatinib medication is safe and feasible in CML patients . Additionally , we found evidence that this procedure could generate stem cell harvests that exhibit non-detectable levels of P11274 / P00519 mRNA . Growth inhibition in clonal subpopulations of a human epithelioid sarcoma cell line by retinoic acid and tumour necrosis factor alpha . Epithelioid sarcoma is a highly malignant soft tissue tumour that is refractory to conventional chemotherapy and irradiation . Since permanent cell lines of this tumour are extremely rare , in vitro data on compounds with significant antiproliferative effects are still lacking . Therefore , we investigated the effects of retinoic acid ( RA ) and tumour necrosis factor alpha ( P01375 ) on tumour cell proliferation of three different clonal subpopulations ( GRU-1A , GRU-1B , GRU-1C ) derived from the same human epithelioid sarcoma cell line , GRU-1 . In GRU-1A both RA ( P=0.01 ) and P01375 ( P=0.002 ) exhibited highly significant and dose-dependent growth inhibitory effects , which could further be increased by a combined application of both compounds ( P < 0.006 ) . GRU-1B proved to be sensitive to RA ( P=0.006 ) , whereas no response to P01375 was observed . GRU-1C was resistant to both RA and P01375 . The antiproliferative effect of P01375 was mediated by P01375 receptor 1( P19438 ) and correlated positively with both the number of P19438 per cell and receptor affinity . No correlation was detected between RA-induced growth inhibition and the expression pattern of the RA receptors ( RARs ) P10276 , P10826 , and P13631 . Plating efficiency , however , could exclusively be reduced by RA in GRU-1B , the only cell line expressing P10276 . Taken together , these data are the first showing significant antiproliferative effects in human epithelioid sarcoma by RA and P01375 . Whereas the P01375 response seems to depend on the expression of P19438 , no simple correlation could be found between RA sensitivity and the expression pattern of RARs . GVHD prophylaxis with sirolimus-tacrolimus may overcome the deleterious effect on survival of HLA mismatch after reduced-intensity conditioning allo- P09683 . Large studies , mostly based on series of patients receiving Q13216 /tacrolimus ( P51854 ) plus MTX as immunoprophylaxis , have demonstrated a deleterious effect on survival of the presence of a single mismatch out of eight loci after allogeneic hematopoietic P09683 ( alloHSCT ) . We retrospectively analyzed a series of 159 adult patients who received sirolimus( Q86TD4 )/ P51854 prophylaxis after alloHSCT . We compared overall outcomes according to HLA compatibility in A , B , C and Q8IUH3 loci at the allele level : 7/8 ( n=20 ) vs 8/8 ( n=139 ) . Donor type was unrelated in 95 % vs 70 % among 7/8 vs 8/8 pairs , respectively ( P=0.01 ) . No significant differences were observed in 3-year OS ( 68 vs 62 % ) , 3-year O43281 ( 53 vs 49 % ) and 1-year non-relapse mortality ( 9 vs 13 % ) . Cumulative incidence of grades II-IV acute GVHD ( aGVHD ) was significantly higher in 7/8 alloHSCT ( 68 % vs 42 % , P < 0.001 ) but no significant differences were found for III-IV aGVHD ( 4.5 % vs 11 % ) , overall ( 35 % vs 53 % ) and extensive ( 20 % vs 35 % ) chronic GHVD in 7/8 vs 8/8 subgroups , respectively . In summary , the present study indicates favorable outcomes after alloHSCT using the combination of Q86TD4 / P51854 combination as GVHD prophylaxis with OS in the range of 55-70 % , and non-significant differences in overall outcomes , irrespective of the presence of any mismatches at obligatory loci . Hepatic stellate cells undermine the allostimulatory function of liver myeloid dendritic cells via P40763 -dependent induction of P14902 . Hepatic stellate cells ( HSCs ) are critical for hepatic wound repair and tissue remodeling . They also produce cytokines and chemokines that may contribute to the maintenance of hepatic immune homeostasis and the inherent tolerogenicity of the liver . The functional relationship between HSCs and the professional migratory APCs in the liver , that is , dendritic cells ( DCs ) , has not been evaluated . In this article , we report that murine liver DCs colocalize with HSCs in vivo under normal , steady-state conditions , and cluster with HSCs in vitro . In vitro , HSCs secrete high levels of DC chemoattractants , such as MΙP-1α and P13500 , as well as cytokines that modulate DC activation , including P01375 -α , P05231 , and IL-1β . Culture of HSCs with conventional liver myeloid ( m ) DCs resulted in increased P05231 and P22301 secretion compared with that of either cell population alone . Coculture also resulted in enhanced expression of costimulatory ( P33681 , P42081 ) and coinhibitory ( Q9NZQ7 ) molecules on mDCs . P19526 -induced mDC maturation required cell-cell contact and could be blocked , in part , by neutralizing MΙP-1α or P13500 . P19526 -induced mDC maturation was dependent on activation of P40763 in mDCs and , in part , on P19526 -secreted P05231 . Despite upregulation of costimulatory molecules , mDCs conditioned by HSCs demonstrated impaired ability to induce allogeneic T cell proliferation , which was independent of Q9NZQ7 , but dependent upon P19526 -induced P40763 activation and subsequent upregulation of P14902 . In conclusion , by promoting P14902 expression , HSCs may act as potent regulators of liver mDCs and function to maintain hepatic homeostasis and tolerogenicity . Cordycepin suppresses P01375 -α-induced NF-κB activation by reducing p65 transcriptional activity , inhibiting IκBα phosphorylation , and blocking IKKγ ubiquitination . Cordycepin is reported to participate in multiple pharmacological activities including anti-tumor and anti-inflammation , and is involved in the regulation of NF-κB signaling pathway . However , the detailed molecular mechanism of cordycepin in suppression of NF-κB signaling pathway remains ambiguous . In this study , we first analyzed the effect of cordycepin on NF-κB activity in P29320 -293T cells , and found that cordycepin resulted in a dose-dependent reduction in P01375 -α-induced NF-κB activation . Although cordycepin did not block P01375 -α-induced nuclear translocation of p65 , high concentration of cordycepin reduced the DNA-binding and transcriptional activities of NF-κB . Moreover , cordycepin also inhibited IκBα phosphorylation so as to suppress the degradation of IκBα . Further investigation revealed that cordycepin suppressed IKKs-mediated NF-κB activation and inhibited the ubiquitination of IKKγ . In conclusion , cordycepin effectively inhibits NF-κB signaling through suppressing the activities of NF-κB , IκB and IKK . Thus , cordycepin may provide some potential therapeutic application in inflammation-associated disorders and cancer . Proteome-wide changes induced by the Hsp90 inhibitor , geldanamycin in anaplastic large cell lymphoma cells . The molecular chaperone heat shock protein 90 ( Hsp90 ) affects the function of many oncogenic signaling proteins including nucleophosmin-anaplastic lymphoma kinase ( P06748 - Q9UM73 ) expressed in anaplastic large cell lymphoma ( ALCL ) . While Q9UM73 -positive ALCL cells are sensitive to the Hsp90 inhibitor and the geldanamycin ( GA ) analog , 17-allylamino-17-demethoxygeldanamycin ( 17- P29372 ) , the proteomic effects of these drugs on Q9UM73 -positive ALCL cells are unpublished . In this study , we investigated the cellular , biologic , and proteomic changes occurring in Q9UM73 -positive ALCL cells in response to GA treatment . GA induced G2/M cell cycle arrest and caspase-3-mediated apoptosis . Furthermore , quantitative proteomic changes analyzed by cleavable isotope-coded affinity tag-LC-MS/MS ( cICAT-LC-MS/MS ) identified 176 differentially expressed proteins . Out of these , 49 were upregulated 1.5-fold or greater and 70 