interacts_with DB00619?
Inhibition of c-kit receptor tyrosine kinase activity by DB00619 , a selective tyrosine kinase inhibitor . DB00619 ( formerly known as CGP 57148B ) is a known inhibitor of the c-abl , bcr-abl , and platelet-derived growth-factor receptor ( P09619 ) tyrosine kinases . This compound is being evaluated in clinical trials for the treatment of chronic myelogenous leukemia . We sought to extend the activity profile of DB00619 by testing its ability to inhibit the tyrosine kinase activity of c-kit , a receptor structurally similar to P09619 . We treated a c-kit expressing a human myeloid leukemia cell line , M-07e , with DB00619 before stimulation with Steel factor ( SLF ) . DB00619 inhibited c-kit autophosphorylation , activation of mitogen-activated protein ( Q96HU1 ) kinase , and activation of Akt without altering total protein levels of c-kit , Q96HU1 kinase , or Akt . The concentration that produced 50 % inhibition for these effects was approximately 100 nmol/L . DB00619 also significantly decreased SLF-dependent growth of M-07e cells in a dose-dependent manner and blocked the antiapoptotic activity of SLF . In contrast , the compound had no effect on Q96HU1 kinase activation or cellular proliferation in response to granulocyte-macrophage colony-stimulating factor . We also tested the activity of DB00619 in a human mast cell leukemia cell line ( HMC-1 ) , which has an activated mutant form of c-kit . DB00619 had a more potent inhibitory effect on the kinase activity of this mutant receptor than it did on ligand-dependent activation of the wild-type receptor . These findings show that DB00619 selectively inhibits c-kit tyrosine kinase activity and downstream activation of target proteins involved in cellular proliferation and survival . This compound may be useful in treating cancers associated with increased c-kit kinase activity . DB04894 labeled with Tc-99m for imaging tumors . DB04894 ( RC-160 ) , an octapeptide analog of somatostatin , has a high affinity for somatostatin receptor subtypes P30874 and P35346 . DB04894 binds differently to the tumors of the breast , ovary , exocrine pancreas , prostate and colon , than octreotide another octapeptide analog of somatostatin . DB04894 was labeled with Tc-99m , a radionuclide highly suitable for scintigraphic imaging . The labeling procedure was simple , produced > 70 % yields and could be applicable to label other peptides containing a cystine bridge . HPLC analysis showed that the tracer was stable when Tc-99m-RC-160 was challenged with 100 fold molar excess DTPA ( diethylenetriaminepentaacetic acid ) , HSA ( human serum albumin ) or cysteine and incubated at 37 degrees C for 4 h . HPLC analysis of urine samples obtained from mice that received Tc-99m-RC-160 showed that the preparation was stable in vivo . Rat brain cortex membrane receptor displacement assays showed that the Kd values for Tc-99m-RC-160 ( 71x10(-9) M ) and Tc-99m-octreotide ( 86x10(-9) M ) ( Sandostatin(R) ) were in nM range , and were similar to that for I-125-RC-160 ( 46x10(-9) M ) . High binding affinity of Tc-99m-RC-160 for human breast tumor cells SKBR-3 was also observed . These results suggest that Tc-99m-RC-160 is worthy of evaluation as an agent for scintigraphic imaging of tumors rich in somatostatin receptor subtypes P30874 and P35346 . Lipocalin 2 is required for P11274 - P00519 -induced tumorigenesis . Our previous studies indicate that reduction of lipocalin 2 ( mouse 24p3 ) expression by either anti-sense or siRNA approaches strongly reduces the overgrowth of P11274 - P00519 + mouse myeloid 32D in marrow and spleen of NOD/SCID mice . In this study , we used the mouse bone marrow transplant model to further explore the role of 24p3 in P11274 - P00519 -induced leukemia . Consistent with our previous findings , when using non-irradiated mice as recipient , donor marrow cells expressing P11274 - P00519 but lacking 24p3 did not cause leukemia or any disease after 75 days , whereas all mice receiving wild type P11274 - P00519 donor cells died with CML-like disease . An agar clone of the P11274 - P00519 + human CML cell line K562 ( P01031 ) that secretes relatively high levels of lipocalin 2 ( human P80188 ) induced suppression of hematopoiesis in spleen and marrow of mice , leading to early death in contrast to parental K562 or K562 clone ( P13671 ) expressing low amounts of P80188 . Compared with K562 cells , overexpressing P80188 in K562 led to a higher apoptosis rate and an atrophy phenotype in the spleen of the inoculated mice . Plasma from both leukemic mice and CML patients showed elevated lipocalin 2 levels