interacts_with DB09036?
DB00175 improves renal ischemia-reperfusion injury by inhibiting the mevalonate pathway . Statins are known to lessen the severity of renal ischemia-reperfusion injury . The present study was undertaken to define the mechanism of renoprotective actions of statins using a mouse kidney injury model . Treatment of mice with pravastatin , a widely used statin , improved renal function after renal ischemia-reperfusion without lowering the plasma cholesterol level . Administration of pravastatin with mevalonate , a product of P04035 , eliminated renal protection suggesting an effect of pravastatin on mevalonate or its metabolism . In hypercholestrolemic apolipoprotein E knockout mice with reduced P04035 activity ; the degree of injury was less severe than in control mice , however , there was no protective action of pravastatin on renal injury in the knockout mice . Treatment with a farnesyltransferase inhibitor ( L-744832 ) mimicked pravastatin 's protective effect but co-administration with the statin provided no additional protection . Both pravastatin and L-744832 inhibited the injury-induced increase in plasma P05231 concentration to a similar extent . Our results suggest the protective effect of pravastatin on renal ischemia-reperfusion injury is mediated by inhibition of the mevalonate-isoprenoid pathway independent of its lipid lowering action . The anti-interleukin-6 antibody siltuximab down-regulates genes implicated in tumorigenesis in prostate cancer patients from a phase I study . BACKGROUND : P05231 ( P05231 ) is associated with prostate cancer morbidity . In several experimental models , P05231 has been reported to have anti-apoptotic and pro-angiogenic effects . DB09036 ( CNTO 328 ) is a monoclonal anti- P05231 antibody which has been successfully applied in several models representing prostate cancer . This study was designed to assess preliminary safety of siltuximab in patients with early prostate cancer . PATIENTS AND METHODS : Twenty patients scheduled to undergo radical prostatectomy received either no drug or siltuximab ( 6 mg/kg , five patients per group with administration once , two times , and three times prior to surgery ) . Blood samples were collected for pharmacokinetic and pharmacodynamic analyses . Expression of elements of P05231 signaling pathways was analyzed in tumor tissue by immunohistochemistry . Gene analysis in tumor specimens was performed with the DASL array . RESULTS : No adverse events related to siltuximab were observed . Patients treated with siltuximab presented with higher levels of proliferation and apoptosis markers . Following a single dose , serum concentrations of siltuximab declined in a biexponential manner . This study revealed a decrease in phosphorylation of Stat3 and Q8TCB0 / Q8NFH3 mitogen-activated protein kinases . In addition , gene expression analyses indicate down-regulation of genes immediately downstream of the P05231 signaling pathway and key enzymes of the androgen signaling pathway . CONCLUSIONS : Preliminary safety of siltuximab is favorable . Future studies in which siltuximab could be combined with androgen-deprivation therapy and experimental therapies in advanced prostate cancer are justified . DB09036 : first global approval . The anti-interleukin-6 ( P05231 ) chimeric monoclonal antibody siltuximab is the first drug to be approved for the treatment of multicentric Castleman 's disease ( O95822 ) in the US and European union ( EU ) , having gained approval under the FDA priority review program in the US and from an accelerated assessment and recommendation by the Committee for Medicinal Products for Human Use ( CHMP ) in the EU . Development of the drug is continuing in smoldering multiple myeloma . This article summarizes the milestones in the development of siltuximab leading to this first approval for O95822 . Effects of peroxisome proliferator-activated receptor ligands , bezafibrate and fenofibrate , on adiponectin level . OBJECTIVE : Q15848 is adipose-specific secretory protein and acts as anti-diabetic and anti-atherosclerotic molecule . We previously found peroxisome proliferators response element in adiponectin promoter region , suggesting that peroxisome proliferator-activated receptor ( Q07869 ) ligands elevate adiponectin . Fibrates are known to be PPARalpha ligands and were shown to reduce risks of diabetes and cardiovascular disease . Effect of fibrates on adiponectin has not been clarified , whereas thiazolidinediones enhance adiponectin . Thus , we explored the possibility and mechanism that fibrates enhance adiponectin in humans , mice , and cells . METHODS AND RESULTS : Significant increase of serum adiponectin was observed in bezafibrate-treated subjects compared with placebo group in patients enrolled in The DB01393 Infarction Prevention study . Higher baseline adiponectin levels were strongly associated with reduced risk of new diabetes . Fibrates , bezafibrate and fenofibrate , significantly elevated adiponectin levels in wild-type mice and 3T3- Q9NUQ9 adipocytes . Such an effect was not observed in PPARalpha-deficient mice and adipocytes . Fibrates activated adiponectin promoter but failed to enhance its activity when the point mutation occurred in peroxisome proliferators response element site and the endogenous PPARalpha was knocked down by PPARalpha-RNAi . CONCLUSIONS : Our results suggest that fibrates enhance adiponectin partly through adipose PPARalpha and measurement of adiponectin might be a useful tool for searching subjects at high risk for diabetes . Protection of lung epithelial cells from protease-mediated injury by trappin-2 A62L , an engineered inhibitor of neutrophil serine proteases . Neutrophil serine proteases ( NSPs ) , including elastase , proteinase 3 and cathepsin G , play critical roles in the pathogenesis of chronic inflammatory lung diseases . The release of excess NSPs leads to the destruction of lung tissue and an overexuberant , sustained inflammatory response . Antiproteases could be valuable tools for controlling these NSP-mediated inflammatory events . We have examined the capacity of trappin-2 A62L , a potent engineered inhibitor of all three NSPs , to protect human lung A549 epithelial cells from the deleterious effects of NSPs . Trappin-2 A62L , significantly inhibited the detachment of A549 cells and the degradation of the tight-junction proteins , P12830 , β-catenin and ZO-1 , induced by each individual NSP and by activated neutrophils . Trappin-2 A62L also decreased the release of the pro-inflammatory cytokines P05231 and P10145 from A549 cells that had been stimulated with elastase or LPS . Trappin-2 A62D/M63L , a trappin-2 variant that has no antiprotease activity , has similar properties , suggesting that the anti-inflammatory action of trappin-2 is independent of its antiprotease activity . Interestingly , we present evidence that trappin-2 A62L , as well as wild-type trappin-2 , enter A549 cells and move rapidly to the cytoplasm and nucleus , where they are likely to exert their anti-inflammatory effects . We have also demonstrated that trappin-2 A62L inhibits the early apoptosis of A549 cells mediated by NSPs . Thus , our data indicate that trappin-2 A62L is a powerful anti-protease and anti-inflammatory agent that could be used to develop a treatment for patients with inflammatory lung diseases . DB00067 decreases sepsis-induced pulmonary inflammation through the P30518 . The early use of vasopressors in sepsis has been associated with a decrease in immune activation independent of hemodynamic effects , although the mechanism behind this remains unclear . We hypothesize that low dose vasopressin will reduce the pulmonary inflammation associated with sepsis . Our aims were to ( 1 ) determine whether vasopressin reduces lipopolysaccharide ( LPS ) -induced pulmonary inflammation and ( 2 ) determine which vasopressin receptor is responsible for pulmonary immune modulation . Mice were treated with intraperitoneal LPS to induce both systemic and pulmonary inflammation . DB00067 or saline was infused via peritoneal pump and interleukin 6 ( P05231 ) in lung and serum was measured at 6h . NF-kappaB activation as was determined in the lung through immunoblotting total and phospho-IkappaB . Hemodynamic data was also obtained at the 6h mark . In a separate series of experiments mice received both LPS and vasopressin infusion following pretreatment with vasopressin receptor antagonists to V1R , P30518 and OTR . Low dose LPS dramatically raises both serum P05231 and pulmonary levels of P05231 and phospho-IkappaB despite no significant changes in mean arterial pressure at 6h . Compared to saline , vasopressin infusion significantly decreases both the pulmonary P05231 levels and phospho-IkappaB in LPS treated mice without raising arterial pressure . Pretreatment with P30518 antagonist results in complete attenuation of vasopressin 's immunosuppressive effects , with restoration of pulmonary P05231 and phospho-IkappaB levels to those seen with LPS alone . CONCLUSIONS : DB00067 exerts a local anti-inflammatory effect on the lung through the P30518 in a model of sepsis . Randomised phase II study of siltuximab ( CNTO 328 ) , an anti- P05231 monoclonal antibody , in combination with mitoxantrone/prednisone versus mitoxantrone/prednisone alone in metastatic castration-resistant prostate cancer . PURPOSE : This open-label phase II trial assessed mitoxantrone/prednisone ( M/P ) with and without siltuximab ( CNTO 328 ) , an anti-interleukin-6 chimeric monoclonal antibody , for patients with metastatic castration-resistant prostate cancer who received prior docetaxel-based chemotherapy . METHODS : Part 1 assessed the safety of biweekly siltuximab 6 mg/kg plus M 12 mg/m(2) every 3 weeks and P. Part 2 assessed efficacy and safety of siltuximab plus M/P versus M/P alone . The primary end-point was progression-free survival ( PFS ) . Progression was defined as progressive disease per Response Evaluation Criteria in Solid Tumours ( RECIST ) , or ≥ 3 new skeletal lesions with clinical deterioration or without deterioration confirmed by repeated bone scan . Rising prostate-specific antigen was not considered progression . RESULTS : DB09036 plus M/P was well tolerated in Part 1 ( n=9 ) . In Part 2 , 48 and 49 patients received siltuximab plus M/P or M/P alone , respectively . Enrolment was prematurely terminated by the Independent Data Monitoring Committee since an apparent imbalance in patient baseline characteristics ( favoring the M/P only arm ) made it unlikely that the study could achieve its primary efficacy end-point . Median PFS was 97 days with siltuximab combination and 228 days with M/P alone ( hazard ratio , 1.72 ; P=0.043 ) . Use of a novel non-validated PFS definition may have contributed to this result . Abnormal laboratory assessments were more frequent with the combination . Infection and febrile neutropenia rates were similar between groups . Greater P02741 suppression was achieved during siltuximab combination treatment compared with M/P alone ( P=0.0003 ) . CONCLUSION : While siltuximab plus M/P appeared well tolerated , improvement in outcomes was not demonstrated . Structural and functional similarities between osmotin from Nicotiana tabacum seeds and human adiponectin . Osmotin , a plant protein , specifically binds a seven transmembrane domain receptor-like protein to exert its biological activity via a RAS2/ DB02527 signaling pathway . The receptor protein is encoded in the gene ORE20/PHO36 