MH_dev_136

DB00171 induces synaptic gene expressions in cortical neurons : transduction and transcription control via P47900 REA receptors . Studies in vertebrate neuromuscular synapses have revealed previously that DB00171 , via P2Y receptors , plays a critical role in regulating postsynaptic gene expressions . An equivalent regulatory role of DB00171 and its P2Y receptors would not necessarily be expected for the very different situation of the brain synapses , but we provide evidence here for a brain version of that role . In cultured cortical neurons , the expression of P2Y ( 1 ) receptors increased sharply during neuronal differentiation . Those receptors were found mainly colocalized with the postsynaptic scaffold postsynaptic density protein 95 ( P78352 REA ) . This arises through a direct interaction of a PDZ domain of P78352 REA with the C-terminal PDZ-binding motif , D-T-S-L of the P2Y ( 1 ) receptor , confirmed by the full suppression of the colocalization upon mutation of two amino acids therein . This interaction is effective in recruiting P78352 REA to the membrane . Specific activation of P2Y ( 1 ) ( G-protein-coupled ) receptors induced the elevation of intracellular Ca ( 2 + ) and activation of a mitogen-activated protein kinase / P04049 REA signaling cascade . This led to distinct up-regulation of the genes encoding acetylcholinesterase ( P22303 REA ( T ) variant ) , choline acetyltransferase , and the N-methyl-d-aspartate receptor subunit Q12879 REA . This was confirmed , in the example of P22303 REA , to arise from P2Y ( 1 ) - dependent stimulation of a human P22303 REA gene promoter . That involved activation of the transcription factor Elk - 1 ; mutagenesis of the P22303 REA promoter revealed that Elk - 1 binding at its specific responsive elements in that promoter was induced by P2Y ( 1 ) receptor activation . The combined findings reveal that DB00171 , via its P2Y ( 1 ) receptor , can act trophically in brain neurons to regulate the gene expression of direct effectors of synaptic transmission .

Correlation of somatic mutations and clinical outcome in melanoma patients treated with Carboplatin , Paclitaxel , and sorafenib . PURPOSE : DB00398 SUB is an inhibitor of P15692 REA receptor ( VEGFR ) , platelet-derived growth factor receptor ( P09619 REA ) , and RAF kinases , amongst others . We assessed the association of somatic mutations with clinicopathologic features and clinical outcomes in patients with metastatic melanoma treated on E2603 , comparing treatment with carboplatin , paclitaxel ± sorafenib ( CP vs . CPS ) EXPERIMENTAL DESIGN : Pretreatment tumor samples from 179 unique individuals enrolled on E2603 were analyzed . Genotyping was performed using a custom iPlex panel interrogating 74 mutations in 13 genes . Statistical analysis was performed using Fisher exact test , logistic regression , and Cox proportional hazards models . Progression-free survival ( PFS ) and overall survival were estimated using Kaplan-Meier methods . RESULTS : P15056 REA and P01111 REA mutations were found at frequencies consistent with other metastatic melanoma cohorts . P15056 REA - mutant melanoma was associated with worse performance status , increased number of disease sites , and younger age at diagnosis . P01111 REA - mutant melanoma was associated with better performance status , fewer sites of disease , and female gender . P15056 REA and P01111 REA mutations were not significantly predictive of response or survival when treated with CPS versus CP . However , patients with P01111 REA - mutant melanoma trended toward a worse response and PFS on CP than those with P15056 REA - mutant or WT / WT melanoma , an association that was reversed for this group on the CPS arm . CONCLUSIONS : This study of somatic mutations in melanoma is the last prospectively collected phase III clinical trial population before the era of P15056 REA - targeted therapy . A trend toward improved clinical response in patients with P01111 REA - mutant melanoma treated with CPS was observed , possibly due to the effect of sorafenib on CRAF .

Antitumor activity of sorafenib in human cancer cell lines with acquired resistance to P00533 REA and VEGFR tyrosine kinase inhibitors . Treatment of non small cell lung cancer ( NSCLC ) and colorectal cancer ( CRC ) have substantially changed in the last years with the introduction of epidermal growth factor receptor ( P00533 REA ) inhibitors in the clinical practice . The understanding of mechanisms which regulate cells sensitivity to these drugs is necessary for their optimal use.An in vitro model of acquired resistance to two tyrosine kinase inhibitors ( TKI ) targeting the P00533 REA , erlotinib and gefitinib , and to a TKI targeting P00533 REA and VEGFR , vandetanib , was developed by continuously treating the human NSCLC cell line O43852 REA - 3 and the human CRC cell line HCT 116 with escalating doses of each drug . MTT , western blot analysis , migration , invasion and anchorage-independent colony forming assays were conducted in vitro and experiments with established xenografts in athymic nude mice were performed in vivo in sensitive , wild type ( WT ) and TKI-resistant O43852 REA - 3 and HCT 116 cell lines.As compared to WT O43852 REA - 3 and HCT 116 human cancer cells , TKI-resistant cell lines showed a significant increase in the levels of activated , phosphorylated AKT , MAPK , and of survivin . Considering the role of DB01367 and RAF as downstream signals of both the P00533 REA and VEGFR pathways , we treated resistant cells with sorafenib , an inhibitor of C-RAF , B-RAF , c - P10721 REA , P36888 REA , P07949 REA , P35968 REA , P35916 REA , and P09619 REA - β . DB00398 SUB reduced the activation of MEK and MAPK and caused an inhibition of cell proliferation , invasion , migration , anchorage-independent growth in vitro and of tumor growth in vivo of all TKI-resistant O43852 REA - 3 and HCT 116 cell lines.These data suggest that resistance to P00533 REA inhibitors is predominantly driven by the DB01367 / RAF / MAPK pathway and can be overcame by treatment with sorafenib .