compared with healthy individuals . Moreover , we found that a primary stable cell line from wild-type mouse marrow cells expressing P11274 - P00519 caused solid tumors in nude mice whereas a similar P11274 - P00519 + cell line from 24p3 null mice did not . These findings demonstrate that lipocalin 2 has at least two functions related to tumorigenesis , one involving apoptosis induction of normal hematopoietic cells and the other being tissue invasion by leukemia cells . Enhancement of L-cystine transport activity and its relation to Q9UPY5 gene induction at the blood-brain barrier by diethyl maleate treatment . The purpose of the present study was to elucidate the mechanism of enhancement of L-cystine uptake at the blood-brain barrier ( BBB ) . The uptake of [(14)C]L-cystine and [(3)H]L-glutamic acid ( L- DB00142 ) was determined using a mouse brain endothelial cell line ( MBEC4 ) as an in vitro BBB model . The mRNA levels of L-cystine/L- DB00142 exchanger , system x(c)(-) , which consists of Q9UPY5 and P08195 , were determined by quantitative real-time reverse transcription-polymerase chain reaction analysis . The [(14)C]L-cystine uptake by MBEC4 cells appeared to be mediated via an Na(+)-independent saturable process . The corresponding Michaelis-Menten constant ( K(m) ) was 63.7 microM . In the presence of L- DB00142 , there was competitive inhibition with an inhibition constant ( K(i) ) of 83.5 microM . [(3)H]L- DB00142 uptake in the absence of Na(+) was saturable with a K(m) of 48.1 microM , and it exhibited competitive inhibition with a K(i) of 24.9 microM in the presence of L-cystine . The mutual inhibition between L-cystine and L- DB00142 and the type of inhibition suggest that system x(c)(-) operates in MBEC4 cells . The Q9UPY5 and P08195 mRNAs were expressed in MBEC4 cells and , following diethyl maleate ( DEM ) treatment , the Q9UPY5 mRNA level and L-cystine uptake in MBEC4 cells were enhanced in parallel with an increase in DEM concentration ( up to 500 microM ) . Concomitantly , the glutathione concentration in MBEC4 cells was increased . In conclusion , system x(c)(-)-mediated L-cystine uptake takes place in MBEC4 cells . DB00138 transport via system x(c)(-) at the BBB is likely to be induced under oxidative stress conditions following DEM treatment due to enhanced transcription of the Q9UPY5 gene . Identification of basophils as a major source of hepatocyte growth factor in chronic myeloid leukemia : a novel mechanism of P11274 - P00519 -independent disease progression . Chronic myeloid leukemia ( CML ) is a hematopoietic neoplasm characterized by the Philadelphia chromosome and the related P11274 - P00519 oncoprotein . Acceleration of CML is usually accompanied by basophilia . Several proangiogenic molecules have been implicated in disease acceleration , including the hepatocyte growth factor ( P14210 ) . However , little is known so far about the cellular distribution and function of P14210 in CML . We here report that P14210 is expressed abundantly in purified CML basophils and in the basophil-committed CML line KU812 , whereas all other cell types examined expressed only trace amounts of P14210 or no P14210 . Interleukin 3 , a major regulator of human basophils , was found to promote P14210 expression in CML basophils . By contrast , P11274 - P00519 failed to induce P14210 synthesis in CML cells , and imatinib failed to inhibit expression of P14210 in these cells . Recombinant P14210 as well as basophil-derived P14210 induced endothelial cell migration in a scratch wound assay , and these effects of P14210 were reverted by an anti- P14210 antibody as well as by pharmacologic c- DB00134 inhibitors . In addition , anti- P14210 and c- DB00134 inhibitors were found to suppress the spontaneous growth of KU812 cells , suggesting autocrine growth regulation . Together , P14210 is a P11274 - P00519 -independent angiogenic and autocrine growth regulator in CML . Basophils are a unique source of P14210 in these patients and may play a more active role in disease-associated angiogenesis and disease progression than has so far been assumed . Our data also suggest that P14210 and c- DB00134 are potential therapeutic targets in CML . Molecular markers for novel therapeutic strategies in pancreatic endocrine tumors . OBJECTIVES : Pancreatic endocrine tumors ( PETs ) share numerous features with gastrointestinal neuroendocrine ( carcinoid ) tumors . Targets of novel therapeutic strategies previously assessed in carcinoid tumors were analyzed in PETs ( 44 cases ) . METHODS : Activating mutations in P00533 , P10721 , and P16234 and nonresponse mutations