were downregulated 1.5-fold or greater in GA-treated cells . Analysis of biological functions of differentially expressed proteins revealed diverse changes , including induction of proteins involved in the 26S proteasome as well as downregulation of proteins involved in signal transduction and protein and nucleic acid metabolism . Pathway analysis revealed changes in MAPK , WNT , NF-kappaB , TGFbeta , Q07869 , and integrin signaling components . Our studies reveal some of the molecular and proteomic consequences of Hsp90 inhibition in Q9UM73 -positive ALCL cells and provide novel insights into the mechanisms of its diverse cellular effects . Glioma cell activation by Alzheimer 's peptide Abeta1-42 , alpha1-antichymotrypsin , and their mixture . We compared the effects ofAlzheimer 's peptide ( Abeta1-42 ) , a,-antichymotrypsin ( ACT ) and an ACT/Abeta1-42 mixture on human glioma DK-MG cells . The solution of Abeta ( 5 microM ) formed by 2-h incubation at room temperature induced tumour necrosis factor-alpha ( P01375 ) and interleukin ( IL ) -6 levels by 55 and 45 % , respectively , and increased gelatinase B activity by 67 % , while exposure of cells to the ACT/Abeta1-42 mixture ( 1:10 molar ratio ACT : Abeta1-42 ) under the same experimental conditions showed no effect on P05231 levels or gelatinase B activity , but strongly induced P01375 ( by 190 % ) , compared to the controls . Stimulation of the cells with Abeta1-42 alone , but not with ACT , increased by about 20 % low-density lipoprotein ( LDL ) uptake and mRNA levels for P01130 and P04035 , while the ACT/Abeta1-42 mixture significantly increased LDL uptake ( by 50 % ) , up-regulated mRNA levels for P01130 and P04035 by 48 and 63 % , respectively , and increased lipid accumulation by about 20-fold . These data suggest a possible new role for Abeta in Alzheimer 's disease through its interaction with the inflammatory reactant , ACT . Gating properties of Q14524 mutations and the response to mexiletine in long-QT syndrome type 3 patients . BACKGROUND : DB00379 ( Mex ) has been proposed as a gene-specific therapy for patients with long-QT syndrome type 3 ( LQT3 ) caused by mutations in the cardiac sodium channel gene ( Q14524 ) . The degree of QT shortening and the protection from arrhythmias vary among patients harboring different mutations . We tested whether the clinical response to Mex in LQT3 could be predicted by the biophysical properties of the different mutations . METHODS AND RESULTS : We identified 4 Q14524 mutations in 5 symptomatic LQT3 patients with different responses to Mex ( 6 to 8 mg . kg(-1) . d(-1) ) . We classified the mutations as sensitive to Mex ( P1332L , R1626P ; >/= 10 % of QTc shortening and QTc < 500 ms or no arrhythmias ) or insensitive to Mex ( S941N , M1652R ; negligible or no QTc shortening and sudden death ) . We measured Na(+) current from P29320 293 cells transfected with wild-type ( WT ) or mutant Nav1.5 . All mutations showed impaired inactivation of Na(+) current , but the mutations identified in patient responders to Mex ( P1332L , R1626P ) showed a hyperpolarizing shift of V(1/2) of steady-state inactivation . Furthermore , Mex produced use-dependent block with the order R1626P=P1332L > S941N=WT > M1652R , suggesting that Mex-sensitive mutants present prolonged recovery from Mex block . CONCLUSIONS : We propose that voltage dependence of channel availability and shifts of V(1/2) of steady-state inactivation correlate with the clinical response observed in LQT3 patients . This supports the view that the response to Mex is mutation specific and that in vitro testing may help to predict the response to therapy in LQT3 . P06748 -RAR , not the RAR- P06748 reciprocal t(5;17)(q35;q21) acute promyelocytic leukemia fusion protein , inhibits myeloid differentiation . The t(5;17) variant of acute promyelocytic leukemia ( APL ) fuses the nucleophosmin ( P06748 ) gene at 5q35 with the retinoic acid receptor alpha ( P10276 ) at 17q12-22 . We have previously shown that leukemic cells express both P06748 -RAR and RAR- P06748 reciprocal translocation products . In this study we investigated the potential role of both proteins in modulating myeloid differentiation . Expression of P06748 -RAR inhibited vitamin D3/transforming growth factor β ( TGFβ ) -mediated differentiation of U937 cells by more than 50 % . In contrast , RAR- P06748 expression did not alter vitamin D3/TGFβ-induced differentiation of U937 clones . These results indicate that P06748 -RAR , not RAR- P06748 , is the prime mediator of myeloid differentiation arrest in t(5;17) APL . Molecular and biologic characterization of a newly established Philadelphia-positive acute lymphoblastic leukemia cell line ( Z-33 ) with an autocrine response to GM- P04141 . We have recently established a new Philadelphia chromosome ( Ph1 ) -positive acute lymphoblastic leukemia ( ALL ) cell line , designated Z-33 . This line has Q401N2 morphology , ultrastructural characteristics of lymphoblasts and typical B lineage surface markers identical to those observed in the Ph1-positive ALL patient from whom the line was derived . In addition , a rearranged immunoglobulin heavy-chain gene ( JH ) band was found in Z-33 cells by Southern blot analysis , confirming B cell clonality . Cytogenetic analysis of the cell line revealed t(9;22)(q34;q11.2) . Polymerase chain reaction ( PCR ) -amplified cDNA from Z-33 cells demonstrated an e1-az P11274 - P00519 junction , and the p190BCR- P00519 protein was detected in them by the immune complex kinase assay . Z-33 cells produce interleukin ( IL ) -1 beta , P05231 , granulocyte colony-stimulating factor ( DB00099 ) , granulocyte-macrophage P04141 ( GM- P04141 ) , tumor necrosis factor ( P01375 ) -alpha , and transforming growth factor ( TGF ) -beta , Neither P01584 , DB00099 , P01375 , nor their corresponding antibodies affected the cell line 's growth . In contrast , anti-GM- P04141 neutralizing antibodies suppressed Z-33 colony formation , and GM- P04141 stimulated it in a dose-dependent fashion . In addition , receptor studies with biotinylated GM- P04141 demonstrated specific binding to Z-33 cells , indicating that the cells express GM- P04141 receptors . Taken together , our data suggest that the Ph1-positive Z-33 ALL cells produce GM- P04141 , express GM- P04141 receptors , and show an autocrine proliferative response to this cytokine . Augmentation of methamphetamine-induced behaviors in transgenic mice lacking the trace amine-associated receptor 1 . The trace amine-associated receptor 1 ( Q96RJ0 ) is a G protein-coupled receptor that is functionally activated by amphetamine-based psychostimulants , including amphetamine , methamphetamine and DB01454 . Previous studies have shown that in transgenic mice lacking the Q96RJ0 gene ( Q96RJ0 knockout ; KO ) a single injection of amphetamine can produce enhanced behavioral responses compared to responses evoked in wild-type ( WT ) mice . Further , the psychostimulant effects of cocaine can be diminished by selective activation of Q96RJ0 . These findings suggest that Q96RJ0 might be implicated in the rewarding properties of psychostimulants . To investigate the role of Q96RJ0 in the rewarding effects of drugs of abuse , the psychomotor stimulating effects of amphetamine and methamphetamine and the conditioned rewarding effects of methamphetamine and morphine were compared between WT and Q96RJ0 KO mice . In locomotor activity studies , both single and repeated exposure to DB01576 or methamphetamine generated significantly higher levels of total distance traveled in Q96RJ0 KO mice compared to WT mice . In conditioned place preference ( CPP ) studies , Q96RJ0 KO mice acquired methamphetamine-induced CPP earlier than WT mice and retained CPP longer during extinction training . In morphine-induced