DB00398 SUB in melanoma . INTRODUCTION : DB00398 SUB is an orally available multi-kinase inhibitor that inhibits tumor proliferation by targeting multiple kinases including the vascular endothelial growth factor receptors P17948 REA , P35968 REA , P35916 REA and the platelet-derived growth factor receptor P09619 REA , and it targets tumor progression by inhibiting P36888 REA , C-Kit and P15056 REA . Since P15056 REA mutations are frequent in melanoma , sorafenib was investigated in various Phase I , II and III clinical trials . The drug is well tolerated with mild to moderate adverse effects , which are mostly limited to cutaneous toxicity , diarrhea and fatigue . AREAS COVERED : Systematic literature review of the randomized trials using PubMed was performed . Original articles were reviewed and citations from those were also considered . Additionally , clinical trial databases were examined to identify and summarize ongoing trials of sorafenib in melanoma patients . EXPERT OPINION : DB00398 SUB as a monotherapy or in combination with chemotherapy is of limited use . Combining it with dacarbazine doubled the response rate and the progression-free survival in metastatic melanoma patients . Unfortunately , these results have never been evaluated in large randomized Phase III clinical trials . According to the trials conducted so far a subpopulation of patients experience substantial benefit , therefore it is essential to identify biomarkers to select the subgroups of patients that are more likely to respond to sorafenib . Furthermore , other less frequent subtypes such as mucosal or ocular melanoma still constitute promising targets ; academic institutions are currently launching investigator-initiated trials in these indications .

Peripheral medulloepithelioma : a rare tumor with a potential target therapy . BACKGROUND : Medulloepithelioma ( ME ) is a rare embryonal tumor predominantly located in the eye or in the central nervous system without an established treatment . CASE PRESENTATION : We report of a case of a localized peripheral ME treated with conventional and high dose chemotherapy , surgery and local radiotherapy . At relapse , the tumor tissue revealed a different molecular signature compared to the initial tumor mass . This molecular signature revealed a high expression of platelet derived growth factor receptor ( P09619 REA ) . DB00398 SUB plus irinotecan and temozolomide was started with a 5 month progression free survival . CONCLUSION : Our experience suggests a possible role of sorafenib or different P09619 REA inhibitors in ME . Targeting treatment could represent an adjuvant and / or alternative therapy for ME and other rare tumors .

Pharmacological properties of thalidomide and its analogues . Thalidomide and its immunomodulatory imide drugs ( IMiDs ) analogues DB00480 ( DB00480 , DB00480 ) and CC - 4047 ( Actimid , DB08910 MEN ) have been used as anti-inflammatory and anticancerous drugs in the recent years . Thalidomide and IMiDs inhibit the cytokines tumour necrosis factor-alpha ( P01375 REA ) , interleukins ( IL ) 1 - beta , 6 , 12 , and granulocyte macrophage-colony stimulating factor ( GM - P04141 REA ) . They also costimulate primary human T , NKT and NK lymphocytes inducing their proliferation , cytokine production , and cytotoxic activity . On the other hand , the compounds are anti-angiogenic , anti-proliferative , and pro-apoptotic . Thalidomide analogues have been used as inhibitors of alpha glucosidase and could be potential drugs for diabetes treatment . In this review , we explore the current trend of the different structures , the new patents , and the possible new applications in different pathologies .