in P01116 were evaluated . Copy number of P00533 and HER-2/neu was quantified by fluorescence in situ hybridization . Expression of P00533 , P16234 , P17948 , P36897 , Hsp90 , SSTR2A , P35346 , P08069 , P42345 , and P16455 was measured immunohistochemically . RESULTS : Elevated P00533 copy number was found in 38 % of cases but no P01116 nonresponse mutations . P17948 , P36897 , P16234 , P35346 , SSTR2A , and P08069 exhibited the highest levels of expression in the largest percentages of PETs.Anticancer drugs BMS-754807 ( selective for P08069 /IR ) , 17-(allylamino)-17-demethoxygeldanamycin ( 17- P29372 , targeting Hsp90 ) , and axitinib ( directed toward P17948 -3/ P16234 -B/ P10721 ) induced growth inhibition of human QGP-1 PET cells with IC50 values ( nM ) of 273 , 723 , and 743 , respectively . At growth-inhibiting concentrations , BMS-754807 inhibited P08069 phosphorylation ; 17- P29372 induced loss of P00533 , P08069 , and P35968 ; and axitinib increased P38936 ( P38936 ) expression without inhibiting P35968 phosphorylation . CONCLUSIONS : Results encourage further research into multidrug strategies incorporating inhibitors targeting P08069 or Hsp90 and into studies of axitinib combined with conventional chemotherapeutics toxic to tumor cells in persistent growth arrest . DB00074 induction in patients receiving tacrolimus-based immunosuppressive regimens . PURPOSE : The use of basiliximab induction increased significantly in recent years based on its superior efficacy and excellent safety profile demonstrated in studies with cyclosporine-based immunosuppression . However , its clinical utility in patients receiving tacrolimus-based immunosuppressive regimens is still uncertain . METHODS : We retrospectively reviewed data of 366 low immunological risk recipients of deceased donor kidney transplants . Of them , 134 received basiliximab and tacrolimus ( TAC- P01589 ) , 100 received basiliximab and delayed tacrolimus(dTAC- P01589 ) , and 132 patients received tacrolimus without basiliximab(TAC-No) . The endpoints were the incidence of acute rejection , graft function , and patient and graft survivals at 1 year . RESULTS : The incidence of acute rejection was higher in dTAC- P01589 compared to TAC-IL-2RA and TAC-No Groups ( 33 vs.14.9 vs. 14.3 % , p < 0.001 ) . Inferior creatinine clearance was observed in dTAC- P01589 Group compared to TAC- P01589 and TAC-No Groups at months 1 ( 41.6 vs. 49.9 vs. 44.8 mL/min , p = 0.004 ) , 3 ( 49.8 vs. 57.2 vs. 53.5 mL/min , p = 0.017 ) , and 6 ( 53.1 vs. 61.8 vs. 57.0 mL/min , p = 0.001 ) . Patients who received basiliximab ( TAC- P01589 and dTAC- P01589 Groups ) had lower incidence of posttransplant diabetes ( 24 vs.18 vs. 39.3 % , p = 0.009 ) . Patient and graft survivals were similar among the groups . CONCLUSIONS : In low immunological risk kidney transplant recipients receiving tacrolimus , the use of basiliximab induction was not associated with lower rejection rates and did not allow delayed tacrolimus introduction . Electrostatic steering at acetylcholine binding sites . The electrostatic environments near the acetylcholine binding sites on the nicotinic acetylcholine receptor ( nAChR ) and acetylcholinesterase were measured by diffusion-enhanced fluorescence energy transfer ( DEFET ) to determine the influence of long-range electrostatic interactions on ligand binding kinetics and net binding energy . Changes in DEFET from variously charged Tb3+ -chelates revealed net potentials of -20 mV at the nAChR agonist sites and -14 mV at the entrance to the P22303 active site , in physiological ionic strength conditions . The potential at the alphadelta-binding site of the nAChR was determined independently in the presence of DB01199 to be -14 mV ; the calculated potential at the alphagamma-site was approximately threefold stronger than at the alphadelta-site . By determining the local potential in increasing ionic strength , Debye-Hückel theory predicted that the potentials near the nAChR agonist binding sites are constituted by one to three charges in close proximity to the binding site . Examination of the binding kinetics of the fluorescent acetylcholine analog dansyl- P13671 -choline at ionic strengths from 12.5 to 400 mM revealed a twofold decrease in association rate . Debye-Hückel analysis of the kinetics revealed a similar charge distribution as seen by changes in the potentials . To determine whether the experimentally determined potentials are reflected by continuum electrostatics calculations , solutions to the nonlinear Poisson-Boltzmann equation were used to compute the potentials expected from DEFET measurements