CPP , both WT and KO genotypes displayed similar levels of CPP . Results from locomotor activity studies suggest that Q96RJ0 may have a modulatory role in the behavioral sensitization to amphetamine-based psychostimulants . That methamphetamine-but not morphine-induced CPP was augmented in Q96RJ0 KO mice suggests a selective role of Q96RJ0 in the conditioned reinforcing effects of methamphetamine . Collectively , these findings provide support for a regulatory role of Q96RJ0 in methamphetamine signaling . Prophylaxis and treatment of GVHD : EBMT- P15502 working group recommendations for a standardized practice . GVHD remains the major impediment to broader application of allogeneic haematopoietic P09683 . It can be prevented completely , but at the expense of other complications , rejection , relapse or delayed immune reconstitution . No optimal prevention or treatment method has been defined . This is reflected by enormous heterogeneity in approaches in Europe . Retrospective comparisons between different policies , although warranted , do not give definite answers . In order to improve the present situation , an European Group for Blood and Marrow Transplantation and the European LeukemiaNet working group has developed in a Delphi-like approach recommendations for prophylaxis and treatment of GVHD in the most common allogeneic transplant setting , transplantation from an HLA-identical sibling or unrelated donor for standard risk malignant disease . The working group proposes these guidelines to be adopted as routine standard in transplantation centres and to be used as comparator in systematic studies evaluating the advantages and disadvantages of practices differing from these recommendations . Subclones with the t(9;22)/ P11274 - P00519 rearrangement occur in AML and seem to cooperate with distinct genetic alterations . In AML , cooperation of mutations suppressing differentiation ( ' class-II-mutations ' ) with ' class-I-mutations ' increasing cell proliferation is frequent . In rare cases of myeloid malignancies , the P11274 - P00519 fusion was reported to cooperate as class-I-mutation with class-II-mutations , but most cases had to be classified as blast phase of chronic myeloid leukaemia ( CML ) . We identified five cases of Philadelphia positive subclones in AML occurring in coincidence with other genetic lesions : 1:220 patients with inv(16)/ Q13951 - P35749 ( 0·5 % ) , 2:272 AML cases with t(8;21)/ Q01196 - Q06455 ( 0·7 % ) , 1:1029 P06748 -mutated AML ( 0·1 % ) , and one patient with s-AML following P43034 with a 5q-deletion . Four patients had m- P11274 ( e1a2 ) P11274 - P00519 transcripts ; one case only had an M- P11274 ( b3a2 ) breakpoint . These cases allow some interesting conclusions : The P11274 - P00519 rearrangement apparently can cooperate with the P06748 mutation similar to other class-I-mutations . The identification of Philadelphia positive subclones in < 1 % of patients with Q03701 -leukaemias fits well with previous observations that most Q03701 -AML are accompanied by activating mutations in genes enhancing proliferation . Since we observed the occurrence of the Philadelphia positive subclones at diagnosis , at relapse , or throughout the disease , the time point of the emergence of Philadelphia subclones seems variable in AML . Clinical research should further concentrate on Philadelphia positive subclones in AML to assess the clinical impact . Clinical impact of Q9Y6K1 mutations in younger adult patients with acute myeloid leukemia : results of the AML Study Group ( AMLSG ) . In this study , we evaluated the frequency and prognostic impact of Q9Y6K1 mutations ( Q9Y6K1 (mut) ) in 1770 younger adult patients with acute myeloid leukemia ( AML ) in the context of other genetic alterations and the European LeukemiaNet ( P15502 ) classification . Q9Y6K1 (mut) were found in 20.9 % of AMLs and were associated with older age ( P < .0001 ) , higher white blood cell counts ( P < .0001 ) , cytogenetically normal AML ( CN-AML ; P < .0001 ) , P06748 mutations ( P < .0001 ) , P36888 internal tandem duplications ( P < .0001 ) , and O75874 /2 mutations ( P < .0001 ) . In univariable and multivariable analyses , Q9Y6K1 (mut) did not impact event-free , relapse-free ( RFS ) , or overall survival ( OS ) in either the entire cohort or in CN-AML ; a negative prognostic effect was found only in the P15502 unfavorable CN-AML subset ( OS , P = .011 ) . In addition , R882 mutations vs non-R882 mutations showed opposite clinical effects-unfavorable for R882 on RFS ( all : hazard ratio [ HR ] , 1.29 [ P = .026 ] ; CN-AML : HR , 1.38 [ P = .018 ] ) and favorable for non-R882 on OS ( all : HR , 0.77 [ P = .057 ] ; CN-AML : HR , 0.73 [ P = .083 ] ) . In our statistically high-powered study with minimized selection bias , Q9Y6K1 (mut) represent a frequent genetic lesion in younger adults with AML but have no significant impact on survival end points ; only moderate effects on outcome were found , depending on molecular subgroup and Q9Y6K1 (mut) type . [ DB00707 sodium ( Photofrin-II ) ] . DB00707 sodium ( DB00707 ) is a photosensitizer which distributes selectively to tumor tissues , and causes tumor cell death by combination with light irradiation . Photodynamic therapy ( PDT ) by combination of porfimer sodium and laser was developed as a new cancer therapy . Tumor selectivity of porfimer sodium are based on the following reasons ; 1 ) high affinity for lipoprotein , especially , low density lipoprotein ( LDL ) , 2 ) elevation of P01130 activity in cancer tissue , and 3 ) lack or imcompleteness of lymphatic system in cancer tissue . DB00707 sodium is activated by laser irradiation at 630 nm , which can reacts with tissue oxygen to produce highly reactive excited siglet oxygen ( 1O2 ) . This highly reactive molecule is subsequently capable of killing tumor cells through oxidation of cellular component like mitochondrial enzymes . In addition , this highly reactive intermediate causes destruction of the tumor capillaries , which accelerates tumor cell death . The growth suppression or lethal damage to tumor cells by PDT of porfimer sodium and excimer dye laser were observed in experimental tumor models . In human clinical trials , the rates of complete response ( CR ) for roentgenographically occult lung cancer , stage I lung cancer , superficial esophageal cancer , superficial gastric cancer and carcinoma in situ or dysplasia of the cervix were 84.8 % , 50.0 % , 90.0 % , 87.5 % and 94.4 % , respectively . The major side effects were cutaneous symptoms e.g. photosensitivity , pigmentation , increasing GOT , GPT but these symptoms were not severe . PDT using porfimer sodium and excimer dye laser must be clinically useful for the treatment of inoperable early cancer or conservation of organ functions . Microtubule-depolymerizing agents used in antibody-drug conjugates induce antitumor immunity by stimulation of dendritic cells . Antibody-drug conjugates ( ADC ) are emerging as powerful treatment strategies with outstanding target-specificity and high therapeutic activity in patients with cancer . DB08870 represents a first-in-class ADC directed against P28908 (+) malignancies . We hypothesized that its sustained clinical responses could be related to the stimulation of an anticancer immune response . In this study , we demonstrate that the dolastatin family of microtubule inhibitors , from which the cytotoxic component of brentuximab vedotin is derived , comprises potent inducers of phenotypic and functional dendritic cell ( DC ) maturation . In addition to the direct cytotoxic effect on tumor cells , dolastatins efficiently promoted antigen uptake and migration of tumor-resident DCs to the tumor-draining lymph nodes . Exposure of murine and human DCs to dolastatins significantly increased