interacts_with DB08881?
Signaling pathways regulating interleukin-13-stimulated chemokine release from airway smooth muscle . Interleukin ( IL ) -13 receptor activation on airway smooth muscle cells induces eotaxin release and activates multiple signaling pathways including mitogen-activated protein kinases , and signal transducer and activator of transcription 6 ( P42226 ) . To examine a requirement for P42226 in mediating P35225 -stimulated eotaxin release we used antisense oligodeoxynucleotides ( ODNs ) to downregulate endogenous P42226 protein . P42226 antisense ODNs were taken up by about 85 % of cells . Selective downregulation of P42226 protein occurred with antisense ODNs , but not with sense or scrambled ODNs . P51671 release induced by P35225 or P05112 ( 10 ng/ml ) was reduced by 81 +/- 4 and 75 +/- 7 % , respectively , in cells transfected with antisense ODNs ( p < 0.001 ) , but not with a sense ODN or a scrambled ODN . P51671 release induced by IL-1beta was unaffected by P42226 antisense ODN ( p > 0.05 ) . Finally , P35225 - or P05112 -dependent eotaxin release was abolished when inhibitors of both Q8NFH3 / Q8TCB0 P29323 ( U0126 , 10 microM ) and p38 ( SB202190 , 10 microM ) mitogen-activated protein kinase pathways were combined in P42226 antisense ODN-transfected cells . In contrast , about 25 % of the response remained when each inhibitor was examined alone in P42226 antisense ODN-treated cells . These data support roles for both P42226 - and mitogen-activated protein kinase-dependent pathways in mediating eotaxin release from airway smooth muscle by P35225 or P05112 . Inhibition of p38alpha MAPK disrupts the pathological loop of proinflammatory factor production in the myelodysplastic syndrome bone marrow microenvironment . Myelodysplastic syndromes ( P43034 ) are common causes of ineffective hematopoiesis and cytopenias in the elderly . Various myelosuppressive and proinflammatory cytokines have been implicated in the high rates of apoptosis and hematopoietic suppression seen in P43034 . We have previously shown that p38 MAPK is overactivated in P43034 hematopoietic progenitors , which led to current clinical studies of the selective p38alpha inhibitor , DB05412 , in this disease . We now demonstrate that the myelosuppressive cytokines TNFalpha and IL-1beta are secreted by bone marrow ( BM ) cells in a p38 MAPK-dependent manner . Their secretion is stimulated by paracrine interactions between BM stromal and mononuclear cells and cytokine induction correlates with P28906 + stem cell apoptosis in an inflammation-simulated in vitro bone marrow microenvironment . Treatment with DB05412 inhibits P01375 secretion in primary P43034 bone marrow cells and protects cytogenetically normal progenitors from apoptosis ex vivo . Furthermore , p38 inhibition diminishes the expression of TNFalpha or IL-1beta-induced proinflammatory chemokines in BM stromal cells . These data indicate that p38 inhibition has anti-inflammatory effects on the bone marrow microenvironment that complements its cytoprotective effect on progenitor survival . These findings support clinical investigation of p38alpha as a potential therapeutic target in P43034 and other related diseases characterised by inflammatory bone marrow failure . Dynamic assembly of the urokinase-type plasminogen activator signaling receptor complex determines the mitogenic activity of urokinase-type plasminogen activator . The urokinase-type plasminogen activator ( uPA ) receptor ( Q03405 ) functions in concert with co-receptors , including integrins , P21462 -like receptor-1/lipoxin A4 receptor , and the epidermal growth factor receptor ( P00533 ) , to initiate cell signaling . Q03405 co-receptors may be dynamically organized into a multiprotein signaling receptor complex . In Chinese hamster ovary- P04264 ( CHO- P04264 ) cells , uPA-binding to Q03405 activates P29323 / Q96HU1 kinase , even though these cells do not express the P00533 ; however , when CHO- P04264 cells are transfected to express the P00533 , P29323 activation becomes P00533 -dependent . In this study , we demonstrate that P29323 activation in response to uPA follows equivalent biphasic kinetics in P00533 -expressing and -deficient CHO- P04264 cells . In both cell types , the response is pertussis toxin-sensitive ; however , uPA promotes cell proliferation exclusively in the P00533 -expressing cells . uPA-induced mitogenic activity requires activation