from high-resolution models of the nAChR and P22303 . These calculations are in good agreement with the DEFET measurements for P22303 and for the alphagamma-site of the nAChR . We conclude that long-range electrostatic interactions contribute -0.3 and -1 kcal/mol to the binding energy at the nAChR alphadelta- and alphagamma-sites due to an increase in association rates . P25874 -mediated free fatty acid uncoupling of isolated cortical mitochondria from fasted animals : correlations to dietary modulations . Uncoupling proteins ( P25874 ) translocate protons from the mitochondrial intermembrane space to the matrix , thereby " uncoupling " electron transport from the production of DB00171 . It has been shown that these proteins are highly expressed in animals maintained on the ketogenic diet ( KD ) . Although the exact mechanism remains unclear , it is known that these proteins are activated within a protective antireactive oxygen species ( ROS ) mechanism by free fatty acids ( FFA ) . In our current studies , mitochondrial samples were probed for the presence of P55851 , which is the most ubiquitously expressed P25874 isoform . We found that both traumatic brain injury and fasting upregulated the expression of P55851 , with a synergistic upregulation in fasted injured animals . We then used mitochondria from fasted naive animals to screen a number of FFA for their activation of uncoupling as well as their ability to reduce ROS . We found that arachidonic acid ( AA ) , docosahexaenoic acid ( DB01708 ) , eicosapentaenoic acid ( EPA ) , palmitoleic acid , myristic acid , and butyric acid increased mitochondrial uncoupling when added after oligomycin . These FFA , along with oleic acid , also reduced ROS in mitochondria incubated with oligomycin . In order to correlate our data to KD and fasting , both of which have been shown to be neuroprotective after neurologic insult , we determined the serum levels of FFA in KD and fasted animals using gas chromatography/mass spectroscopy . We also determined brain and cerebrospinal fluid ( P04141 ) FFA levels from fasted animals . Molecular mechanisms of patupilone resistance . DB03010 is an epothilone in advanced clinical development that has shown promising efficacy in heavily pretreated patients . This study aimed at characterizing the mechanisms of patupilone activity in resistant patients . To this end , we generated patupilone-resistant cells using two cellular models , the first characterized by high chemosensitivity and low class III beta-tubulin ( Q13509 ) expression ( A2780 ) , and the second by low chemosensitivity and high Q13509 expression ( OVCAR-3 ) . The obtained cell lines were named EPO3 and OVCAR-EPO , respectively . The same selection procedure was done in A2780 cells to generate a paclitaxel-resistant cell line ( TAX50 ) . Factors of resistance are expected to increase in the drug-resistant cell lines , whereas factors of drug sensitivity will be down-regulated . Using this approach , we found up-regulation of Q13509 in TAX50 , but not EPO3 , cells , showing that Q13509 mediates the resistance to paclitaxel but not to patupilone . Moreover , Q13509 was a factor of patupilone sensitivity because OVCAR-EPO cells exhibited a dramatic reduction of Q13509 and a concomitant sensitization to hypoxia and cisplatin-based chemotherapy . To identify the mechanisms underlying patupilone resistance , tubulin genes were sequenced , thereby revealing that a prominent mechanism of drug resistance is represented by point mutations in class I beta-tubulin . Overall , these results suggest that paclitaxel and patupilone have nonoverlapping mechanisms of resistance , thus allowing the use of patupilone for those patients relapsing after paclitaxel-based chemotherapy . Furthermore , patupilone represents a promising first-line option for the treatment of high-risk ovarian cancer patients , who exhibit high Q13509 levels and poor response to standard paclitaxel-platin chemotherapy . P11274 - P00519 suppresses C/EBPalpha expression through inhibitory action of Q15366 . The arrest of differentiation is a feature of both chronic myelogenous leukemia cells in myeloid blast crisis and myeloid precursors that ectopically express the p210BCR- P00519 oncoprotein ; however , its underlying mechanisms remain poorly understood . Here we show that expression of P11274 - P00519 in myeloid precursor cells leads to transcriptional suppression of the granulocyte colony-stimulating factor receptor Q99062 ( encoded by Q99062 ) , possibly through down-modulation of C/EBPalpha-the principal regulator of granulocytic differentiation . Expression of C/EBPalpha protein is barely detectable in primary marrow cells taken from individuals affected with chronic myeloid leukemia in blast crisis . In contrast , P49715 RNA is clearly present . Ectopic expression of C/EBPalpha induces granulocytic differentiation of myeloid precursor cells expressing P11274 - P00519 . Expression of C/EBPalpha is suppressed at the translational level by interaction of the poly(rC)-binding protein Q15366 with P49715 mRNA , and ectopic expression of Q15366 in myeloid precursor cells down-regulates both C/EBPalpha and Q99062 and leads to rapid cell death on treatment with DB00099 ( encoded by P09919 ) . Our results indicate that P11274 - P00519 regulates the expression of C/EBPalpha by inducing Q15366 -which inhibits the translation of P49715 mRNA . Q9HBE4 signalling via P40763 primes human naive B cells to respond to P60568 to enhance their differentiation into plasmablasts . B-cell responses are guided by the integration of signals through the B-cell receptor ( P11274 ) , P25942 , and cytokine receptors . The common γ chain (γc)-binding cytokine interleukin ( IL ) -21 drives humoral immune responses via P40763 -dependent induction of transcription factors required for plasma cell generation . We investigated additional mechanisms by which Q9HBE4 / P40763 signaling modulates human B-cell responses by studying patients with P40763 mutations . Q9HBE4 strongly induced CD25 ( IL-2Rα ) in normal , but not P40763 -deficient , P29965 -stimulated naïve B cells . Chromatin immunoprecipitation confirmed P01589 as a direct target of P40763 . Q9HBE4 -induced CD25 expression was also impaired on B cells from patients with P31785 or Q9HBE5 mutations , confirming a requirement for intact Q9HBE5 signaling in this process . P60568 increased plasmablast generation and immunoglobulin secretion from normal , but not CD25-deficient , naïve B cells stimulated with P29965 / Q9HBE4 . P60568 and Q9HBE4 were produced by T follicular helper cells , and neutralizing both cytokines abolished the B-cell helper capacity of these cells . Our results demonstrate that Q9HBE4 , via P40763 , sensitizes B cells to the stimulatory effects of P60568 . Thus , P60568 may play an adjunctive role in Q9HBE4 -induced B-cell differentiation . Lack of this secondary effect of Q9HBE4 may amplify the humoral immunodeficiency in patients with mutations in P40763 , P31785 , or Q9HBE5 due to impaired responsiveness to Q9HBE4 . Mobilization of Ph chromosome-negative peripheral blood stem cells in chronic myeloid leukaemia patients with imatinib mesylate-induced complete cytogenetic remission . Imatinib mesylate ( IM , DB00619 , Glivec ) can induce a high rate of complete cytogenetic response ( CCR ) in chronic myeloid leukaemia ( CML ) patients , although to date the majority of patients continue to have detectable disease by sensitive reverse transcription polymerase chain reaction ( RT-PCR ) . It is therefore possible that these patients may ultimately relapse and require treatment such as autologous peripheral blood stem cell transplant ( APBSCT ) . We attempted mobilization of haemopoietic progenitor cells from 58 patients in CCR using recombinant human granulocyte colony-stimulating factor [ rHu- DB00099 ; 10 micro g/kg/d subcutaneously ( s.c. ) for at least 4 d ] alone , while continuing IM treatment . The median d 5 ( peak ) P28906 + count was 11.5/ microl ( range 0-108/ microl ) , and 43/58 ( 74 % ) patients underwent a median of two ( range 1-3 ) apheresis procedures . A median dose of 2.1 x 10(6)/kg P28906 + cells ( range 0.1-6.5 x 10(6)/kg ) was collected . Some 84 % of 31 collections analysed were negative for the Philadelphia ( Ph ) chromosome or breakpoint cluster region and Abelson murine leukaemia viral oncogene homologue ( P11274 - P00519 ) translocation by cytogenetics or fluorescent in situ hybridization respectively . No toxicity was reported with the regimen . Overall , the target P28906 + dose ( 2 x 10(6)/kg P28906 + ) was attained in 23/58 ( 40 % ) patients who entered the study . In summary , we have demonstrated that successful mobilization of Ph- P28906 + cells from IM-treated patients in CCR is possible using rHu-G- P04141 alone . DB02426 effects on brown-fat mitochondria imply that the adenine nucleotide translocator isoforms P12235 and P05141 may be responsible for basal and fatty-acid-induced uncoupling respectively . In brown-fat mitochondria , fatty acids induce thermogenic uncoupling through activation of P25874 ( uncoupling protein 1 ) . However , even in brown-fat mitochondria from P25874 -/- mice , fatty-acid-induced uncoupling exists . In