their capacity to prime T cells . Underlining the requirement of an intact host immune system for the full therapeutic benefit of dolastatins , the antitumor effect was far less pronounced in immunocompromised mice . We observed substantial therapeutic synergies when combining dolastatins with tumor antigen-specific vaccination or blockade of the P18621 - Q9NZQ7 and P16410 coinhibitory pathways . Ultimately , treatment with ADCs using dolastatins induces DC homing and activates cellular antitumor immune responses in patients . Our data reveal a novel mechanism of action for dolastatins and provide a strong rationale for clinical treatment regimens combining dolastatin-based therapies , such as brentuximab vedotin , with immune-based therapies . DB08870 followed by allogeneic transplantation as salvage regimen in patients with relapsed and/or refractory Hodgkin 's lymphoma . Patients with relapsed or refractory Hodgkin lymphoma ( RR-HL ) have poor outcomes . DB08870 ( BV ) , an antibody-drug conjugate comprising an anti- P28908 antibody conjugated to the potent anti-microtubule agent , monomethyl auristatin E , induces high tumour responses with moderate adverse effects . In a retrospective study , we describe objective response rates and subsequent allogeneic stem cell transplantation ( allo- P09683 ) in patients with RR-HL treated by BV in a named patient program in two French institutions . Twenty-four adult patients with histologically proven P28908 (+) RR-HL treated with BV were included from July 2009 to November 2012 . Response to BV treatment was evaluated after four cycles . Eleven patients were in complete response ( 45.8 % ) , while five patients were in partial response ( 20.8 % ) , with an overall response rate of 66.6 % . Eight patients failed to respond to BV ( 33.3 % ) . All of the responding patients could receive consolidation treatment after BV : three patients underwent autologous stem cell transplantation ( auto- P09683 ) , three patients received a tandem auto- P09683 /allo- P09683 , nine patients received allo- P09683 and one patient was treated with donor lymphocyte infusion . We found no treatment-related mortality at day 100 among the 12 patients who underwent BV following by allogeneic transplantation . With a median follow-up of 20 months ( range 10.5-43.2 ) , none of them relapsed or died . BV followed by allo- P09683 represents an effective salvage regimen in patients with RR-HL . [ Signal transduction inhibitor -- STI571 -- a new treatment for chronic myeloid leukemia ( CML ) , which opens a new targeted approach to cancer therapy ] . Chronic myeloid leukemia ( CML ) , in most of the cases , is the molecular consequence of the t(9,22) translocation , resulting in the Philadelphia ( Ph ) chromosome and the creation of the fusion gene P11274 - P00519 . The fusion gene is translated to the protooncogen P11274 - P00519 , a constitutively activated tyrosine kinase that is linked to the malignant transformation . Thus , this tyrosine kinase became an attractive target for drug design . The development of the novel investigational drug DB00619 is based on its potent and selective ability to inhibit this fusion tyrosine kinase . In preclinical studies , DB00619 selectively inhibited the growth of CML cells that carry the Ph chromosome . In this review we discuss the drug development and design , its mechanism of action , the preclinical studies and the results of phase I and II clinical trials . Results of a pivotal phase II study of brentuximab vedotin for patients with relapsed or refractory Hodgkin 's lymphoma . PURPOSE : DB08870 is an antibody-drug conjugate ( ADC ) that selectively delivers monomethyl auristatin E , an antimicrotubule agent , into P28908 -expressing cells . In phase I studies , brentuximab vedotin demonstrated significant activity with a favorable safety profile in patients with relapsed or refractory P28908 -positive lymphomas . PATIENTS AND METHODS : In this multinational , open-label , phase II study , the efficacy and safety of brentuximab vedotin were evaluated in patients with relapsed or refractory Hodgkin 's lymphoma ( HL ) after autologous stem-cell transplantation ( auto- P09683 ) . Patients had histologically documented P28908 -positive HL by central pathology review . A total of 102 patients were treated with brentuximab vedotin 1.8 mg/kg by intravenous infusion every 3 weeks . In the absence of disease progression or prohibitive toxicity , patients received a maximum of 16 cycles . The primary end point was the overall objective response rate ( ORR ) determined by an independent radiology review facility . RESULTS : The ORR was 75 % with complete remission ( CR ) in 34 % of patients . The median progression-free survival time for all patients was 5.6 months , and the median duration of response for those in CR was 20.5 months . After a median observation time of more than 1.5 years , 31 patients were alive and free of documented progressive disease . The most common treatment-related adverse events were peripheral sensory neuropathy , nausea , fatigue , neutropenia , and diarrhea . CONCLUSION : The ADC brentuximab vedotin was associated with manageable toxicity and induced objective responses in 75 % of patients with relapsed or refractory HL after auto- P09683 . Durable CRs approaching 2 years were observed , supporting study in earlier lines of therapy . DB00227 -stimulated superinduction of P16581 , P05362 and P19320 in P01375 activated human vascular endothelial cells . Inhibitors of P04035 ( statins ) reveal important pharmacological effects in addition to reducing the plasma LDL cholesterol level . In the pathogenesis of arteriosclerosis , transendothelial migration of various leukocytes including monocytes is a crucial step . We , therefore , investigated the expression of P16581 , intercellular cell adhesion molecule-1 ( P05362 ) and vascular cell adhesion molecule-1 ( P19320 ) in vascular endothelial cells as influenced by lovastatin . Human umbilical vein endothelial cells ( HUVECs ) express significant amounts of selectins and cell adhesion molecules ( CAMs ) within a few hours after stimulation with P01375 . This effect is potentiated by 100-200 % when the cells are pretreated with 0.1-2.5 microM lovastatin . The lovastatin-mediated increase in the cytoplasm and at the cell surface is dose-dependent and significant at lovastatin concentrations comparable to plasma levels in patients under lovastatin treatment . The lovastatin-potentiated increase of P16581 and CAMs is correlated with a corresponding increase of selectin- and P62158 -specific mRNA . We conclude that , in vivo , statin treatment could trigger an enhanced recruitment of macrophages that might support the cholesteryl ester efflux from the arteriosclerotic plaque . [ Functional characteristics of calcium-sensitive adenylyl cyclase of ciliate Tetrahymena pyriformis ] . DB01373 -sensitive forms of adenylyl cyclase ( AC ) were revealed in most vertebrates and invertebrates and also in some unicellular organisms , in particular ciliates . We have shown for the first time that calcium cations influence the AC activity of ciliate Tetrahymena pyriformis . These cations at the concentrations of 0.2-20 microM stimulated the enzyme activity , and maximum of catalytic effect was observed at 2 microM Ca2+ . DB01373 cations at a concentrations of 100 microM or higher inhibited the AC activity . P62158 antagonists W-5 and W-7 at the concentrations of 20-100 microM inhibited the catalytic effect induced by 5 microM Ca2+ and blocked the effect at higher concentrations of Ca2+ . DB00477 , another calmodulin antagonist , reduced Ca2+-stimulated AC activity only at the concentrations of 200-1000 microM . AC stimulating effects of serotonin , P01133 and DB02527 increased in the presence of 5 microM Ca2+ . AC stimulating effects of P01133 , DB02527 and insulin decreased in the presence of 100 microM Ca2+ , and AC stimulating effect of DB02527 decreased also in the presence of calmodulin antagonists ( 1 mM ) . At the same time , stimulating effect of D-glucose in the presence of Ca2+ and calmodulin antagonists did not change essentially . The data obtained speak in favor of the presence of calcium-sensitive forms of AC in ciliate T. pyriformis which mediate enzyme stimulation by P01133 , DB02527 , insulin , and serotonin . 