Transduction of P28906 REA + cells with lentiviral vectors enables the production of large quantities of transgene-expressing immature and mature dendritic cells . BACKGROUND : Genetically engineered dendritic cells ( DC ) presenting specific antigens to T cells may be of great interest for immunotherapy . For this reason , the production of transgene-expressing DC derived from P28906 REA + cells transduced either shortly after ex vivo purification or during their differentiation into DC were evaluated . METHODS : P28906 REA + cells were transduced with lentivectors encoding for GFP before or after 21 days of culture with P36888 REA - ligand , thrombopoietin and stem cell factor and induction into DC with GM - P04141 REA + P05112 REA ( G4 ) or G4 + P01375 REA ( GT4 ) . GFP and DC-specific marker expression was assessed by flow cytometry , and allostimulatory capacity was evaluated on GFP + and GFP - sorted cells . RESULTS : Immature ( G4 - induced ) DC obtained from amplified P28906 REA + cells were transducible by lentiviral vectors while mature ( GT4 - induced ) DC were rather refractory . Moreover , since differentiated DC did not proliferate , large quantities of vectors were required to generate transgene-expressing cells with this protocol . In contrast , greater numbers of both immature and mature GFP - expressing DC were obtained with P28906 REA + cells exposed to lentivector shortly after purification . By the time of DC induction , GFP + cells had increased by approximately 170 - fold . After DC induction with G4 , 32 % of CD1a + , HLA-DR + , or P25942 REA + cells expressed GFP . CD1a + P12830 REA + GFP + Langerhans-like DC were also obtained . Incubation with P01375 REA induced mature Q01151 + GFP + DC that displayed a higher allostimulatory capacity than cells induced with G4 alone . CONCLUSION : The transduction of a small number of P28906 REA + cells with minimal doses of lentivector may allow for the production of a large number of DC expressing selected antigens useful for immunotherapy .

The unexpected effect of cyclosporin A on CD56 + CD16 - and CD56 + CD16 + natural killer cell subpopulations . DB00091 ( Q13216 REA ) is commonly used to prevent graft-versus-host disease . The influence of Q13216 REA on T-cell function has been extensively investigated ; however , the effect of Q13216 REA on natural killer ( NK ) cells is less understood . NK cells were cultured with P60568 REA and P40933 REA with and without Q13216 REA for 1 week . Compared with controls , Q13216 REA - treated cultures showed fewer CD56 ( + ) CD16 ( + ) P55040 ( + ) NK cells and a reciprocal increase in CD56 ( + ) CD16 ( - ) P55040 ( - ) cells . These changes were due mainly to a reduced proliferation of the CD56 ( dim ) NK-cell subpopulation and a relative resistance of CD56 ( bright ) NK cells to Q13216 REA . Following coculture with K562 targets , Q13216 REA - exposed NK cells differed from controls and lacked Ca ( 2 + ) oscillations , nuclear factor of activated T cells ( NFAT ) dephosphorylation , and NFAT nuclear translocation . NK cells cultured in Q13216 REA retained cytotoxicity against K562 , Raji , and P55040 ligand-expressing lymphoblastoid cells . NK cells cultured in Q13216 REA showed increases in O14931 REA and reductions in O95944 REA and P26718 REA . Following IL - 12 and Q14116 REA stimulation , Q13216 REA - treated NK cells showed more P01579 REA - producing cells . Using in vitro NK-cell differentiation , progenitor cells gave rise to more CD56 ( + ) P55040 ( - ) NK cells in the presence of Q13216 REA than controls . Collectively , these studies show that Q13216 REA influences NK-cell function and phenotype , which may have important implications for graft-versus-leukemia effects .

The important roles of P07949 REA , P35968 REA and the RAF / MEK / P29323 REA pathway in cancer treatment with sorafenib . AIM : To elucidate the roles of receptor tyrosine kinases P07949 REA and P35968 REA and the RAF / MEK / P29323 REA signaling cascade in cancer treatment with sorafenib . METHODS : The cell lines A549 , HeLa , and HepG 2 were tested . The enzyme activity was examined under cell-free conditions using 384 - well microplate assays . Cell proliferation was evaluated using the Invitrogen Alarmar Blue assay . Gene expression was analyzed using the Invitrogen SYBR Green expression assays with a sequence detection system . Protein expression analysis was performed using Western blotting . RESULTS : DB00398 SUB potently suppressed the activities of cRAF , P35968 REA , and P07949 REA with IC ( 50 ) values of 20.9 , 4 and 0.4 nmol / L , respectively . DB00398 SUB inhibited cRAF , P35968 REA , and P07949 REA via non - DB00171 - competitive , DB00171 - competitive and mixed-type modes , respectively . In contrast , sorafenib exerted only moderate cytotoxic effects on the proliferation of the 3 cell lines . The IC ( 50 ) values for inhibition of A549 , HeLa , and HepG 2 cells were 8572 , 4163 , and 8338 nmol / L , respectively . In the 3 cell lines , sorafenib suppressed the cell proliferation mainly by blocking the MEK / P29323 REA downstream pathway at the posttranscriptional level , which in turn regulated related gene expression via a feed-back mechanism . CONCLUSION : This study provides novel evidence that protein kinases P07949 REA and P35968 REA play crucial roles in cancer treatment with sorafenib .