of both STAT5b and P29323 . STAT5b was tyrosine-phosphorylated , in response to uPA , only in P00533 -expressing cells . uPA-induced cell proliferation was blocked by dominant-negative Q02750 , dominant-negative STAT5b , and by expression of an P00533 that is mutated at DB00135 -845 , which is essential for STAT5b activation . In two cell culture models of uPA-stimulated breast cancer growth , MDA-MB 468 cells treated with uPA and MCF-7 cells treated with uPA-plasminogen activator inhibitor-1 complex , proliferation was completely inhibited when P00533 expression or activity was blocked . We conclude that expression and assembly of Q03405 co-receptors in a specific cell type determines the response to uPA . The P00533 selectively cooperates with Q03405 to mediate mitogenesis . Phosphodiesterase 4B mediates extracellular signal-regulated kinase-dependent up-regulation of mucin P98088 protein by Streptococcus pneumoniae by inhibiting DB02527 -protein kinase A-dependent P28562 phosphatase pathway . Otitis media ( OM ) is the most common childhood bacterial infection and the major cause of conductive hearing loss in children . Mucus overproduction is a hallmark of OM . Streptococcus pneumoniae is the most common gram-positive bacterial pathogen causing OM . Among many mucin genes , P98088 has been found to be greatly up-regulated in the middle ear mucosa of human patients with OM . We previously reported that S. pneumoniae up-regulates P98088 expression in a MAPK P29323 -dependent manner . We also found that MAPK phosphatase-1 ( P28562 ) negatively regulates S. pneumoniae-induced P29323 -dependent P98088 up-regulation . Therapeutic strategies for up-regulating the expression of negative regulators such as P28562 may have significant therapeutic potential for treating mucus overproduction in OM . However , the underlying molecular mechanism by which P28562 expression is negatively regulated during S. pneumoniae infection is unknown . In this study we show that phosphodiesterase 4B ( Q07343 ) mediates S. pneumoniae-induced P98088 up-regulation by inhibiting the expression of a negative regulator P28562 , which in turn leads to enhanced MAPK P29323 activation and subsequent up-regulation of P98088 . Q07343 inhibits P28562 expression in a DB02527 -PKA-dependent manner . DB05876 -specific inhibitor rolipram inhibits S. pneumoniae-induced P98088 up-regulation both in vitro and in vivo . Moreover , we show that Q07343 plays a critical role in P98088 induction . Finally , topical and post-infection administration of rolipram into the middle ear potently inhibited S. pneumoniae-induced P98088 up-regulation . Collectively , these data demonstrate that Q07343 mediates P29323 -dependent up-regulation of mucin P98088 by S. pneumoniae by inhibiting DB02527 -PKA-dependent P28562 pathway . This study may lead to novel therapeutic strategy for inhibiting mucus overproduction . Ca2+ response of rat mesangial cells to DB00171 analogues . The aim of this investigation was to characterise the effects of DB00171 analogues and UTP on the single cell intracellular Ca2+ concentration ( [Ca2+]i ) in cultured rat mesangial cells . Typically , there were two phases in the Ca2+ response to the agonists , an initial fast transient peak and a subsequent slower decline , or plateau , phase . For the peak amplitude in [Ca2+]i the agonists had about equal effect . But when taking in consideration the percentage of responding cells and the integrated Ca2+ response over 1 min , the order of efficacy of nucleotide agonists ( 100 microM ) was UTP = DB00171 > ATPgammaS > ADP = 2MeS- DB00171 ( 2-methylthio- DB00171 ) . DB00640 , AMP and beta,gamma-Me- DB00171 ( 100 microM ) had no effect . DB04786 ( 100 microM ) and reactive blue ( 50 microM ) decreased the number of responding cells . Removing Ca2+ from the bath diminished neither the peak in [Ca2+]i nor the percentage of responding cells , but the average [Ca2+]i increase in 1 min was significantly reduced . The results indicate that P41231 receptors are present in rat mesangial cells but it can not be excluded that there are receptors distinct from P41231 which also mediate a rise in [Ca2+]i . Serotonin increases P27361 /2 phosphorylation in astrocytes by stimulation of P41595 and P28335 receptors . We have previously shown that fluoxetine causes P29323 (1/2) phosphorylation in cultured mouse astrocytes mediated exclusively by stimulation of 5-HT(2B) receptors ( Li et al. , 2008b ) . This raises the question whether this is also the case for serotonin ( 5-HT ) itself . In the present study serotonin was found to induce P29323 (1/2) phosphorylation by stimulation of 5-HT(2B) receptors with high affinity ( EC(50) : 20-30 pM ) , and by stimulation of 5-HT(2C) receptor with low affinity ( EC(50) : 1 microM or higher ) . P29323 (1/2) phosphorylation induced by stimulation of either 5-HT(2B) or 5-HT(2C) receptors was mediated by epidermal growth factor ( P01133 ) receptor transactivation ( Peng et al. , this issue ) , shown by the inhibitory effect of AG1478 , an inhibitor of the P01133 receptor tyrosine kinase , and DB02255 , an inhibitor of Zn-dependent metalloproteinases , and thus of 5-HT(2B) receptor-mediated P01133 receptor agonist release . It is discussed that the high potency of the 5-HT(2B)-mediated effect is consistent with literature data for binding affinity of serotonin to cloned human 5-HT(2B) receptors and with observations of low extracellular concentrations of serotonin in brain , which would allow a demonstrated moderate and modality-dependent increase in specific brain areas to activate 5-HT(2B) receptors . In contrast the relevance of the observed 5-HT(2C) receptors on astrocytes is questioned . DB00114 values in cerebrospinal fluid : reference values and diagnosis of Q9NVS9 deficiency in paediatric patients . Our aim was to establish reference values for cerebrospinal fluid ( P04141 ) pyridoxal 5'-phosphate ( PLP ) in a paediatric population for the diagnosis of pyridox(am)ine 5'-phosphate oxidase ( Q9NVS9 ) deficiency . For reference values , P04141 samples from 113 paediatric controls ( age range : 1 day-18 years ) from Barcelona and London were analysed . Cerebrospinal fluid PLP and biogenic amine concentrations were analysed by HPLC with fluorescence and electrochemical detection . DB00114 concentrations in 4 patients with Q9NVS9 deficiency were determined . A negative correlation between P04141 PLP values and age of controls was observed in both populations ( r=-0.503 ; p < 0.0001 and r=-0.542 ; p=0.002 ) . Reference values were stratified into 4 ( Barcelona ) and 3 age groups ( London ) . For the newborn period , P04141 PLP reference intervals were 32-78 and 44-89 nmol/L for the Barcelona and London centers , respectively ) . No correlation was observed in the different age groups between PLP values and biogenic amines metabolites . PLP values in neonates with Q9NVS9 deficiency were clearly decreased ( PLP=3.6 , 12.0 , 14.0 and 18.0 nmol/L ) compared with our reference ranges . In conclusion , reference values for P04141 PLP should be stratified according to age . No association was observed between PLP values and biogenic amines metabolites . In our 4 cases with Q9NVS9 deficiency , P04141 PLP values were clearly below the reference values . SAR and in vivo evaluation of 4-aryl-2-aminoalkylpyrimidines as potent and selective O60674 ( O60674 ) inhibitors . We report the discovery of a series of 4-aryl-2-aminoalkylpyrimidine derivatives as potent and selective O60674 inhibitors . High throughput screening of our in-house compound library led to the identification of hit 1 , from which optimization resulted in the discovery of highly potent and selective O60674 inhibitors . Advanced lead 10d demonstrated a significant dose-dependent pharmacodynamic and antitumor effect in a mouse xenograft model . Based upon the desirable profile of 10d ( DB05243 ) it was advanced into clinical trials . A Type II Arabinogalactan from Anoectochilus formosanus for G- P04141 Production in Macrophages and Leukopenia Improvement in Q86TM3 -Bearing Mice Treated with DB00544 . Anoectochilus formosanus is an herb well known in Asian countries . The polysaccharide isolated from A. formosanus consists of type II arabinogalactan ( AGAF ) , with branched 3,6-Gal as the major moiety . In this study , AGAF was examined for the granulocyte colony-stimulating factor ( DB00099 ) production and related protein expression in RAW 264.7 murine macrophages . The signaling pathway of G- P04141 production involves AGAF and mitogen-activated protein kinases ( MAPKs ) inhibitors and pattern-recognition receptor antibodies . AGAF was evaluated to ease the leukopenia in Q86TM3 -colon-cancer-bearing mice treated with 5-fluorouracil ( DB00544 ) . The results of this study showed that AGAF was a stimulant for O60603 and Q9BXN2 and that it induced