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 . Malignant transformation of P01730 + T lymphocytes mediated by oncogenic kinase P06748 / Q9UM73 recapitulates P60568 -induced cell signaling and gene expression reprogramming . Q9UM73 ( Q9UM73 ) , physiologically expressed only by nervous system cells , displays a remarkable capacity to transform P01730 (+) T lymphocytes and other types of nonneural cells . In this study , we report that activity of nucleophosmin ( P06748 ) / Q9UM73 chimeric protein , the dominant form of Q9UM73 expressed in T cell lymphomas ( TCLs ) , closely resembles cell activation induced by P60568 , the key cytokine supporting growth and survival of normal P01730 (+) T lymphocytes . Direct comparison of gene expression by Q9UM73 (+) Q9H4E5 cells treated with an Q9UM73 inhibitor and P60568 -dependent Q9UM73 (-) Q9H4E5 cells stimulated with the cytokine revealed a very similar , albeit inverse , gene-regulation pattern . Depending on the analysis method , up to 67 % of the affected genes were modulated in common by P06748 / Q9UM73 and P60568 . Based on the gene expression patterns , Jak/ P35610 - and P60568 -signaling pathways topped the list of pathways identified as affected by both P60568 and P06748 / Q9UM73 . The expression dependence on P06748 / Q9UM73 and P60568 of the five selected genes-CD25 ( IL-2Rα ) , Egr-1 , Fosl-1 , O14543 , and Irf-4-was confirmed at the protein level . In both Q9UM73 (+) Q9H4E5 and P60568 -stimulated Q9UM73 (-) Q9H4E5 cells , CD25 , O14543 , and Irf-4 genes were activated predominantly by the P42229 and P40763 transcription factors , whereas transcription of Egr-1 and Fosl-1 was induced by the MEK- P29323 pathway . Finally , we found that Egr-1 , a protein not associated previously with either P60568 or Q9UM73 , contributes to the cell proliferation . These findings indicate that P06748 / Q9UM73 transforms the target P01730 (+) T lymphocytes , at least in part , by using the pre-existing , P60568 -dependent signaling pathways . Quantitative study of the interactome of PKCζ involved in the P01133 -induced tumor cell chemotaxis . Chemotaxis plays an important role in metastasis . In our previous studies , we reported that protein kinase C ζ ( PKCζ ) mediated cancer cell chemotaxis by regulating cytoskeleton rearrangement and cell adhesion . To further study the molecular mechanism of chemotaxis , mass spectrometry-based approaches were employed to investigate the interactome of PKCζ and its changes upon stimulation by epidermal growth factor ( P01133 ) . As a result , 233 proteins were identified as potential PKCζ binding partners . Label free quantification was applied to examine the quantitative changes of these interactions involved in the P01133 induced chemotaxis . Fifteen identified proteins were enriched and 9 proteins were reduced in the presence of P01133 ( ≥ 1.5 folds , p ≤ 0.05 ) . The interaction between cofilin-1 ( P23528 ) and PKCζ was evidenced and this interaction was enhanced in the P01133 induced chemotaxis signaling transduction . In addition , novel PKCζ interacting proteins potentially related with chemotaxis were characterized , such as isoform 1 of nucleophosmin ( P06748 ) . Furthermore , Western blotting and chemotaxis assays were also applied to validate the proteomics result and explore its biological implications . Collectively , the combination of quantitative proteomics and biological assays provides a powerful strategy for elucidating the signaling pathway of tumor cell chemotaxis . Influence of a 3-day regimen of azithromycin on the disposition kinetics of cyclosporine A in stable renal transplant patients . Some macrolide antibiotics have been shown to produce significant drug-drug interactions through the inhibition of cytochrome P450 ( CYP ) enzymes . In renal transplant patients these interactions pose potentially serious problems for the safe administration of cyclosporine A ( Q13216 ) , a substrate of P08684 . The effects of azithromycin on Q13216 disposition kinetics were evaluated in eight stable renal transplant patients . Patients had been stabilized on individualized doses of Q13216 which remained unchanged throughout the study . DB00207 was administered for 3 days . Baseline measurements of Q13216 disposition kinetics were taken prior to azithromycin treatment ( study day 2 ) and after 3 days ( study day 5 ) of azithromycin treatment ( 500mg/day , orally ) . The key parameters of interest were the area under the Q13216 blood concentration versus time curve ( AUC ) measured for 24h after the morning dose of Q13216 on both days 2 and 5 , and the C(max) values of Q13216 . The geometric mean ratios ( GMRs ) of those parameters ( day 5/day 2 ) and their 90 % confidence intervals ( 90 % CI ) were 107 ( 98,116 ) and 119 ( 104,136 ) , respectively . The 7 % increase in exposure level and 19 % increase in peak plasma concentration are not likely to be clinically significant . It is concluded that azithromycin ( 500mg/dayx3 days ) does not alter the disposition kinetics of Q13216 in a clinically significant way , and that Q13216 dosage adjustments are not warranted in renal transplant patients taking these two drugs together . Activity of retinoic acid receptor-gamma selectively binding retinoids alone and in combination with interferon-gamma in breast cancer cell lines . Retinoids modulate several cell functions and especially inhibit the growth of a wide variety of cells including breast cancer . Retinoic acid receptor-gamma ( P13631 ) has been shown to mediate the antiproliferative activity of retinoids . To further test this hypothesis we examined the effects of different P13631 selectively binding retinoids ( CD2325 , CD2247 , CD666 and CD437 ) on breast cancer cell lines . With exception of CD2247 , all retinoids inhibited proliferation of MCF-7 , SKBR-3 , T47D and ZR-75-1 breast cancer cell lines , similar to the natural compound all-trans retinoic acid ( DB00755 ) . In addition , all 4 compounds were able to act synergistically with interferon-gamma ( P01579 ) in all breast cancer cell lines including the retinoid-resistant BT-20 and 734-B lines . In functional transactivation assays we demonstrated that only in the MCF-7 cell line , TPA-mediated AP-1 activity was suppressed only by DB00755 and CD2325 , whereas in SKBR-3 , another RA-sensitive breast cancer cell line , it was not . The synergistic antiproliferative activity involving retinoids and P01579 could not be explained by an enhanced anti-AP-1 activity . No correlation was found between expression of RARs and cellular retinoic acid binding proteins ( CRABPs ) and antiproliferative effects of the retinoids . P13631 selectively binding retinoids are potent inhibitors of breast cancer cell proliferation , alone and in combination with P01579 . For this reason and because of a possible low toxicity , as compared with retinoic acid , we speculate that these P13631 selective binding retinoids might be of clinical importance . [ Cutaneous non-tuberculous mycobacterial infection following cord blood stem cell transplantation ] . We describe a 4-year-old-girl with familial hemophagocytic lymphohistiocytosis ( FHL ) who developed disseminated cutaneous nontuberculous mycobacterial ( Q9P121 ) infection