The ability of sorafenib to inhibit oncogenic PDGFRbeta and P36888 REA mutants and overcome resistance to other small molecule inhibitors . BACKGROUND AND OBJECTIVES : Activated tyrosine kinases are implicated in the pathogenesis of chronic and acute leukemia , and represent attractive targets for therapy . DB00398 SUB ( BAY 43-9006 , Nexavar ) is a small molecule B-RAF inhibitor that is used for the treatment of renal cell carcinoma , and has been shown to have activity against receptor tyrosine kinases from the platelet-derived growth factor receptor ( P09619 REA ) and vascular endothelial growth factor receptor ( VEGFR ) families . We investigated the efficacy of sorafenib at inhibiting mutants of the receptor tyrosine kinases PDGFRbeta , P10721 REA , and P36888 REA , which are implicated in the pathogenesis of myeloid malignancies . DESIGN AND METHODS : We tested the effect of sorafenib on the proliferation of hematopoietic cells transformed by P41212 REA - PDGFRbeta , P36888 REA with an internal tandem duplication or D8 35Y point mutation , and the P10721 REA ( D8 16V ) mutant . The direct effect of sorafenib on the activity of these kinases and their downstream signaling was tested using phospho-specific antibodies . RESULTS : We show that sorafenib is a potent inhibitor of P41212 REA - PDGFRbeta and P36888 REA mutants , including some of the mutants that confer resistance to PKC 412 and other P36888 REA inhibitors . DB00398 SUB induced a cell cycle block and apoptosis in the acute myeloid leukemia cell lines MV4 - 11 and MOLM - 13 , both expressing P36888 REA with an internal tandem duplication , whereas no effect was observed on four other acute myeloid leukemia cell lines . The imatinib-resistant P10721 REA ( D8 16V ) mutant , associated with systemic mastocytosis , was found to be resistant to sorafenib . INTERPRETATION AND CONCLUSIONS : These results warrant further clinical studies of sorafenib for the treatment of myeloid malignancies expressing activated forms of PDGFRbeta and P36888 REA .

Critical role of sorafenib exposure over time for its antitumor activity in thyroid cancer . DB00398 SUB , a multi-kinase inhibitor that targets the P15692 REA , PDGF and P15056 REA pathways , has demonstrated significant clinical activity in metastatic differentiated thyroid cancer . However , all patients eventually experience disease progression with a median progression-free survival close to 10 months . Since sorafenib exposure is known to decrease over time , we hypothesized that dose adjustments aiming to restore adequate exposure could lead to further clinical activity . We report , as a proof of concept on a patient with radio-iodine resistant metastatic thyroid cancer , who experienced disease progression after an initial response to sorafenib ( 400 mg twice daily ) . Whereas the thyroglobulin-progression-free survival at standard doses was 6 months , iterative dose optimization led to a prolonged progression-free survival up to 41 months . DB00398 SUB doses were increased up to 1600 mg bid , in order to maintain clinical activity , and to restore active plasma concentration , since sorafenib exposure had decreased over the time . Toxicity was mild and manageable for more than 2 years . However , the patient eventually experienced grade 3 proteinuria leading to treatment discontinuation . This observation opens up new horizons for daily management of radioactive iodine-refractory differentiated thyroid cancer patients progressing under standard doses of sorafenib , and stress the need to monitor its plasma concentration .

DB00398 SUB inhibits the angiogenesis and growth of orthotopic anaplastic thyroid carcinoma xenografts in nude mice . Anaplastic thyroid carcinoma ( ATC ) remains one of the most lethal human cancers . We hypothesized that sorafenib , a multikinase inhibitor of the BRaf , vascular endothelial growth factor receptor - 2 , and platelet-derived growth factor receptor-beta kinase , would decrease tumor growth and angiogenesis in an orthotopic model of ATC . The in vitro antiproliferative and proapoptotic effects of sorafenib on ATC cell lines were examined . To study the in vivo effects of sorafenib on orthotopic ATC tumors in nude mice , sorafenib was given p . o . at 40 or 80 mg / kg daily . Intratumoral effects were studied using immunohistochemical analysis . The effect of sorafenib on survival of the mice was also studied . DB00398 SUB inhibited the in vitro proliferation of ATC cell lines . DB00398 SUB also significantly inhibited tumor angiogenesis via the induction of endothelial apoptosis in an orthotopic model of thyroid cancer . As result , the growth of orthotopic ATC xenografts was reduced and the survival of the test animals was improved . DB00398 SUB exerts significant antitumor activity in an orthotopic xenograft model of ATC via a potent antiangiogenic effect . The antiangiogenic effects of sorafenib suggest that its use in clinical setting may not depend on the P15056 REA mutational status of thyroid tumors . Given the lack of curative options for patients with ATC , sorafenib warrants further study as a therapeutic agent against ATC .