and the mammalian homolog of PHO36 is a receptor for the human hormone adiponectin ( Q96A54 ) . Moreover it is known that the osmotin domain I can be overlapped to the β-barrel domain of adiponectin . Therefore , these observations and some already existing structural and biological data open a window on a possible use of the osmotin or of its derivative as adiponectin agonist . We have modelled the three-dimensional structure of the adiponectin trimer ( Q15848 ) , and two Q96A54 and PHO36 receptors . Moreover , we have also modelled the following complexes : Q15848 / Q96A54 , osmotin/PHO36 and osmotin/ Q96A54 . We have then shown the structural determinants of these interactions and their physico-chemical features and analyzed the related interaction residues involved in the formation of the complexes . The stability of the modelled structures and their complexes was always evaluated and controlled by molecular dynamics . On the basis of these results a 9 residues osmotin peptide was selected and its interaction with Q96A54 and PHO36 was modelled and analysed in term of energetic stability by molecular dynamics . To confirm in vivo the molecular modelling data , osmotin has been purified from nicotiana tabacum seeds and its nine residues peptide synthesized . We have used cultured human synovial fibroblasts that respond to adiponectin by increasing the expression of P05231 , P01375 and IL-1beta via Q96A54 . The biological effect on fibroblasts of osmotin and its peptide derivative has been found similar to that of adiponectin confirming the results found in silico . Effects of siltuximab on the P05231 -induced signaling pathway in ovarian cancer . PURPOSE : To explore potential therapeutic strategies for interrupting the interleukin-6 ( P05231 ) signaling pathway , we measured P05231 expression in ovarian cancer tissues , and evaluated the effects of a monoclonal anti- P05231 antibody ; siltuximab ( CNTO 328 ) , on levels of P05231 -induced Stat3 phosphorylation , Stat3 nuclear translocation , and Stat3 downstream antiapoptotic genes . We then looked for enhancing paclitaxel sensitivity in multidrug-resistant ovarian cancer cell lines . EXPERIMENTAL DESIGN : Expressions of P05231 in ovarian cancer patient specimens were assessed by immunohistochemistry . Effects of siltuximab on P05231 -induced activation of Stat3 in an ovarian cancer cell line were determined by Western blot and real-time analysis of Stat3 nucleocytoplasmic translocation . Influence of combination of siltuximab and paclitaxel on tumor growth was evaluated in a xenograft mouse mode in vivo . RESULTS : Metastatic and drug-resistant recurrent tumors have significantly higher P05231 expression when compared with the matched primary tumors . DB09036 specifically suppressed P05231 -induced Stat3 phosphorylation and Stat3 nuclear translocation . Treatment with siltuximab significantly decreased the levels of Stat3 downstream proteins such as Q8WXI8 -1 , Bcl-X(L) , and survivin . Treatment with siltuximab reduced expression of multiple P05231 -induced genes in these cell lines . Furthermore , siltuximab increased the cytotoxic effects of paclitaxel in a paclitaxel resistant ovarian cancer cell line in vitro , but combination therapy with siltuximab did not have a significant effect on paclitaxel resistant tumor growth in vivo . CONCLUSIONS : These results show that siltuximab effectively block the P05231 signaling pathways and P05231 -induced gene expression . Blockage of P05231 signaling may provide benefits for the treatment of ovarian cancer . Phase 1 study in Japan of siltuximab , an anti- P05231 monoclonal antibody , in relapsed/refractory multiple myeloma . DB09036 , a chimeric monoclonal antibody with high affinity and specificity for interleukin-6 , has been shown to enhance anti-multiple myeloma activity of bortezomib and corticosteroid in vitro . We evaluated the safety , pharmacokinetics , immunogenicity , and antitumor effect of siltuximab in combination with bortezomib and dexamethasone in Japanese patients with relapsed or refractory multiple myeloma . This open-label , phase 1 , dose-escalating study used two doses of siltuximab : 5.5 and 11.0 mg/kg ( administered on day 1 of each 21-day cycle ) . In total , nine patients were treated . The most common grade 3/4 adverse events , lymphopenia ( 89 % ) and thrombocytopenia ( 44 % ) , occurred in patients receiving both doses of siltuximab ; however , no dose-limiting toxicities ( DLTs ) were observed . Following intravenous administration of siltuximab at 5.5 and 11.0 mg/kg , the maximum serum concentration and the area under the curve from 0 to 21 days and from 0 to infinity increased in an approximately dose-proportional manner . Mean half-life , total systemic clearance , and volume of distribution were similar at doses of 5.5 and 11.0 mg/kg . Across both doses , six of the nine patients had complete or partial response ( 22 and 44 % , respectively ) . In conclusion , as no DLT was observed , the recommended dose for this combination is 11.0 mg/kg once every 3 weeks . The study is registered at http://www.clinicaltrials.gov as NCT01309412 . DB06212 , a selective oral vasopressin V2 receptor antagonist , ameliorates podocyte injury in puromycin aminonucleoside nephrotic rats . BACKGROUND : Proteinuria caused by glomerular disease is characterized by podocyte injury . P30518 antagonists are effective in reducing albuminuria , although their actions on glomerular podocytes have not been explored . The objective of this study was to evaluate the effects of tolvaptan , a selective oral V2 receptor antagonist , on podocytes in a puromycin aminonucleoside ( PAN ) -induced nephrosis rat model . METHODS : Rats were allocated to a control , PAN nephrosis , or tolvaptan-treated PAN nephrosis group ( n = 9 per group ) . Urinary protein excretion and serum levels of total protein , albumin , creatinine , and total cholesterol were measured on day 10 . The influence of tolvaptan on podocytes was examined in renal tissues by immunofluorescence and electron microscopy . RESULTS : PAN induced massive proteinuria and serum creatinine elevation on day 10 , both of which were significantly ameliorated by tolvaptan . Immunofluorescence studies of the podocyte-associated proteins nephrin and podocin revealed granular staining patterns in PAN nephrosis rats . In tolvaptan-treated rats , nephrin and podocin expressions retained their normal linear pattern . Electron microscopy showed foot process effacement was ameliorated in tolvaptan-treated rats . CONCLUSIONS : DB06212 is protective against podocyte damage and proteinuria in PAN nephrosis . This study indicates that tolvaptan exerts a renoprotective effect by affecting podocyte morphology and probably function in PAN nephrosis . DB06212 is a promising pharmacological tool in the treatment of renal edema . P05231 sensitizes prostate cancer to the antiproliferative effect of IFNα2 through Q00978 . Development and progression of prostate cancer ( PCa ) are associated with chronic inflammation . The cytokine interleukin 6 ( P05231 ) can influence progression , differentiation , survival , and angiogenesis of PCa . To identify novel pathways that are triggered by P05231 , we performed a gene expression profiling of two PCa cell lines , LNCaP and MDA PCa 2b , treated with 5 ng/ml P05231 . Interferon ( IFN ) regulatory factor 9 ( Q00978 ) was identified as one of the most prevalent P05231 -regulated genes in both cell lines . Q00978 is a mediator of type I IFN signaling and acts together with P42224 and 2 to activate transcription of IFN-responsive genes . The P05231 regulation of Q00978 was confirmed at mRNA and protein levels by quantitative real-time PCR and western blot respectively in both cell lines and could be blocked by the anti- P05231 antibody DB09036 . Three PCa cell lines , PC3 , Du-145 , and LNCaP- P05231 + , with an autocrine P05231 loop displayed high expression of Q00978 . A tissue microarray with 36 PCa tissues showed that Q00978 protein expression is moderately elevated in malignant areas and positively correlates with the tissue expression of P05231 . Downregulation and overexpression of Q00978 provided evidence for an IFN-independent role of Q00978 in cellular proliferation of different PCa cell lines . Furthermore , expression of Q00978 was essential to mediate the antiproliferative effects of IFNα2 . We concluded that P05231 is an inducer of Q00978 expression in PCa and a sensitizer for the antiproliferative effects of IFNα2 . Accelerated and long-term hematopoietic engraftment in mice transplanted with ex vivo expanded bone marrow . Using a murine experimental model , we investigated whether ex vivo expansion of BM grafts under P08700 / P05231 stimulation accelerates the early hematopoietic recovery of recipients of BM transplants . To facilitate the ex vivo expansion of hematopoietic progenitors , BM was first enriched in proliferatively active hematopoietic stem cells by a single treatment with 5-fluorouracil ( 5FU ) 4 days prior to the BM harvest . The results showed that the number of CFU-GM and CFU- P28222 progenitors in the graft was significantly increased ( 56-fold and 14-fold , respectively ) , as a result of a 3 day incubation in the presence of P08700 and P05231 . Daily analysis of animals transplanted with 5 x 10(4) BM cells , either freshly harvested or expanded for 3 days , showed that the expanded grafts consistently allowed a faster hematopoietic recovery of recipients . Differences between both groups of transplanted animals were most evident when the number of either femoral or splenic CFU-GMs were compared , with increases close to 70-fold at the fifth day of engraftment being observed . Similarly , mice transplanted with expanded grafts showed a hastened recovery in the cellularity of both organs that was most significant during the second week following transplantation , with maximal increases of 15 and 40-fold in the BM and spleen , respectively . Differences in peripheral leukocyte numbers between both groups of recipients were much less remarkable than those observed in the hematopoietic organs , although from the nadir period to the 11th day post-transplantation differences ranging from twofold to sixfold were apparent , consistent with a higher rate of mouse survival. ( ABSTRACT TRUNCATED AT 250 WORDS ) Nimotuzumab suppresses epithelial-mesenchymal transition and enhances apoptosis in low-dose UV-C treated salivary adenoid cystic carcinoma cell lines in vitro . Salivary adenoid cystic carcinoma ( SACC ) , which is one of the most common malignant tumors of the salivary glands , is associated with a poor long-term outcome . There are currently few therapeutic options for patients with SACC . Recent studies have shown the potential of the application of ultraviolet-C ( UV-C ) irradiation for the treatment of human cancer . In the present study , we investigated the effects of UV-C in the SACC cell lines SACC-83 and SACC-LM . High-dose UV-C ( 200 J/m ) induced apoptosis and inhibited colony formation significantly . However , low-dose UV-C ( 10 J/m ) , which had little effect on apoptosis and colony formation , increased the ability of migration in SACC cells accompanied by a decrease in P12830 and an increase in vimentin , suggesting the occurrence of epithelial-mesenchymal transition ( EMT ) . Low-dose UV-C ( 10 J/m ) also resulted in upregulation of the phosphorylated forms of epidermal growth factor receptor ( P00533 ) and Akt ( p- P00533 