after unrelated cord blood stem cell transplantation ( uCBSCT ) . After transplantation , the patient developed steroid-refractory acute graft-versus-host disease , and was given methylprednisolone , cyclosporin and mycophenolate mofetil . Six months after uCBSCT , cutaneous lesions that looked like insect bites appeared and spread widely over the thighs . Q9P121 infection was diagnosed by skin biopsy although no organism could be identified . DB01017 ( MINO ) and sulfamethoxazole/trimethoprim ( ST ) were administered . However , the cutaneous disease followed a course of remissions and exacerbations . One month after the skin biopsy , mycobacterium chelonae was detected by bacteriological culture of abscess drainage . Ten months after uCBSCT , the cutaneous lesions quickly progressed and the inguinal lymph nodes became enlarged and painful . Then the antibiotics were switched from MINO and ST to amikacin and clarithromycin ( P62158 ) based on the results of mycobacterial susceptibility test . The cutaneous lesions gradually improved after continuous administration of P62158 . Cutaneous Q9P121 infection is rare , but it may occur in immunocompromised patients after P09683 . P16410 ( P16410 ) modulates the Th subset response and alters the course of experimental Leishmania major infection . Since both the nature and the amplitude of an antigen-specific T cell response are dependent on co-stimulatory signals , we have investigated the role of P10747 / P16410 -mediated T cell co-stimulation in the regulation of experimental cutaneous leishmaniasis . P10747 -deficient mice and their wild-type littermates are equally susceptible to Leishmania major infection . Whole anti- P16410 antibody significantly exacerbates the disease while anti- P16410 Fab ameliorates the disease in genetically susceptible BALB/c mice but not in C57BL/6 , a resistant strain . The anti- P16410 -induced exacerbation of the disease is accompanied by increased P05112 -secreting cell number , diminished parasite-specific delayed-type hypersensitivity ( DTH ) response and augmented anti-2,4,6-trinitrophenyl ( TNP ) IgG1 in response to TNP-leishmanial antigen crude soluble antigen ( Q13216 ) , suggesting an exaggerated Th2 type of response . Anti- P16410 Fab-mediated amelioration of the disease is associated with increased P01579 -secreting cell number , increased parasite-specific DTH response and enhanced IgG2a isotype in response to TNP- Q13216 suggesting a Th1 type of response . Unlike TNP- Q13216 , TNP- DB05299 does not induce the change in Ig isotype , indicating that the immunomodulatory effect of anti- P16410 is antigen specific . Anti- P16410 antibody-induced early change in Th subsets suggests an important role for P16410 in determining the course of L. major infection , perhaps by alteration of Th subset differentiation . Expression of vitamin D3 receptor and retinoid receptors in human breast cancer : identification of potential heterodimeric receptors . DB00169 ( VD ) and all-trans-retinoic acid ( DB00755 ) have been postulated as a novel treatment option for breast carcinoma . Since the combined effects of retinoids and VD derivatives are attributed to heterodimeric interactions between members of the nuclear receptor family , the expression patterns of the heterodimers formed by vitamin D3 receptor ( P11473 ) and the retinoid receptors RARs ( P10276 , P10826 and P13631 ) and RXRs ( RXR-alpha , RXR-beta and RXR-gamma ) have been studied by immunohistochemistry in benign and malignant breast tissues . Present results revealed that immunoexpressions to all receptor types studied were higher in both in situ and infiltrative carcinomas than in benign breast diseases . In a variable number of cases of infiltrative carcinoma , immunostaining appeared in the nucleus , whereas in the other two disorders immunostaining was only cytoplasmic . The correlation established between P11473 and the different isoforms of retinoid receptors revealed that P11473 seems to select mainly P10276 to form heterodimers and to exert their properties as transcription factor . The results of this study suggest that this heterodimer plays a critical role in cancer malignancy , and its presence indicates those patient groups presenting a better response to adjuvant therapies based on the combination of vitamin D and DB00755 . Interaction of murine peritoneal leukocytes and mesothelial cells : in vitro model system to survey cellular events on serosal membranes during inflammation . All serosal cavities including peritoneum are lined with a simple squamous mesothelium . Primary culture of murine mesothelial cells has been established to study their cellular interactions with peritoneal leukocytes . The mesothelial character was determined by the cytokeratin and vimentin expression . The mesothelial cells expressed P05362 and P16070 molecules . The expression of P05362 , but not P16070 , was significantly enhanced by the treatment with P01375 ( 100 U/ml ) . We have also investigated possible influence of transforming growth factors , TGF-alpha ( 20 ng/ml ) and TGF-beta ( 2 ng/ml ) , and epidermal growth factor ( 20 ng/ml ) . These factors were not found to modulate P05362 or P16070 expression in vitro . During coculture experiments unstimulated mesothelial cells were almost nonadherent for both resident and elicited peritoneal mononuclear leukocytes for several hours . P01375 or P01133 pretreatment of mesothelial cells greatly enhanced their adhesive affinity to peritoneal mononuclear leukocytes , while TGF-beta pretreatment even reduced the low basal adhesion . Prolonged coculture for 3 weeks resulted in remarkable proliferation and differentiation of both resident and elicited monocytes/macrophages on the mesothelial surface . The stimulation of mesothelial cell culture with P01133 resulted in the macrophage colony-stimulating activity ( M- Q13216 ) production . M- Q13216 was mainly due to P09603 as confirmed with anti P09603 monoclonal antibody ; the residual M- Q13216 was not formed by GM- P04141 . After several passages the mesothelial cells started to produce M- Q13216 spontaneously . Scutellarein Reduces Inflammatory Responses by Inhibiting Src Kinase Activity . Flavonoids are plant pigments that have been demonstrated to exert various pharmacological effects including anti-cancer , anti-diabetic , anti-atherosclerotic , anti-bacterial , and anti-inflammatory activities . However , the molecular mechanisms in terms of exact target proteins of flavonoids are not fully elucidated yet . In this study , we aimed to evaluate the anti-inflammatory mechanism of scutellarein ( P09683 ) , a flavonoid isolated from Erigeron breviscapus , Clerodendrum phlomidis and Oroxylum indicum Vent that have been traditionally used to treat various inflammatory diseases in China and Brazil . For this purpose , a nitric oxide ( NO ) assay , polymerase chain reaction ( PCR ) , nuclear fractionation , immunoblot analysis , a kinase assay , and an overexpression strategy were employed . Scutellarein significantly inhibited NO production in a dose-dependent manner and reduced the mRNA expression levels of inducible NO synthase ( P35228 ) and tumor necrosis factor ( P01375 ) -α in lipopolysaccharide ( LPS ) -activated RAW264.7 cells . In addition , P09683 also dampened nuclear factor ( NF ) -κB-driven expression of a luciferase reporter gene upon transfection of a TIR-domain-containing adapter-inducing interferon-β ( Q8IUC6 ) construct into Human embryonic kidney 293 ( P29320 293 ) cells ; similarly , NF-κ B nuclear translocation was inhibited by P09683 . Moreover , the phosphorylation levels of various upstream signaling enzymes involved in NF-κB activation were decreased by P09683 treatment in LPS-treated RAW264.7 cells . Finally , P09683 strongly inhibited