Assessing tumor mutations to gain insight into base excision repair sequence polymorphisms and smoking in colon cancer . DNA repair enzymes function in major pathways to reverse DNA damage , including base excision repair ( BER ) . Missense polymorphisms in BER repair genes may contribute to differences in DNA repair capacity , specific mutations , and susceptibility to cancer in the presence of exposure to carcinogens such as cigarette smoking . In a study of 1,604 incident colon cancer cases and 1,969 matched population-based controls genotyped for BER variants O15527 REA ( S326C ) and P18887 REA ( R194W , R280H , and R399Q ) , we found no associations with colon cancer overall . However , a 2 - fold increased risk of P15056 REA V600E tumor mutation was observed in current and former cigarette smokers homozygous for the O15527 REA polymorphism ( odds ratio , 2.2 ; 95 % confidence interval , 1.02- 4.9 , recessive model ) ; similar associations were not observed for microsatellite instability , CpG island methylator phenotype , P01116 REA mutations , or P04637 REA mutations . The P18887 REA R194W polymorphism was associated with a modest increased risk of P04637 REA tumor mutations in those who regularly smoked cigarettes ( odds ratio , 1.4 ; 95 % confidence interval , 1.02- 1.9 ) . These findings point to the importance of studying tumor mutations when examining DNA repair polymorphisms and cigarette smoke exposure to identify potentially relevant associations with colorectal cancer .

Iodide - and glucose-handling gene expression regulated by sorafenib or cabozantinib in papillary thyroid cancer . CONTEXT : The aberrant silencing of iodide-handling genes accompanied by up-regulation of glucose metabolism presents a major challenge for radioiodine treatment of papillary thyroid cancer ( PTC ) . OBJECTIVE : This study aimed to evaluate the effect of tyrosine kinase inhibitors on iodide-handling and glucose-handling gene expression in BHP 2-7 cells harboring P07949 REA / Q13635 REA rearrangement . MAIN OUTCOME MEASURES : In this in vitro study , the effects of sorafenib or cabozantinib on cell growth , cycles , and apoptosis were investigated by cell proliferation assay , cell cycle analysis , and P08758 REA - FITC apoptosis assay , respectively . The effect of both agents on signal transduction pathways was evaluated using the Western blot . Quantitative real-time PCR , Western blot , immunofluorescence , and radioisotope uptake assays were used to assess iodide-handling and glucose-handling gene expression . RESULTS : Both compounds inhibited cell proliferation in a time-dependent and dose-dependent manner and caused cell cycle arrest in the G0 / P55008 phase . DB00398 SUB blocked P07949 REA , AKT , and P27361 REA / 2 phosphorylation , whereas cabozantinib blocked P07949 REA and AKT phosphorylation . The restoration of iodide-handling gene expression and inhibition of glucose transporter 1 and 3 expression could be induced by either drug . The robust expression of sodium / iodide symporter induced by either agent was confirmed , and ( 125 ) I uptake was correspondingly enhanced . ( 18 ) F - DB09150 accumulation was significantly decreased after treatment by either sorafenib or cabozantinib . CONCLUSIONS : DB00398 SUB and cabozantinib had marked effects on cell proliferation , cell cycle arrest , and signal transduction pathways in PTC cells harboring P07949 REA / Q13635 REA rearrangement . Both agents could be potentially used to enhance the expression of iodide-handling genes and inhibit the expression of glucose transporter genes .

Nerve growth factor activation of the extracellular signal-regulated kinase pathway is modulated by Ca ( 2 + ) and calmodulin . Nerve growth factor is a member of the neurotrophin family of trophic factors that have been reported to be essential for the survival and development of sympathetic neurons and a subset of sensory neurons . Nerve growth factor exerts its effects mainly by interaction with the specific receptor TrkA , which leads to the activation of several intracellular signaling pathways . Once activated , TrkA also allows for a rapid and moderate increase in intracellular calcium levels , which would contribute to the effects triggered by nerve growth factor in neurons . In this report , we analyzed the relationship of calcium to the activation of the Ras / extracellular signal-regulated kinase pathway in PC12 cells . We observed that calcium and calmodulin are both necessary for the acute activation of extracellular signal-regulated kinases after TrkA stimulation . We analyzed the elements of the pathway that lead to this activation , and we observed that calmodulin antagonists completely block the initial P04049 REA activation without affecting the function of upstream elements , such as Ras , Grb 2 , Shc , and Trk . We have broadened our study to other stimuli that activate extracellular signal-regulated kinases through tyrosine kinase receptors , and we have observed that calmodulin also modulates the activation of such kinases after epidermal growth factor receptor stimulation in PC12 cells and after TrkB stimulation in cultured chicken embryo motoneurons . P62158 seems to regulate the full activation of P04049 REA after Ras activation , since functional Ras is necessary for P04049 REA activation after nerve growth factor stimulation and calmodulin-Sepharose is able to precipitate P04049 REA in a calcium-dependent manner .