and p-Akt , respectively ) . Pretreatment with Nimotuzumab , an anti- P00533 monoclonal antibody , reversed the EMT as well as upregulation of p- P00533 /p-Akt induced by UV-C . Moreover , Nimotuzumab enhanced UV-C induced apoptosis and inhibition of colony formation . Our results indicate that EMT exerts a protective effect against apoptosis induced by low-dose UV-C . Thus , the combined application of Nimotuzumab and low-dose UV-C in vitro has an advantageous antitumor effect in SACC compared with the application of UV-C alone . Correlation between tumor volume response to radiotherapy and expression of biological markers in patients with cervical squamous cell carcinoma . OBJECTIVE : To determine the factors associated with tumor volume response to radiotherapy ( RT ) in cervical cancer patients , and the relationship between the tumor volume response and alteration of the expression of biological markers during RT . METHODS : Twenty consecutive patients with cervical squamous cell carcinoma who received definitive RT were enrolled . Tumor volumes were calculated by Q9BWK5 examinations performed at the start of RT ( pre-RT ) , at the fourth week of RT ( mid-RT ) , and 1 month after RT completion ( post-RT ) . Two serial punch biopsies were performed at pre- and mid-RT , and immunohistochemical staining was performed for cyclooxygenase ( P36551 ) -2 and epidermal growth factor receptor ( P00533 ) . RESULTS : For the pre-RT evaluation , fourteen ( 70 % ) and eleven ( 55 % ) patients showed positive immunoreactivity for P35354 and P00533 , respectively . Among the seven patients whose median percentage residual tumor at mid-RT ( P30518 ) was greater than 0.5 , seven ( 100 % , p=0.0515 ) and five ( 71.4 % , p=0.3742 ) patients showed positive immunoreactivity for P35354 and P00533 , respectively . The logistic regression analysis showed that positive immunoreactivity for both P35354 and P00533 at pre-RT were associated with P30518 ( p=0.0782 ) . For the mid-RT evaluation , eight cases showed an interval increase in the distribution of immunoreactivity for P35354 , and six out of the eight patients had a P30518 greater than 0.5 ( p=0.2222 ) . CONCLUSION : The poor mid-RT tumor response was associated with the coexpression of P35354 and P00533 . Q9BQB6 pharmacogenetics and pharmacoproteomics in patients on warfarin anticoagulant therapy : transthyretin precursor as a potential biomarker . BACKGROUND : Recognizing specific protein changes in response to drug administration in humans has the potential for the development of personalized medicine . Such changes can be identified by pharmacoproteomics approach based on proteomic technologies . It can also be helpful in matching a particular target-based therapy to a particular marker in a subgroup of patients , in addition to the profile of genetic polymorphism . DB00682 is a commonly prescribed oral anticoagulant in patients with prosthetic valve disease , venous thromboembolism and stroke . METHODS AND FINDING : We used a combined pharmacogenetics and iTRAQ-coupled LC-MS/MS pharmacoproteomics approach to analyze plasma protein profiles of 53 patients , and identified significantly upregulated level of transthyretin precursor in patients receiving low dose of warfarin but not in those on high dose of warfarin . In addition , real-time RT-PCR , western blotting , human P05231 ELISA assay were done for the results validation . CONCLUSION : This combined pharmacogenomics and pharmacoproteomics approach may be applied for other target-based therapies , in matching a particular marker in a subgroup of patients , in addition to the profile of genetic polymorphism . Blockade of interleukin-6 signalling with siltuximab enhances melphalan cytotoxicity in preclinical models of multiple myeloma . Signalling through the interleukin ( IL ) -6 pathway induces proliferation and drug resistance of multiple myeloma cells . We therefore sought to determine whether the P05231 -neutralizing monoclonal antibody siltuximab , formerly CNTO 328 , could enhance the activity of melphalan , and to examine some of the mechanisms underlying this interaction . DB09036 increased the cytotoxicity of melphalan in KAS-6/1 , Q16352 -6 , ANBL-6 , and RPMI 8226 human myeloma cell lines ( HMCLs ) in an additive-to-synergistic manner , and sensitized resistant RPMI 8226.LR5 cells to melphalan . These anti-proliferative effects were accompanied by enhanced activation of drug-specific apoptosis in HMCLs grown in suspension , and in HMCLs co-cultured with a human-derived stromal cell line . DB09036 with melphalan enhanced activation of caspase-8 , caspase-9 , and the downstream effector caspase-3 compared with either of the single agents . This increased induction of cell death occurred in association with enhanced Bak activation . Neutralization of P05231 also suppressed signalling through the phosphoinositide 3-kinase/Akt pathway , as evidenced by decreased phosphorylation of Akt , P08133 S6 kinase and Q13541 . Importantly , the siltuximab/melphalan regimen demonstrated enhanced anti-proliferative effects against primary plasma cells derived from patients with myeloma , monoclonal gammopathy of undetermined significance , and amyloidosis . These studies provide a rationale for translation of siltuximab into the clinic in combination with melphalan-based therapies . Targeting interleukin-6 in inflammatory autoimmune diseases and cancers . P05231 ( P05231 ) is a pleiotropic cytokine with significant functions in the regulation of the immune system . As a potent pro-inflammatory cytokine , P05231 plays a pivotal role in host defense against pathogens and acute stress . However , increased or deregulated expression of P05231 significantly contributes to the pathogenesis