the present investigation , we used the inhibitor CAtr ( carboxyatractyloside ) to examine the involvement of the ANT ( adenine nucleotide translocator ) in the mediation of this P25874 -independent fatty-acid-induced uncoupling in brown-fat mitochondria . We found that the contribution of ANT to fatty-acid-induced uncoupling in P25874 -/- brown-fat mitochondria was minimal ( whereas it was responsible for nearly half the fatty-acid-induced uncoupling in liver mitochondria ) . As compared with liver mitochondria , brown-fat mitochondria exhibit a relatively high ( P25874 -independent ) basal respiration ( ' proton leak ' ) . Unexpectedly , a large fraction of this high basal respiration was sensitive to CAtr , whereas in liver mitochondria , basal respiration was CAtr-insensitive . Total ANT protein levels were similar in brown-fat mitochondria from wild-type mice and in liver mitochondria , but the level was increased in brown-fat mitochondria from P25874 -/- mice . However , in liver , only Ant2 mRNA was found , whereas in brown adipose tissue , Ant1 and Ant2 mRNA levels were equal . The data are therefore compatible with a tentative model in which the P05141 isoform mediates fatty-acid-induced uncoupling , whereas the P12235 isoform may mediate a significant part of the high basal proton leak in brown-fat mitochondria . DB06643 in postmenopausal osteoporosis : what the clinician needs to know . DB06643 is a subcutaneously ( SC ) administered investigational fully human monoclonal antibody to receptor activator of nuclear factor-kB ligand ( O14788 ) , a cytokine member of the tumor necrosis factor family that is the principal mediator of osteoclastic bone resorption . O14788 stimulates the formation , activity , and survival of osteoclasts , and is implicated in the pathogenesis of postmenopausal osteoporosis and other skeletal disorders associated with increased bone remodeling . DB06643 binds O14788 , preventing it from binding to Q9Y6Q6 , thereby reducing the formation , activity , and survival of osteoclasts and slowing the rate of bone resorption . Postmenopausal women with low bone mineral density ( BMD ) treated with denosumab have a reduction of bone turnover markers and an increase in BMD that is rapid , sustained , and reversible . In postmenopausal women with osteoporosis , denosumab reduces the risk of vertebral , hip , and nonvertebral fractures . In postmenopausal women with low BMD randomized to receive denosumab or alendronate , denosumab is associated with a significantly greater increase in BMD and further reduction in bone turnover markers compared with alendronate . In postmenopausal women with low BMD who were previously treated with alendronate , those who switched to denosumab have a significantly greater BMD increase and further reduction in bone turnover markers compared with those continuing alendronate . DB06643 is well tolerated with a favorable safety profile . It is a promising emerging drug for the prevention and treatment of osteoporosis , offering a long dosing interval of every 6 months and convenient SC dosing , with the potential of improving long-term adherence to therapy compared with current oral treatments . Update on the biology and therapy of gastrointestinal stromal tumors . BACKGROUND : Gastrointestinal stromal tumors ( GISTs ) , the most common mesenchymal tumors of the gastrointestinal tract , are an example of a disease with an effective , molecularly targeted therapy . METHODS : Published articles and author experience were used to comprehensively define the clinical features , biology , and state-of-the-art therapy of GISTs . RESULTS : GISTs are thought to originate from the neoplastic transformation of the interstitial cells of Cajal , the intestinal pacemaker cells . GISTs commonly have mutations in the kit gene , resulting in a gain-of-function mutation and ligand-independent constitutive activation of the P10721 receptor tyrosine kinase . Successful tyrosine kinase inhibitors target the aberrant pathways that are critical for tumor cell viability . The development of imatinib mesylate ( formerly DB00619 ) in the treatment of metastatic GISTs represents a therapeutic breakthrough . CONCLUSIONS : Progress in the clinical diagnosis has led to an increased recognition of this disease as a distinct clinical entity . Treatment of metastatic GIST with imatinib has led to unprecedented improvements in progression-free and overall survival . The use of imatinib in the preoperative and postoperative treatment of GISTs is an area of intense investigation . Delineation of gastric cancer subtypes by co-regulated