Medical treatments : in association or alone , their roles and their future perspectives : the Western experience . Management of hepatocellular carcinoma ( HCC ) is a complex issue , as it needs to take into account the liver disease , the cancer stage and the performance status of the patient . The treatment decision has to be based on robust scientific evidence and for this it is instrumental to have a proper staging system linked to the treatment indication . The BCLC proposal serves these two purposes and has been validated worldwide and endorsed by several scientific associations . The sole systemic therapy that has shown efficacy in improving the survival of HCC patients is sorafenib , an oral kinase inhibitor that blocks the Raf / MEK / P29323 REA pathway and the receptor for VEGFR 2 and P09619 REA . DB00398 SUB has been recognized as the standard of care for patients who can not benefit from treatments of higher priority and established efficacy , such as surgical resection , transplantation , ablation and transarterial chemoembolization . DB00398 SUB has changed the management of HCC , opening the path to combination therapies for patients at advanced stages and to evaluation as an adjuvant for those in earlier evolutionary stages .

A randomized phase II trial of maintenance therapy with DB00398 SUB in front-line ovarian carcinoma . OBJECTIVES : DB00398 SUB , an oral multikinase inhibitor of the VEGFR / P09619 REA / Raf / MEK / P29323 REA pathway , has shown potential activity in patients with recurrent ovarian cancer ( OC ) . One strategy to prolong disease control and survival in patients with OC is maintenance therapy after achieving a complete response . A double-blind , randomized , placebo-controlled , phase II study to assess the efficacy and safety of maintenance therapy with sorafenib in the treatment of OC is presented . METHODS : Patients with epithelial OC or primary peritoneal cancer in complete remission were randomized to sorafenib 400mg P55957 REA or matching placebo . The primary endpoint was progression-free survival ( PFS ) . RESULTS : Of 246 randomized patients , 93 % had OC ; baseline characteristics were balanced between treatment arms . There was no significant difference between sorafenib and placebo arms for PFS ( median 12.7 vs 15.7 months ; hazard ratio 1.09 ; 95 % CI 0.72- 1.63 ) , although there was a notable imbalance in early censoring . The most common ≥ grade 3 adverse events ( AEs ) were hand-foot skin reaction ( 39.0 % vs 0.8 % ) and rash ( 14.6 % vs 0 % ) . More patients receiving sorafenib versus placebo required dose reductions ( 67.5 % vs 30.1 % ) , resulting in a lower than planned median daily dose ( median 584.6 vs 800.0 mg ) . Treatment with sorafenib was of shorter duration ( median 17.6 vs 51.9 weeks ) with more frequent discontinuations due to AEs ( 37.4 % vs 6.5 % ) . CONCLUSIONS : DB00398 SUB 400mg P55957 REA can not be recommended as maintenance therapy for patients with OC in complete remission . Assessment of efficacy was limited by the high rate of dose reductions and early discontinuations .

The behavior of stem cells and progenitor cells in the periodontal ligament during wound healing as observed using immunohistochemical methods . BACKGROUND AND OBJECTIVE : The aim of this study was to identify stem cells or progenitor cells in the periodontal ligament and to investigate their behavior during wound healing of bone defects created experimentally in the alveolar process . MATERIAL AND METHODS : Intradentinal cavities were created in the mesial root of the first molar of 25 adult male rats that were killed 1 , 3 , 5 , 7 and 14 d after surgery . At each time-point , sections were stained immunohistochemically for CD44s ( standard ) , P28906 REA , c - P10721 REA , P12004 REA , Cbfa - 1 and 5 - bromo - 2 - deoxyuridine using primary antibodies . For morphometric analysis , the ratios of Cbfa - 1 and P12004 REA - positive cells were calculated from the total number of positive cells / 10 ( 4 ) microm ( 2 ) in the cavities . RESULTS : 5 - Bromo - 2 - deoxyuridine-positive cells were observed in the periodontal ligament and had migrated into the wound areas . A small number of CD44s - , P28906 REA - and c - P10721 REA - positive cells were observed in the bone marrow , but none were observed in the periodontal ligament . CD44s - positive cells were only observed in the alveolar bone cavity at 5 d after surgery . P28906 REA - and c - P10721 REA - positive cells were only observed in the dentin cavity at 7 d after surgery . Cbfa - 1 and P12004 REA scores tended to show an increase 7 d after surgery . CONCLUSION : Mesenchymal stem cells and hematopoietic stem cells in the bone marrow are not involved in the regeneration of the periodontium . Cells that migrated from the residual periodontal ligament regenerated new alveolar bone at the early stage , and the regeneration around the dentin in the cavity was later than in other parts .

Renal cell carcinoma and the use of sorafenib . Immunotherapy results in a small overall survival advantage in metastatic renal cell carcinoma ( RCC ) , but there is a need to develop more effective systemic therapies . Angiogenesis has an important role in the pathophysiology of RCC and vascular endothelial growth factor ( P15692 REA ) is a key mediator of this process . DB00398 SUB ( BAY 43-9006 ) is a new agent belonging to a class of drugs called kinase inhibitors and inhibits the P15692 REA , platelet-derived growth factor ( PDGF ) , and c - P10721 REA receptor tyrosine kinases , amongst others . DB00398 SUB has shown significant activity with manageable toxicity in metastatic RCC in phase 2 studies in patients pretreated with immunotherapy , whilst prolonged progression-free survival in comparison with placebo in a phase 3 study has been reported . Further phase 3 trials in advanced disease are ongoing and a trial of adjuvant sorafenib therapy in RCC is planned .