of various human diseases . Numerous preclinical and clinical studies have revealed the pathological roles of the P05231 pathway in inflammation , autoimmunity , and cancer . Based on the rich body of studies on biological activities of P05231 and its pathological roles , therapeutic strategies targeting the P05231 pathway are in development for cancers , inflammatory and autoimmune diseases . Several anti- P05231 / P05231 receptor monoclonal antibodies developed for targeted therapy have demonstrated promising results in both preclinical studies and clinical trials . DB06273 , an anti- P05231 receptor antibody , is effective in the treatment of various autoimmune and inflammatory conditions notably rheumatoid arthritis . It is the only P05231 pathway targeting agent approved by the regulatory agencies for clinical use . DB09036 , an anti- P05231 antibody , has been shown to have potential benefits treating various human cancers either as a single agent or in combination with other chemotherapy drugs . Several other anti- P05231 -based therapies are also under clinical development for various diseases . P05231 antagonism has been shown to be a potential therapy for these disorders refractory to conventional drugs . New strategies , such as combination of P05231 blockade with inhibition of other signaling pathways , may further improve P05231 -targeted immunotherapy of human diseases . Dose selection of siltuximab for multicentric Castleman 's disease . PURPOSE : DB09036 is a monoclonal antibody that binds to interleukin ( IL ) -6 with high affinity and specificity ; P02741 ( CRP ) is an acute-phase protein induced by P05231 . CRP suppression is an indirect measurement of P05231 activity . Here , modeling and simulation of the pharmacokinetic ( PK ) /pharmacodynamic ( PD ) relationship between siltuximab and CRP were used to support dose selection for multicentric Castleman 's disease ( CD ) . METHODS : PK/PD modeling was applied to explore the relationship between siltuximab PK and CRP suppression following intravenous siltuximab infusion in 47 patients with B cell non-Hodgkin 's lymphoma ( n = 17 ) , multiple myeloma ( n = 13 ) , or CD ( n = 17 ) . DB09036 was administered as 2.8 , 5.5 , or 11 mg/kg q2wks , 11 mg/kg q3wks , or 5.5 mg/kg weekly . Simulations of studied or hypothetical siltuximab dosage regimens ( 15 mg/kg q4wks ) were also performed to evaluate maintenance of CRP suppression below the cutoff value of 1 mg/L . RESULTS : A two-compartment PK model and an inhibitory indirect response PD model adequately described the serum siltuximab and CRP concentration-time profiles simultaneously . PD parameter estimates were physiologically plausible . For all disease types , simulations showed that 11 mg/kg q3wks or 15 mg/kg q4wks would reduce serum CRP to below 1 mg/L after the second dose and throughout the treatment period . CONCLUSIONS : PK/PD modeling was used to select doses for further development of siltuximab in multicentric CD . The dosing recommendation was also supported by the observed efficacy dose-response relationship . CRP suppression in the subsequent randomized multicentric CD study was in agreement with the modeling predictions . Gender difference in the activity but not expression of estrogen receptors alpha and beta in human lung adenocarcinoma cells . The higher frequency of lung adenocarcinoma in women smokers than in men smokers suggests a role for gender-dependent factors in the etiology of lung cancer . We evaluated estrogen receptor ( ER ) alpha and beta expression and activity in human lung adenocarcinoma cell lines and normal lung fibroblasts . Q8N1N2 -length ERalpha and ERbeta proteins were expressed in all cell lines with higher ERbeta than ERalpha . Although estradiol ( E(2) ) binding was similar , E(2) stimulated proliferation only in cells from females , and this response was inhibited by anti-estrogens 4-hydroxytamoxifen ( DB04468 ) and DB00947 . In contrast , E(2) did not stimulate replication of lung adenocarcinoma cells from males and DB04468 or ICI did not block cell proliferation . Similarly , transcription of an estrogen response element-driven reporter gene was stimulated by E(2) in lung adenocarcinoma cells from females , but not males . P06401 ( PR ) expression was increased by E(2) in two out of five adenocarcinoma cell lines from females , but none from males . E(2) decreased P12830 protein expression in some of the cell lines from females , as it did in MCF-7 breast cancer cells , but not in the cell lines from males . Thus , ERalpha and ERbeta expression does not correlate with the effect of ER ligands on cellular activities in lung adenocarcinoma cells . On the other hand , coactivator Q15648 expression was higher in lung adenocarcinoma cells from females versus males and higher in adenocarcinoma cells than in normal human bronchial epithelial cells . Q15648 and other ER coregulators may contribute to differences in estrogen responsiveness between lung adenocarcinoma cells in females and males . Effects of external calcium on the biotransformation of DB06749 to ginsenoside Rd by Paecilomyces bainier 229-7 . DB01373 is a known signalling molecule in eukaryotic cells and plays a central role in the regulation of many cellular processes . In the following study , we report on the effect of external calcium treatments on the biotransformation of DB06749 to ginsenoside Rd by Paecilomyces bainier 229-7 . We observed that the intracellular calcium content of P. bainier 229-7 mycelia was increased in response to exposure to high external Ca(2+) concentrations . Both ginsenoside Rd biotransformation and β-glucosidase activity were both found to be dependent on the external calcium concentration . At an optimal Ca(2+) concentration