expression of receptor tyrosine kinases and chemosensitivity genes . Chemotherapy plays a key role in improving disease-free survival and overall survival of gastric cancer ( GC ) ; however , response rates are variable and a non-negligible proportion of patients undergo toxic and costly chemotherapeutic regimens without a survival benefit . Several studies have shown the existence of GC subtypes which may predict survival and respond differently to chemotherapy . It is also known that the expression level of chemotherapy-related and target therapy-related genes correlates with response to specific antitumor drugs . Nevertheless , these genes have not been considered jointly to define GC subtypes . In this study , we evaluated seven genes known to influence chemotherapeutic response ( P07992 , P38398 , P23921 , Q13509 , P16949 , P04818 and P11388 ) and five receptor tyrosine kinases ( RTKs ) ( P00533 , P04626 , P09619 , P17948 and P35968 ) . We demonstrate significant heterogeneity of gene expression among GC patients and identified four GC subtypes using the expression profiles of eight genes in two co-regulation groups : chemosensitivity ( P38398 , P16949 , P04818 and P11388 ) and RTKs ( P00533 , P09619 , P17948 and P35968 ) . The results are of immediate translational value regarding GC diagnostics and therapeutics , as many of these genes are curently widely used in relevant clinical testing . The role of the granulocyte colony-stimulating factor receptor ( Q99062 ) in disease . P09919 ( DB00099 ) is a key regulator of granulopoiesis via stimulation of a specific cell-surface receptor , the Q99062 , found on hematopoietic progenitor cells as well as neutrophilic granulocytes . It is perhaps not surprising , therefore , that mutations of the Q99062 has been implicated in several clinical settings that affect granulocytic differentiation , particularly severe congenital neutropenia , myelodysplastic syndrome and acute myeloid leukemia . However , other studies suggest that signalling via the Q99062 is also involved in a range of other malignancies . This review focuses on the molecular mechanisms through which the Q99062 contributes to disease . Critical role of P21453 and integrin β4 in P14210 /c- DB00134 -mediated increases in vascular integrity . Vascular endothelial cell ( EC ) barrier integrity is critical to vessel homeostasis whereas barrier dysfunction is a key feature of inflammatory disorders and tumor angiogenesis . We previously reported that hepatocyte growth factor ( P14210 ) -mediated increases in EC barrier integrity are signaled through a dynamic complex present in lipid rafts involving its receptor , c- DB00134 . We extended these observations to confirm that P21453 ( sphingosine 1-phosphate receptor 1 ) and integrin β4 ( P16144 ) are essential participants in P14210 -induced EC barrier enhancement . Immunoprecipitation experiments demonstrated P14210 -mediated recruitment of c- DB00134 , P16144 and P21453 to caveolin-enriched lipid rafts in human lung EC with direct interactions of c- DB00134 with both P21453 and P16144 accompanied by c- DB00134 -dependent P21453 and P16144 transactivation . Reduced P21453 expression ( siRNA ) attenuated both P16144 and Rac1 activation as well as c- DB00134 / P16144 interaction and resulted in decreased transendothelial electrical resistance . Furthermore , reduced P16144 expression attenuated P14210 -induced c- DB00134 activation , c- DB00134 / P21453 interaction , and effected decreases in Q14703 - and P14210 -induced EC barrier enhancement . Finally , the c- DB00134 inhibitor , DB05030 , suppressed P14210 -induced c- DB00134 activation as well as P21453 and P16144 transactivation . These results support a critical role for P21453 and P16144 transactivation as rate-limiting events in the transduction of P14210 signals via a dynamic c- DB00134 complex resulting in enhanced EC barrier integrity . Polyamines and membrane transporters . In recent years , our understanding of the importance of membrane transporters ( MTs ) in the disposition of and response to drugs has increased significantly . MTs are proteins that regulate the transport of endogenous molecules and xenobiotics across the cell membrane . In mammals , two super-families have been identified : DB00171 -binding cassette ( DB01048 ) and solute carrier ( O00585 ) transporters . There is evidence that MTs might mediate polyamines ( PA ) transport . PA are ubiquitous polycations which are found in all living cells . In mammalian cells , three major PA are synthesised : putrescine , spermidine and spermine ; whilst the decarboxylated arginine ( agmatine ) is not produced by mammals but is synthesised by plants and bacteria . In addition , research in the PA field suggests that PA are transported into cells via a specific transporter , the polyamine transport system(s) ( Q03393 ) . Although the Q03393 has not been fully defined , there is evidence that some of the known MTs might be involved in PA transport . In this mini review , eight O00585 transporters will be reviewed and their potential to mediate PA transport in human cells discussed . These transporters are O15245 , O15244 , O75751 , Q96FL8 , P30825 , P08195 , SLC12A8A , and Q86VW1 . Preliminary data from our laboratory have revealed that O15245 might be involved in the PA uptake ; in addition to one member of ABC superfamily ( P08183 protein ) might also mediate the efflux of polyamine like molecules . Imatinib mesylate ( Gleevec ) enhances mature osteoclast apoptosis and suppresses osteoclast bone resorbing activity . Recent studies have reported that imatinib mesylate , a kinase inhibitor that targets the intracellular tyrosine kinase P11274 - P00519 and the platelet derived growth factor ( PDGF ) receptor , is an effective inhibitor of the macrophage colony stimulating factor ( P09603 ) receptor , c- P07333 . Given that P09603 signalling through c- P07333 plays an important role in osteoclast biology , we speculated that blocking such a pathway with imatinib may modulate osteoclast activity . Using a cell model of mature rabbit osteoclasts , we thus investigated the effect of imatinib on in vitro osteoclast apoptosis and bone resorbing activity . Our findings demonstrate that imatinib dose-dependently stimulates osteoclast apoptosis , a phenomenon which is blocked by the caspase I inhibitor Z-VAD-fmk . The ability of imatinib to enhance osteoclast cell death was accompanied by a dose-dependent inhibition of osteoclast bone resorbing activity . Imatinib was also found to inhibit P09603 -induced osteoclast survival as well as P09603 -induced osteoclast bone resorbing activity , but was without effect on interleukin 1alpha ( IL-1alpha ) and receptor activator of nuclear factor kappa B ligand ( O14788 ) -induced inhibition of osteoclasts apoptosis , further supporting the hypothesis that imatinib may affect mature osteoclasts through the inhibition of c- P07333 . Taken together , these results suggest that imatinib could be of clinical value in treating diseases where bone destruction can occur due to excessive P09603 production such as osteoporosis , inflammatory-and tumor-induced osteolysis . Inhibition of P08183 does not sensitize primitive chronic myeloid leukemia P28906 + cells to imatinib . OBJECTIVE : To investigate the interaction of imatinib mesylate ( IM ) with the clinically relevant adenosine triphosphate-binding cassette efflux transporter P08183 ( P08183 ) in cells from patients with chronic myeloid leukemia ( CML ) and to explore whether inhibition of this transporter would improve IM 's efficacy in the elimination of CML P28906 (+) cells by increasing cell-associated drug accumulation . MATERIALS AND METHODS : Cells from newly diagnosed chronic-phase CML patients were harvested by leukapheresis and enriched to > 95 % P28906 (+) . Expression of the transporter gene P08183 was performed by quantitative reverse transcription polymerase chain reaction . Interaction of IM with P08183 was analyzed by substrate ( rhodamine 123 ) displacement assay . Cell-associated levels of IM in CML P28906 (+) cells were measured by high-pressure liquid chromatography . Intracellular phospho-CrkL levels , apoptosis in total CML P28906 (+) cells and high-resolution tracking of cell division were assayed by flow cytometry . RESULTS : Measurements of cell-associated IM uptake showed significantly lower drug levels in P28906 (+) cells , particularly the P28907 (-) subpopulation , as compared to IM-sensitive K562 cells . P08183 was expressed at low level and dye efflux studies demonstrated very little P08183 activity in CML P28906 (+) cells . Furthermore , combination treatment of primitive CML cells with IM and the P08183 inhibitor PSC833 did not result in elevated cell-associated IM levels . Although we observed slightly enhanced cytostasis with IM when combined with PSC833 , this was independent of P11274 - P00519 inhibition because no associated decrease in phospho-CrkL was observed . CONCLUSIONS : Our findings demonstrate that inhibition of P08183 neither enhances the effect of IM against P11274 - P00519 activity , nor significantly potentiates IM 's efficiency in eliminating primitive CML cells . [ 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 .