G- P04141 production , through p38 and P29323 MAPK , and NF- κ B pathways . In vivo examination showed that the oral administration of AGAF mitigated the side effects of leukopenia caused by DB00544 in colon-cancer-bearing mice . In conclusion , the botanic type II AGAF in this study was a potent G- P04141 inducer in vivo and in vitro . Thrombin and activated protein C inhibit the expression of secretory group IIA phospholipase A(2) in the P01375 -activated endothelial cells by Q9UNN8 and P25116 dependent mechanisms . INTRODUCTION : Thrombin and tumor necrosis factor ( P01375 ) -alpha up-regulate the expression of proinflammatory molecules in human umbilical vein endothelial cells ( HUVECs ) . However , activated protein C ( P25054 ) down-regulates the expression of the same molecules . The expression level of secretory group IIA phospholipase A(2) ( sPLA(2)-IIA ) is known to be elevated in inflammatory disorders including in sepsis . Here , we investigated the effects of P25054 and thrombin on the expression of sPLA(2)-IIA and extracellular signal-regulated kinase ( P29323 ) in HUVECs . MATERIALS AND METHODS : The expression level of sPLA(2)-IIA was quantitatively measured by an enzyme-linked-immunosorbent-assay following stimulation of HUVECs with either thrombin or P01375 in the absence and presence of the phosphatidylinositol 3-kinase ( P19957 -kinase ) inhibitor LY294002 and the cholesterol-depleting drug methyl-beta-cyclodextrin ( MbetaCD ) . RESULTS AND CONCLUSIONS : Thrombin had no effect on the expression of sPLA(2)-IIA in HUVECs , however , P01375 potently induced its expression . The prior treatment of cells with P25054 inhibited expression of sPLA(2)-IIA through the Q9UNN8 -dependent cleavage of P25116 . Further studies revealed that if HUVECs were pretreated with the zymogen protein C to occupy Q9UNN8 , thrombin also inhibited the P01375 -mediated expression of sPLA(2)-IIA through the cleavage of P25116 . The Q9UNN8 -dependent cleavage of P25116 by both P25054 and thrombin increased the phosphorylation of P29323 1/2 . Pretreatment of cells with either LY294002 or MbetaCD abolished the inhibitory activity of both P25054 and thrombin against sPLA(2)-IIA expression , suggesting that the protein C occupancy of Q9UNN8 confers a P19957 -kinase dependent protective activity for thrombin such that its cleavage of the lipid-raft localized P25116 inhibits the P01375 -mediated expression of sPLA(2)-IIA in HUVECs . Interpretation of point-of-care INR results in patients treated with dabigatran . BACKGROUND : Point-of-care devices for measurement of the international normalized ratio ( INR ) are commonly used to monitor therapy and maintain therapeutic levels of anticoagulation in patients treated with vitamin K antagonists . DB06695 , a new oral , reversible direct thrombin inhibitor approved for stroke prevention in patients with atrial fibrillation does not require routine coagulation monitoring . However , case reports have identified falsely elevated point-of-care INR levels in patients treated with dabigatran using one of these devices ( Hemochron ) . This in vitro study was designed to verify this issue . METHODS : We compared INR levels in whole blood and plasma using a Hemochron Jr . Signature+ point-of-care device ( International Technidyne Corporation , Edison , NJ ) with routine laboratory monitoring , using blood from healthy volunteers that was spiked with increasing concentrations of dabigatran . RESULTS : P00734 time and INR levels were increased about 2- to 4-fold with the point-of-care device compared with laboratory measures across the plasma dabigatran concentration range 50-1400 ng/mL . At plasma concentrations of dabigatran likely to be observed in patients , at a dose of 150 mg twice daily ( 60-275 ng/mL ) , whole blood point-of-care INR values increased from 1.7 to 4.0 , versus 1.1 to 1.5 measured with the laboratory coagulometer . Similar differences in prothrombin time were observed in plasma samples . CONCLUSIONS : INR levels in patients taking dabigatran are substantially higher using a Hemochron Jr. point-of-care device compared with laboratory values . We discourage the use of these devices specifically , as well as the use of the INR in general , for measuring the anticoagulant effect of dabigatran . Pannexin 1 channels link chemoattractant receptor signaling to local excitation and global inhibition responses at the front and back