of 45 mM , maximal ginsenoside Rd bioconversion rate of 92.44 % was observed and maximal β-glucosidase activity of 0.1778 U was reached in a 72-h biotransformation . The Ca(2+) channel blocker Verapamil blocked the trans-membrane influx of calcium and decreased ginsenoside Rd biotransformatiom . In addition , β-glucosidase activity and ginsenoside Rd content decreased by 36.0 and 29.2 % respectively after a 72-h incubation in the presence of 0.05 mM P62158 ( P62158 ) antagonist DB00850 . These results suggest that both Ca(2+) channels and P62158 are involved in ginsenoside Rd biotransformation via regulation of β-glucosidase activity . This is the first report regarding the effects of calcium signal transduction on biotransformation and enzyme activity in fungi . DB09036 for multicentric Castleman disease . Dysregulated secretion of P05231 plays a pivotal role in the pathogenesis of Castleman disease ( CD ) , a rare lymphoproliferative disorder . In contrast to unicentric CD for which surgery is considered the treatment of choice , there is no standard therapeutic approach for multicentric CD ( O95822 ) . DB09036 ( trade name : Sylvant , formerly known as CNTO 328 ) is a chimeric monoclonal antibody with high binding affinity for human P05231 . In a recent randomized placebo-controlled Phase II trial , subjects with HIV-negative , HHV8-negative O95822 who received siltuximab demonstrated a significantly higher rate of durable tumor and symptomatic response with a tolerable safety profile , leading to its approval for the treatment of HIV-negative HHV8-negative O95822 by the US FDA and the European Commission in April and May 2014 , respectively . This article will cover the current treatment options of O95822 , the drug profile of siltuximab and future directions in the management of O95822 . P06401 level as a predictor of response to megestrol acetate in advanced breast cancer : a retrospective study . DB00351 ( 160 mg/day ) produced a response rate of 44 % in a retrospective series of 39 evaluable patients with advanced breast cancer . The estrogen-receptor ( ER ) level was greater than 10 fmols/mg of protein in 28 patients , and the progesterone-receptor ( PR ) level was greater than 10 fmols/mg of protein in 26 patients . ER and PR levels , age , and disease-free interval were analyzed for their relationship to response . The PR was the single best predictor of response to megestrol acetate ; the addition of ER added 2 % to the predictive accuracy rate of PR alone . A phase 2 , randomized , double-blind , placebo-controlled study of siltuximab ( anti- P05231 mAb ) and bortezomib versus bortezomib alone in patients with relapsed or refractory multiple myeloma . We compared the safety and efficacy of siltuximab ( S ) , an anti-interleukin-6 chimeric monoclonal antibody , plus bortezomib ( B ) with placebo ( plc ) + B in patients with relapsed/refractory multiple myeloma in a randomized phase 2 study . DB09036 was given by 6 mg/kg IV every 2 weeks . On progression , B was discontinued and high-dose dexamethasone could be added to S/plc . Response and progression-free survival ( PFS ) were analyzed pre-dexamethasone by European Group for Blood and Marrow Transplantation ( EBMT ) criteria . For the 281 randomized patients , median PFS for S + B and plc + B was 8.0 and 7.6 months ( HR 0.869 , P = 0.345 ) , overall response rate was 55 versus 47 % ( P = 0.213 ) , complete response rate was 11 versus 7 % , and median overall survival ( OS ) was 30.8 versus 36.8 months ( HR 1.353 , P = 0.103 ) . Sustained suppression of P02741 , a marker reflective of inhibition of interleukin-6 activity , was seen with S + B . DB09036 did not affect B pharmacokinetics . DB09036 /placebo discontinuation ( 75 versus 66 % ) , grade ≥3 neutropenia ( 49 versus 29 % ) , thrombocytopenia ( 48 versus 34 % ) , and all-grade infections ( 62 versus 49 % ) occurred more frequently with S + B . The addition of siltuximab to bortezomib did not appear to improve PFS or OS despite a numerical increase in response rate in patients with relapsed or refractory multiple myeloma . Mutation of the calmodulin binding motif IQ of the L-type Ca(v)1.2 Ca2+ channel to EQ induces dilated cardiomyopathy and death . Cardiac excitation-contraction coupling ( EC coupling ) links the electrical excitation of the cell membrane to the mechanical contractile machinery of the heart . DB01373 channels are major players of EC coupling and are regulated by voltage and Ca(2+)/calmodulin ( P62158 ) . P62158 binds to the IQ motif located in the C terminus of the Ca(v)1.2 channel and induces Ca(2+)-dependent inactivation ( CDI ) and facilitation ( P05231 ) . Mutation of DB00167 to DB00142 ( Ile1624Glu ) in the IQ motif abolished regulation of the channel by CDI and P05231 . Here , we addressed the physiological consequences of such a mutation in the heart . Murine hearts expressing the Ca(v)1.2(I1624E) mutation were generated in adult heterozygous mice through inactivation of the floxed WT Ca(v)1.2( Q401N2 ) allele by tamoxifen-induced cardiac-specific activation of the MerCreMer Cre recombinase . Within 10 days after the first tamoxifen injection these mice developed dilated cardiomyopathy ( DCM ) accompanied by apoptosis of cardiac myocytes ( CM ) and fibrosis . In Ca(v)1.2(I1624E) hearts , the activity of phospho- P62158 kinase II and phospho-MAPK was increased . CMs expressed reduced levels of Ca(v)1.2(I1624E) channel protein and I(Ca) . The Ca(v)1.2(I1624E) channel showed " CDI " kinetics . Despite a lower sarcoplasmic reticulum Ca(2+) content , cellular contractility and global Ca(2+) transients remained unchanged because the EC coupling gain was up-regulated by an increased neuroendocrine activity . Treatment of mice with