Lymphagenesis correlates with expression of vascular endothelial growth factor-C in colorectal cancer . Lymphagenesis in gastrointestinal tumors is not well described . To clarify its presence and regulation , we assessed the microlymphatic count ( MLC ) in colorectal cancer patients . Lymphatic vessels were evaluated by enzyme-histochemistry for 5 ' - nucleotidase ( 5 ' - NA ) . Since vascular endothelial growth factor ( P15692 REA ) - C is reportedly associated with lymphagenesis , the expression of P49767 REA protein was immunohistochemically assessed by the catalyzed signal amplification ( Q13216 REA ) method . MLC of peritumoral lesions was significantly higher than that of non-cancer and intratumoral lesions ( p < 0.01 ) ; it increased where P49767 REA was highly expressed ( p < 0.01 ) and increased with the depth of invasion in peritumoral lesions . These results indicate significant findings at peritumoral lesion : that lymphagenesis may be elicited by tumor spread ; that P49767 REA expression is associated with lymphagenesis and is a potent factor stimulating lymphagenesis .

Synthesis , biological evaluation and 3D - QSAR studies of novel 4,5- dihydro - 1H - pyrazole niacinamide derivatives as P15056 REA inhibitors . A series of novel 4,5- dihydropyrazole derivatives containing niacinamide moiety as potential V600E mutant P15056 REA kinase ( P15056 REA ( V600E ) ) inhibitors were designed and synthesized . Results of the bioassays against P15056 REA ( V600E ) and WM266 . 4 human melanoma cell line showed several compounds to be endowed potent activities with IC ( 50 ) and GI ( 50 ) value in low micromolar range , among which compound 27e , ( 5 - ( 4 - Chlorophenyl ) - 3 - ( 4 - methoxyphenyl ) -4,5- dihydro - 1H - pyrazol - 1 - yl ) 6 - methylpyridin - 3 - yl methanone ( IC ( 50 )= 0.20 μM , GI ( 50 )= 0.89 μM ) was bearing the best bioactivity comparable with the positive control DB00398 SUB . Docking simulation was performed to determine the probable binding model and 3D - QSAR model was built to provide more pharmacophore understanding that could use to design new agents with more potent P15056 REA ( V600E ) inhibitory activity .

Molecular targets in Gastrointestinal Stromal Tumors ( GIST ) therapy . Gastrointestinal Stromal Tumors ( GISTs ) are the most common mesenchimal tumors of the gastrointestinal tract . Such tumors usually have activating mutations in either P10721 REA ( 75-80 % ) or Platelet Derived Growth Factor Receptor alpha ( PDGFRa ) ( 5-10 % ) which lead to ligand-independent signal transduction . Targeting these activated proteins with Imatinib mesylate , a small-molecule kinase inhibitor , has proven useful in the treatment of recurrent or metastatic GISTs . However , more than half of patients develop resistance to Imatinib after about 2 years . Therefore , other targets have been studying in order to implement the therapeutical armamentarium for this disease . DB01268 malate is an oral multikinase inhibitor that targets several receptor tyrosine kinases and has proved to prolong survival in Imatinib-resistant patients . Other molecules , such as DB04868 , DB00398 SUB and Dasatinib were shown to be useful in Imatinib resistant mutant cell lines and the results of their activity in humans are being awaited . Recent evidence suggests that GIST cells acquire the capability to escape from the control of P10721 REA and PDGFRa through the activation of alternative pathways . Therefore , further effort should be invested in the discovery of new signaling pathways , such as P30530 REA , MET , IGF-R , which might be involved in the evolution of the disease . After a description of P10721 REA and PDGFRa as known targets of anti-GIST treatments , we review other mechanisms and mediators that might be potential targets of new therapies , providing a comprehensive revision of the new molecular strategies under investigation .