of polarized neutrophils . Neutrophil chemotaxis requires excitatory signals at the front and inhibitory signals at the back of cells , which regulate cell migration in a chemotactic gradient field . We have previously shown that DB00171 release via pannexin 1 ( Q96RD7 ) channels and autocrine stimulation of P41231 receptors contribute to the excitatory signals at the front . Here we show that Q96RD7 also contributes to the inhibitory signals at the back , namely by providing the ligand for A2A adenosine receptors . In resting neutrophils , we found that A2A receptors are uniformly distributed across the cell surface . In polarized cells , A2A receptors redistributed to the back where their stimulation triggered intracellular DB02527 accumulation and protein kinase A ( PKA ) activation , which blocked chemoattractant receptor signaling . Inhibition of Q96RD7 blocked A2A receptor stimulation and DB02527 accumulation in response to formyl peptide receptor stimulation . Treatments that blocked endogenous A2A receptor signaling impaired the polarization and migration of neutrophils in a chemotactic gradient field and resulted in enhanced P29323 and p38 MAPK signaling in response to formyl peptide receptor stimulation . These findings suggest that chemoattractant receptors require Q96RD7 to trigger excitatory and inhibitory signals that synergize to fine-tune chemotactic responses at the front and back of neutrophils . Q96RD7 channels thus link local excitatory signals to the global inhibitory signals that orchestrate chemotaxis of neutrophils in gradient fields . Serial changes in serum vitamin P04264 , triglyceride , cholesterol , osteocalcin and 25-hydroxyvitamin D3 in patients after hip replacement for fractured neck of femur or osteoarthritis . Serum vitamin P04264 concentrations were measured at presentation ( just before surgery ) and then at weekly intervals for 3 weeks in two groups of elderly patients requiring either hemiarthroplasty for fractured neck of femur ( FON , n = 13 ) or total hip replacement for osteoarthritis of the hip ( OA , n = 16 ) . In comparison with healthy elderly volunteers ( n = 25 ) , serum vitamin P04264 concentrations were significantly lower in both groups at presentation , and fell significantly within 24 h after surgery to concentrations approaching non-detectable , subsequently returning to pre-operative values within 3 weeks . Serum vitamin P04264 tended to be lower in the fracture group both before and after operation , although calculation of a vitamin P04264 -triglyceride ratio reduced the apparent difference as triglyceride concentrations were lower in the fracture group . P02818 concentrations were similar and fell significantly after operation in both groups , returning to pre-operative levels within 7 days . No differences in the two forms of osteocalcin ( carboxylated and undercarboxylated ) were observed either before or after operation in either group . DB00146 concentrations were not significantly different between the two groups at any time . DB01022 status may be lower than desirable in certain groups of the elderly population , and supplementation should be considered as prophylactic therapy . The interaction between the internal clock and antidepressant efficacy . Sleep disturbances are often associated with depression and mood disorders , and certain manipulations of the sleep-wake cycle are effective as therapeutic interventions in the treatment of depression . Dysregulated circadian rhythms are thereby considered as causal . Circadian rhythms in mammals are mainly regulated by a core biological clock , located in the hypothalamic suprachiasmatic nucleus ; its pacemaker activity is regulated by light and nonphotic modulatory pathways , and the driving mechanisms are serotonergic input from the raphe and the hormone melatonin originating from the pineal gland . In line , the concentration of brain serotonin and the levels of P28335 receptors are high and highly expressed there . DB06594 , a novel antidepressant drug with proven clinical efficacy in major depressive disorder , has a unique mechanism of action ; it acts as an agonist at melatonergic MT1 and P02795 receptors and as an antagonist at P28335 receptors . In animals , agomelatine was shown to increase noradrenaline and dopamine ( but not serotonin ) in the frontal cortex , to resynchronize the sleep-wake cycle in models with disrupted circadian rhythms , and to exhibit a clear antidepressant effect in various animal models of depression . On the basis of the functional relationship between melatonergic and serotonergic signaling in the suprachiasmatic nucleus , and given agomelatine 's affinity at melatonergic and P28335 receptors , the therapeutic efficacy of the drug may be due to the potential synergy of its action at these different receptors . Suppression of human inflammatory cell function by subtype-selective DB05876 inhibitors correlates with inhibition of P27815 and Q07343 . 