Src kinase activity and also inhibited the autophosphorylation of overexpressed Src . Therefore , our data suggest that P09683 can block the inflammatory response by directly inhibiting Src kinase activity linked to NF-κB activation . Q07869 - γ Regulates Trophoblast Differentiation in the BeWo Cell Model . Common pregnancy complications , such as severe preeclampsia and intrauterine growth restriction , disrupt pregnancy progression and impair maternal and fetal wellbeing . Placentas from such pregnancies exhibit lesions principally within the syncytiotrophoblast ( P09683 ) , a layer in direct contact with maternal blood . In humans and mice , glial cell missing-1 ( GCM-1 ) promotes differentiation of underlying cytotrophoblast cells into the outer P09683 layer . GCM-1 may be regulated by the transcription factor peroxisome proliferator-activated receptor-gamma ( Q07869 - γ ) ; in mice , Q07869 - γ promotes labyrinthine trophoblast differentiation via Gcm-1 , and , as we previously demonstrated , Q07869 - γ activation ameliorates disease features in rat model of preeclampsia . Here , we aimed to characterize the baseline activity of Q07869 - γ in the human choriocarcinoma BeWo cell line that mimics P09683 formation in vitro and modulate Q07869 - γ activity to study its effects on cell proliferation versus differentiation . We report a novel negative autoregulatory mechanism between Q07869 - γ activity and expression and show that blocking Q07869 - γ activity induces cell proliferation at the expense of differentiation , while these remain unaltered following treatment with the agonist rosiglitazone . Gaining a deeper understanding of the role and activity of Q07869 - γ in placental physiology will offer new avenues for the development of secondary prevention and/or treatment options for placentally-mediated pregnancy complications . Respective role of humoral factors and blood pressure in aortic remodeling of DOCA hypertensive rats . Hypertension results in increased thickness and stiffness of large artery walls . The goal of our study was to assess the respective roles of humoral factors such as Ang II , endothelin and blood pressure in these aortic modifications . For this purpose , uninephrectomized rats received DOCA and high salt diet , and when hypertension was installed , they were treated for 5 weeks with either a long-acting calcium antagonist , mibefradil ( 30 mg/kg/day ) , an P12821 inhibitor , enalapril ( 3 mg/kg/day ) , or a mixed P25101 and ETB endothelin receptor antagonist , DB00559 ( 100 mg/kg/day ) . A group of hypertensive rats was left untreated and a sham-operated group of normotensive rats was used for control . At the end of treatment , aortic medial thickness and elastin as well as collagen were evaluated by quantitative morphometry . DOCA-salt hypertensive rats exhibited a marked increase in medial thickness associated with no change in absolute content in extracellular matrix . P15502 relative density decreased in DOCA rats . Enalapril had no effect on arterial pressure . DB00559 decreased slightly ( by 12 mm Hg ) , but not significantly , blood pressure . None of these drugs had an effect on medial thickness suggesting that in DOCA hypertensive rats neither Ang II nor endothelin play a significant role in the remodeling of the aorta . In contrast , mibefradil almost normalized arterial pressure , prevented medial hypertrophy and increased elastin density . Further studies are required in order to assess if this effect is directly linked to the blood pressure decrease or to another mechanism related to the calcium antagonistic property of mibefradil . Microenvironment of the murine mammary carcinoma 4T1 : endogenous P01579 affects tumor phenotype , growth , and metastasis . P01579 has a profound influence on growth and metastasis of solid tumors . This is true for the murine mammary carcinoma 4T1 which grows faster and metastasizes much more readily when transplanted into the mammary fatpads of P01579 (-/-) mice . We were interested in determining which infiltrating hematopoietic cells produce P01579 within the 4T1 tumor microenvironment . 4T1 tumors were infiltrated with progressively increasing numbers of F4/80(+)/CD11c(+) myeloid cells , many of which were also Gr-1(+) , and Gr-1(+)/CD11b(+) granulocytes . Only small numbers of P01730 T cells , CD8 T cells , NK cells , and gammadelta T cells , the most likely P01579 -producing cells , were seen at any time point . Sensitive intracellular cytokine staining and flow cytometry revealed no tumor-infiltrating hematopoietic cells with detectable levels of intracellular P01579 , although P01579 mRNA transcripts were detected in tumor tissue . However , a progressive increase in the expression of three P01579 -inducible surface membrane proteins ( Q9NZQ7 , I-A(d) , and P05362 ) on growing 4T1 tumor cells indicated the presence of biologically active P01579 in the tumor microenvironment . Moreover , 4T1 tumor cells from in vitro culture expressed these surface molecules 48 h after intratumoral injection into mature tumors . These data suggest that very low amounts of endogenous P01579 elaborated by infiltrating hematopoietic cells within the microenvironment of a solid tumor can achieve biologically active concentrations and affect tumor phenotype , growth , and metastasis . Activation of the P18621 pathway contributes to immune escape in P00533 -driven lung tumors . The success in lung cancer therapy with programmed death ( PD ) -1 blockade suggests that immune escape mechanisms contribute to lung tumor pathogenesis . We identified a correlation between P01133 receptor ( P00533 ) pathway activation and a signature of immunosuppression manifested by upregulation of P18621 , Q9NZQ7 , CTL antigen-4 ( P16410 ) , and multiple tumor-promoting inflammatory cytokines . We observed decreased CTLs and increased markers of T-cell exhaustion in mouse models of P00533 -driven lung cancer . P18621 antibody blockade improved the survival of mice with P00533 -driven adenocarcinomas by enhancing effector T-cell function and lowering the levels of tumor-promoting cytokines . Expression of mutant P00533 in bronchial epithelial cells induced Q9NZQ7 , and Q9NZQ7 expression was reduced by P00533 inhibitors in non-small cell lung cancer cell lines with activated P00533 . These data suggest that oncogenic P00533 signaling remodels the tumor microenvironment to trigger immune escape and mechanistically link treatment response to P18621 inhibition . SIGNIFICANCE : We show that autochthonous P00533 -driven lung tumors inhibit antitumor immunity by activating the P18621 / Q9NZQ7 pathway to suppress T-cell function and increase levels of proinflammatory cytokines . These findings indicate that P00533 functions as an oncogene through non-cell-autonomous mechanisms and raise the possibility that other oncogenes may drive immune escape . Serum macrophage migration inhibitory factor ( MIF ) levels after allogeneic hematopoietic stem cell transplantation . P14174 ( MIF ) may play an important role in the pathogenesis of acute graft-versus-host disease ( aGVHD ) after allogeneic hematopoietic stem cell transplantation ( allo-HSCT ) , as MIF plays an important role to regulate the production of tumor necrosis factor-alpha ( P01375 ) , one of the inflammatory cytokines which induces and exacerbates aGVHD . We examined the association between serum MIF levels and aGVHD vs. chronic GVHD ( cGVHD ) in allo- P09683 patients in this study . We found a significant increase in the peak serum MIF ( 14.46 ng +/- 1.47 ng/ml ) at onset in patients that developed aGVHD ( n = 23 , P = 0.009 ) . We also found that mean serum MIF levels in patients who developed extensive type cGVHD within 6 months ( 12.58 +/- 2.18 ng/ml , n = 13 ) were significantly higher than MIF