metoprolol and captopril reduced DCM in Ca(v)1.2(I1624E) hearts at day 10 . We conclude that mutation of the IQ motif to IE leads to dilated cardiomyopathy and death . YAP modifies cancer cell sensitivity to P00533 and survivin inhibitors and is negatively regulated by the non-receptor type protein tyrosine phosphatase 14 . The Yes-associated protein ( YAP ) is a transcriptional factor involved in tissue development and tumorigenesis . Although YAP has been recognized as a key element of the Hippo signaling pathway , the mechanisms that regulate YAP activities remain to be fully characterized . In this study , we demonstrate that the non-receptor type protein tyrosine phosphatase 14 ( Q15678 ) functions as a negative regulator of YAP . We show that YAP forms a protein complex with Q15678 through the WW domains of YAP and the PPXY motifs of Q15678 . In addition , Q15678 inhibits YAP-mediated transcriptional activities . Knockdown of YAP sensitizes cancer cells to various anti-cancer agents , such as cisplatin , the P00533 tyrosine kinase inhibitor erlotinib and the small-molecule antagonist of survivin , P28222 . YAP-targeted modalities may be used in combination with other cancer drugs to achieve maximal therapeutic effects . Antitumor efficacy of the anti-interleukin-6 ( P05231 ) antibody siltuximab in mouse xenograft models of lung cancer . INTRODUCTION : P05231 ( P05231 ) can activate downstream signaling pathways in lung cancer cells , such as the P40763 pathway , and is reported to be produced by tumor cells with activating P00533 mutations . We examined P05231 / P40763 in lung cancer tumor tissues and the effects of siltuximab , a neutralizing antibody to human P05231 , in mouse models of lung cancer . METHODS : P05231 and P40763 activation levels were compared with tumor histology and presence of P01116 mutations in snap-frozen , non-small-cell lung cancer tumors . The effects of siltuximab alone or in combination with erlotinib were examined in mouse xenograft models constructed using three cell line xenograft models and one primary explant mouse model . We examined the influence of cancer-associated fibroblasts ( CAFs ) on tumor growth and siltuximab effects . RESULTS : P05231 levels were higher in tumors of squamous cell versus adenocarcinoma histology and were not associated with presence of P01116 mutations . Tyrosine phosphorylation status of P40763 did not correlate with tumor P05231 levels . DB00133 phosphorylation of P40763 was correlated with P01116 mutation status . Both tumor and stromal cells contributed to total P05231 within tumors . DB09036 had minimal effect as a single agent in xenografts with tumor cells alone ; however , in models coadministered with CAFs , siltuximab had more potent effects on tumor inhibition . We observed no effects of combined erlotinib and siltuximab . CONCLUSIONS : P05231 is elevated in subsets of human NSCLCs , especially with squamous cell histology . Tumors supported by stromal production of P05231 seem to be the most vulnerable to tumor growth inhibition by siltuximab . No significant association between genetic variants in 7 candidate genes and response to methylphenidate treatment in adult patients with ADHD . Results from pharmacogenetic investigations of methylphenidate ( DB00422 ) response in patients with ADHD are still inconsistent , especially among adults . This study investigates the role of genetic variants ( P31645 , P28222 , Q8IWU9 , P09172 , P21917 , P21964 , and P60880 ) in the response to DB00422 in a sample of 164 adults . Genes were chosen owing to previous evidence for an influence in ADHD susceptibility . No significant differences in allele or genotype frequencies between DB00422 responders and nonresponders were detected . In conclusion , our findings do not support an effect of these genes in the pharmacogenetics of DB00422 among adults with ADHD . P23458 activates P40763 activity in non-small-cell lung cancer cells and P05231 neutralizing antibodies can suppress P23458 - P40763 signaling . Members of the signal transducer and activator of transcription ( P35610 ) family of transcription factors are potential targets for the treatment and prevention of cancers including non-small-cell lung cancer . P35610 proteins can be phosphorylated and activated by diverse upstream kinases including cytokine receptors and tyrosine kinases . We examined P35610 protein activation in lung cancer cell lines including those with activating mutations in the P00533 and examined upstream kinases responsible for P40763 phosphorylation and activation using small molecules , antibodies , and RNA interference . We found more pronounced P40763 activation in cells with activating P00533 mutations , yet inhibition of P00533 activity had no effect on P40763 activation . Inhibition of P23458 with small molecules or RNA interference resulted in loss of P40763 tyrosine phosphorylation and inhibition of cell growth . An interleukin-6 neutralizing antibody , siltuximab ( CNTO 328 ) could inhibit P40763 tyrosine phosphorylation in a cell-dependent manner . DB09036 could completely inhibit P40763 tyrosine phosphorylation in H1650 cells , and this resulted in inhibition of lung cancer cell growth in vivo . Combined P00533 inhibition with erlotinib and siltuximab resulted in dual inhibition of both tyrosine and serine P40763 phosphorylation , more pronounced inhibition of P40763 transcriptional activity , and translated into combined effects on lung cancer growth in a mouse model . Our results suggest that P23458 is responsible for P40763 activation in lung cancer cells and that indirect attacks on P23458 - P40763 using an P05231 neutralizing antibody with or without P00533 inhibition can inhibit lung cancer growth in lung cancer subsets .