1. Of the four major phosphodiesterase 4 ( DB05876 ) subtypes , P27815 , Q07343 and Q08499 are widely expressed in human inflammatory cells , including monocytes and T lymphocytes . We explored the functional role of these subtypes using ten subtype-selective DB05876 inhibitors , each belonging to one of two classes : ( i ) dual P27815 / Q07343 inhibitors or ( ii ) Q08499 inhibitors . 2 . These compounds were evaluated for their ability to inhibit antigen-stimulated T-cell proliferation and bacterial lipopolysaccharide ( LPS ) -stimulated tumour necrosis factor alpha ( TNFalpha ) release from peripheral blood monocytes . 3 . All compounds inhibited T-cell proliferation in a concentration-dependent manner ; with IC50 values distributed over an approximately 50 fold range . These compounds also inhibited TNFalpha release concentration-dependently , with a wider ( approximately 1000 fold ) range of IC50 values . 4 . In both sets of experiments , mean IC50 values were significantly correlated with compound potency against the catalytic activity of recombinant human P27815 or Q07343 when analysed by either linear regression of log IC50 values or by Spearman 's rank-order correlation . The correlation between inhibition of inflammatory cell function and inhibition of recombinant Q08499 catalytic activity was not significant in either analysis . 5 . These results suggest that P27815 and/or Q07343 may play the major role in regulating these two inflammatory cell functions but do not rule out Q08499 as an important mediator of other activities in mononuclear leukocytes and other immune and inflammatory cells . Much more work is needed to establish the functional roles of the DB05876 subtypes across a broader range of cellular functions and cell types . Opposing actions of extracellular signal-regulated kinase ( P29323 ) and signal transducer and activator of transcription 3 ( P40763 ) in regulating microtubule stabilization during cardiac hypertrophy . Excessive proliferation and stabilization of the microtubule ( MT ) array in cardiac myocytes can accompany pathological cardiac hypertrophy , but the molecular control of these changes remains poorly characterized . In this study , we examined MT stabilization in two independent murine models of heart failure and revealed increases in the levels of post-translationally modified stable MTs , which were closely associated with P40763 activation . To explore the molecular signaling events contributing to control of the cardiac MT network , we stimulated cardiac myocytes with an α-adrenergic agonist phenylephrine ( PE ) , and observed increased tubulin content without changes in detyrosinated ( glu-tubulin ) stable MTs . In contrast , the hypertrophic interleukin-6 ( P05231 ) family cytokines increased both the glu-tubulin content and glu-MT density . When we examined a role for P29323 in regulating cardiac MTs , we showed that the MEK/ P29323 -inhibitor U0126 increased glu-MT density in either control cardiac myocytes or following exposure to hypertrophic agents . Conversely , expression of an activated Q02750 mutant reduced glu-tubulin levels . Thus , P29323 signaling antagonizes stabilization of the cardiac MT array . In contrast , inhibiting either O60674 with AG490 , or P40763 signaling with Stattic or siRNA knockdown , blocked cytokine-stimulated increases in glu-MT density . Furthermore , the expression of a constitutively active P40763 mutant triggered increased glu-MT density in the absence of hypertrophic stimulation . Thus , P40763 activation contributes substantially to cytokine-stimulated glu-MT changes . Taken together , our results highlight the opposing actions of P40763 and P29323 pathways in the regulation of MT changes associated with cardiac myocyte hypertrophy . NSA9 , a human prothrombin kringle-2-derived peptide , acts as an inhibitor of kringle-2-induced activation in EOC2 microglia . In neurodegenerative diseases , such as Alzheimer 's and Parkinson 's , microglial cell activation is thought to contribute to CNS injury by producing neurotoxic compounds . P00734 and kringle-2 increase levels of NO and the mRNA expression of P35228 , IL-1beta , and P01375 in microglial cells . In contrast , the human prothrombin kringle-2 derived peptide NSA9 inhibits NO release and the production of pro-inflammatory cytokines such as IL-1beta , P01375 , and P05231 in LPS-activated EOC2 microglia . In this study , we investigated the anti-inflammatory effects of NSA9 in human prothrombin- and kringle-2-stimulated EOC2 microglia . Treatment with 20-100 muM of NSA9 attenuated both prothrombin- and kringle-2-induced microglial activation . NO production induced by MAPKs and NF-kappaB was similarly reduced by inhibitors of P29323 ( PD98059 ) , p38 ( SB203580 ) , NF-kappaB ( DB06151 ) , and NSA9 . These results suggest that NSA9 acts independently as an inhibitor of microglial activation and that its effects in EOC2 microglia are not influenced by the presence of kringle-2 . P15056 inhibitors suppress apoptosis through off-target inhibition of JNK signaling . DB08881 and dabrafenib selectively inhibit the P15056 ( P15056 ) kinase , resulting in high response rates and increased survival in melanoma . Approximately 22 % of individuals treated with vemurafenib develop cutaneous squamous cell carcinoma ( cSCC ) during therapy . The prevailing explanation for this is drug-induced paradoxical P29323 activation , resulting in hyperproliferation . Here we show an unexpected and novel effect of vemurafenib/PLX4720 in suppressing apoptosis through the inhibition of multiple off-target kinases upstream of c-Jun N-terminal kinase ( JNK ) , principally Q9NYL2 . JNK signaling is suppressed in multiple contexts , including in cSCC of vemurafenib-treated patients , as well as in mice . Expression of a mutant Q9NYL2 that can not be inhibited reverses the suppression of JNK activation and apoptosis . Our results implicate suppression of JNK-dependent apoptosis as a significant , independent mechanism that cooperates with paradoxical P29323 activation to induce cSCC , suggesting broad implications for understanding toxicities associated with P15056 inhibitors and for their use in combination therapies . DOI : http://dx.doi.org/10.7554/eLife.00969.001 . Direct intracerebral delivery of cintredekin besudotox ( P35225 -PE38QQR ) in recurrent malignant glioma : a report by the DB05305 Intraparenchymal Study Group . PURPOSE : Glioblastoma multiforme ( GBM ) is a devastating brain tumor with a median survival of 6 months after recurrence . Cintredekin besudotox ( CB ) is a recombinant protein consisting of interleukin-13 ( P35225 ) and a truncated form of Pseudomonas exotoxin ( PE38QQR ) . Convection-enhanced delivery ( DB01333 ) is a locoregional-administration method leading to high-tissue concentrations with large volume of distributions . We assessed the use of intracerebral DB01333 to deliver CB in patients with recurrent malignant glioma ( MG ) . PATIENTS AND METHODS : Three phase I clinical studies evaluated intracerebral DB01333 of CB along with tumor resection . The main objectives were to assess the tolerability of various concentrations and infusion durations ; tissue distribution ; and methods for optimizing delivery . All patients underwent tumor resection followed by a single intraparenchymal infusion ( in addition to the intraparenchymal one following resection ) , with a portion of patients who had a preresection intratumoral infusion . RESULTS : A total of 51 patients with MG were treated including 46 patients with GBM . The maximum tolerated intraparenchymal concentration was 0.5 microg/mL and tumor necrosis was observed at this concentration . Infusion durations of up to 6 days were well tolerated . Postoperative catheter placement appears to be important for optimal drug distribution . CB- and procedure-related adverse events were primarily limited to the CNS . Overall median survival for GBM patients is 42.7 weeks and 55.6 weeks for patients with optimally positioned catheters with patient follow-up extending beyond 5 years . CONCLUSION : CB appears to have a favorable risk-benefit profile . DB01333 is a complex delivery method requiring catheter placement via a second procedure to achieve accurate catheter positioning , better drug distribution , and better outcome .