levels before allo-HSCT ( 7.86 +/- 1.17 ng/ml , n = 19 , P = 0.04 ) . Therefore , we speculated that serum MIF levels increase during the active phase of both aGVHD and cGVHD . Advances in immunotherapy of chronic myeloid leukemia CML . Tyrosine kinase inhibitors induce sustained disease remissions in chronic myeloid leukemia by exploiting the addiction of this type of leukemia to the activity of the fusion oncogene P11274 - P00519 . However , these agents fail to eradicate CML stem cells which are ultimately responsible for disease relapses upon treatment discontinuation . Evidence that the immune system can effectively reject CML stem cells potentially leading to patient cure is provided by the experience with patients receiving allogeneic bone marrow transplantations . Compelling evidence indicates that more modern , antigen-specific immunotherapeutic approaches are also feasible and hold strong potential to be clinically effective . Amongst these , particularly promising is the use of autologous dendritic cells pulsed with antigens or direct application of in vitro transcribed RNA encoding for leukemia-associated antigens , since this approach allows to circumvent HLA-restriction of the leukemia-associated T cell epitopes that have been eventually identified . Combining these strategies with monoclonal antibodies , such as anti- P16410 or anti- P18621 , may help to obtain even stronger immune responses and better clinical results . This narrative review addresses this topic by focusing in particular on the cell-based immunotherapeutic strategies for CML and on the issue of the leukemia-associated antigens to be selected for targeting . Pharmacological properties of thalidomide and its analogues . Thalidomide and its immunomodulatory imide drugs ( IMiDs ) analogues DB00480 ( DB00480 , DB00480 ) and CC-4047 ( Actimid , DB08910 ) have been used as anti-inflammatory and anticancerous drugs in the recent years . Thalidomide and IMiDs inhibit the cytokines tumour necrosis factor-alpha ( P01375 ) , interleukins ( IL ) 1-beta , 6 , 12 , and granulocyte macrophage-colony stimulating factor ( GM- P04141 ) . They also costimulate primary human T , NKT and NK lymphocytes inducing their proliferation , cytokine production , and cytotoxic activity . On the other hand , the compounds are anti-angiogenic , anti-proliferative , and pro-apoptotic . Thalidomide analogues have been used as inhibitors of alpha glucosidase and could be potential drugs for diabetes treatment . In this review , we explore the current trend of the different structures , the new patents , and the possible new applications in different pathologies . DB08870 : its role in the treatment of anaplastic large cell and Hodgkin 's lymphoma . DB08870 is being developed in a joint collaboration between Seattle Genetics and Millennium : The Takeda Oncology Company . In August 2011 , it was approved by the FDA for the treatment of patients with Hodgkin 's lymphoma ( HL ) and anaplastic large cell lymphoma ( ALCL ) . DB08870 is an antibody-drug conjugate that specifically targets the P01375 receptor superfamily member 8 ( P28908 ) antigen on the surface of cancer cells to induce cell death . DB08870 has shown efficacy in inducing apoptosis in HL and ALCL cell lines that express P28908 and reducing tumor size in preclinical models . DB08870 is under clinical evaluation for the treatment of relapsed or refractory HL and ALCL in both adults and children . It is being investigated for use as a combination agent with pre-existing frontline chemotherapies and as a stand-alone salvage therapy for use prior to autologous stem cell transplant . Treatment with brentuximab vedotin is generally well tolerated although it is associated with grade 1-2 adverse reactions such as neutropenia and there have been reports of grade 3-4 serious adverse events . In particular its use with chemotherapy regimens that include bleomycin is contraindicated because of adverse pulmonary effects . Mobilization of P29590 - P10276 negative blood stem cells and salvage with autologous peripheral blood stem cell transplantation in children with relapsed acute promyelocytic leukemia . BACKGROUND : Relapsed acute promyleocytic leukemia ( APL ) is treated with re-induction chemotherapy , commonly arsenic trioxide , and stem cell transplantation ( P09683 ) . The effect of arsenic trioxide on autologous peripheral blood stem cell collection is unknown . PROCEDURE : Five pediatric patients with relapsed APL had P29590 - P10276 negative peripheral blood stem cells mobilized ( four after arsenic trioxide ) and underwent autologous P09683 after cyclophosphamide ( 60 mg/kg x 2 ) and total body irradiation ( TBI-fractionated 1,200 cGy ) conditioning . RESULTS : All five patients remain in molecular remission a median of 20 months post-transplant . CONCLUSION : Autologous P09683 performed during molecular remission is a treatment option for pediatric patients with relapsed APL and may provide durable leukemia-free survival without the complications of allogeneic transplantation . Extrinsic apoptosis is impeded by direct binding of the APL fusion protein P06748 -RAR to Q15628 . A subset of acute promyelocytic leukemia ( APL ) cases has been characterized by the t(5;17)(q35;q21) translocation variant , which fuses nucleophosmin ( P06748 ) to retinoic acid receptor α ( P10276 ) . The resultant P06748 -RAR fusion protein blocks myeloid differentiation and leads to a leukemic phenotype similar to that caused by the t(15;17)(q22;q21) P29590 -RAR fusion . The contribution of the N-terminal 117 amino acids of P06748 contained within P06748 -RAR has not been well studied . As a molecular chaperone , P06748 interacts with a variety of proteins implicated in leukemogenesis . Therefore , a proteomic analysis was conducted to identify novel P06748 -RAR-associated proteins . P01375 receptor type I-associated DEATH domain protein ( Q15628 ) was identified as a relevant binding partner for P06748 -RAR . This interaction was validated by coprecipitation and colocalization analysis . Biologic assessment found that P06748 -RAR expression impaired P01375 -induced signaling through Q15628 , blunting P01375 -mediated activation of caspase-3 ( P42574 ) and caspase-8 ( Q14790 ) , to ultimately block apoptosis . IMPLICATIONS : This study identifies a novel mechanism through which P06748 -RAR affects leukemogenesis . DB08870 in anaplastic large cell lymphoma . INTRODUCTION : DB08870 , a novel anti- P28908 antibody-drug conjugate , delivers a cytotoxic agent into P28908 (+) cells . P28908 expression is characteristic of anaplastic large cell lymphoma ( ALCL ) and Hodgkin lymphoma ( HL ) . AREAS COVERED : We reviewed data on brentuximab vedotin , focusing on ALCL and discuss pharmacology , clinical trials leading to approval and future research directions . Systemic ALCL , 3 % of adult Q9NZ71 , is characterized by large anaplastic P28908 (+) cells . The fusion protein P06748 - Q9UM73 , when present in systemic ALCL , confers better prognosis , although even Q9UM73 - patients with IPI score ≥ 3 are high-risk . For patients with systemic ALCL , 25 - 45 % relapse after frontline therapy , and > 50 % of patients will relapse following high-dose chemotherapy with autologous stem-cell support . There has been no standard therapy for relapsed/refractory systemic ALCL . DB08870 , combines a monoclonal antibody targeted to P28908 with a microtubule disrupting agent and was recently approved for treatment of patients with systemic ALCL that is refractory or relapsed after at least one multiagent chemotherapy regimen . EXPERT OPINION : DB08870 provides targeted therapy to P28908 (+) lymphomas , including ALCL and HL , with high response rates and manageable toxicity , predominantly myelosuppression and peripheral neuropathy .