The activated targets of P42345 REA signaling pathway are characteristic for P16234 REA mutant and wild-type rather than P10721 REA mutant GISTs . The therapy for gastrointestinal stromal tumors ( GISTs ) has been revolutionized by tyrosin kinase inhibitors . Clinicopathologic studies have been conducted to assess therapeutical responses in cases with P10721 REA and platelet-derived growth factor receptor α ( P16234 REA ) gene mutations . Cell culture data suggest that Akt / mammalian target of rapamycin ( P42345 REA ) kinase signaling may be important in GIST . The aim of our study was to determine the activity of the P42345 REA pathway in a larger series of GISTs ( 108 different cases ) with different exon mutation types . The P10721 REA and / or P16234 REA mutation status of 108 GIST patients was analyzed by direct DNA sequencing . Immunohistochemistry was performed on tissue microarrays using antibodies for phospho-p 70S6 kinase , phospho - 4EBP1 , and phospho-S 6 , which are downstream target proteins of P42345 REA . DNA sequencing identified 73 cases with mutations of P10721 REA and 12 cases with P16234 REA mutations . Wild-type receptors were present in 23 cases . P10721 REA exon mutations were accompanied by the activation of the P42345 REA pathway in 28 of 73 ( 38.4 % ) cases , whereas P16234 REA mutant GISTs showed activation in 10 of 12 ( 83.3 % ) cases . Wild-type cases were accompanied by P42345 REA activation in 17 of 23 ( 73.9 % ) cases . Our results indicate that the activation of the P42345 REA pathway is not a general hallmark of GIST with P10721 REA mutations . However , P42345 REA signaling seems to be activated in P16234 REA mutants and in wild-type cases , which suggests that P42345 REA or upstream P42345 REA inhibitors may be therapeutically useful in primary resistant GISTs and confirms earlier data that P42345 REA is a crucial survival pathway in resistant GISTs .

A randomized phase I clinical and biologic study of two schedules of sorafenib in patients with myelodysplastic syndrome or acute myeloid leukemia : a NCIC ( National Cancer Institute of Canada ) Clinical Trials Group Study . DB00398 SUB is a small molecule inhibitor of RAF kinase , P35968 REA , c - P10721 REA , and P36888 REA . In this randomized phase I study , eligible patients had relapsed / refractory acute myeloid leukemia ( AML ) , and one prior induction regimen , or were age > 65 with untreated myelodysplastic syndrome ( P43034 REA ) or secondary AML . DB00398 SUB was given orally for 28 days ( cont ) or 14 days ( int ) every 4 weeks at three dose levels ( 100 , 200 , and 400 mg P55957 REA ) ; 300 mg cont was also tested . Forty-two patients were enrolled ( median age 71 [ 37-82 ] ; prior chemotherapy : 22 ) . Dose-limiting toxicity ( DLT ) was : 100 mg P55957 REA : 0/7 patients ; 200 mg P55957 REA : 2/12 patients ; 400 mg P55957 REA : 1/17 patients . DB00398 SUB 400 mg cont was not tolerated in this population : 6/8 received < 14 days of treatment due to toxicity ; no DLT was seen with 300 mg cont . One CR was seen in a patient with AML with P36888 REA - ITD . Flow cytometry studies suggest that sorafenib inhibits P29323 REA phosphorylation via c - P10721 REA . The recommended phase II dose in AML is 300 mg P55957 REA continuously , and testing in combination and in P36888 REA - ITD AML is warranted .

Bypassing tumor-specific and bispecific antibodies : triggering of antitumor immunity by expression of anti-FcgammaR scFv on cancer cell surface . We have developed a novel immunostimulatory molecule against tumor cells , composed of an anti-FcgammaRIII ( CD16 ) scFv fused to the platelet-derived growth factor receptor ( P09619 REA ) transmembrane region . This fusion molecule was stably expressed on the tumor cell surface and retained the ability of the parental antibody to bind soluble CD16 . Tumor cells expressing anti-CD 16 scFv triggered the release of P60568 REA by Jurkat-CD 16 / gamma cells and of TNFalpha by monocytes when co-cultured with these cells . Furthermore , NK cells could kill scFv-transfected HLA + class I H1299 lung carcinoma tumor cells , but not the parental cells , indicating that anti-CD 16 scFv tumor expression prevents the killer inhibitory receptor ( P55040 ) - mediated inhibition of NK cell cytotoxicity . This anti-CD 16 scFv tumor expression also enhanced tumor phagocytosis by IFNgamma-activated macrophages , a mechanism known to induce a protective long-term adaptative immunity to tumors . In vivo Winn tests performed in SCID mice showed that the expression of anti-CD 16 scFv on tumor cells , but not of the negative control anti-phOx scFv , prevented tumor cell growth . Thus , expression of FcR antibodies or other FcR-specific ligands on tumor cells represents a novel and potent antibody-based gene therapy approach , which may have clinical applications in cancer

Effect of clopidogrel on circulating biomarkers of angiogenesis and endothelial activation . Angiogenic cytokines have been shown to influence vessel injury , and platelets represent a disposable circulating pool of angiogenic molecules . In the present study , objectives were to determine whether clopidogrel could have a potential effect on levels of circulating biomarkers of angiogenesis and endothelial activation . We explored 28 healthy white male volunteers treated for 7 days with clopidogrel 75 mg / day . We quantified angiogenic growth factors that have been shown to be correlated to cardiovascular risk or endothelial progenitor cell mobilization such as vascular endothelial growth factor ( P15692 REA ) - A and its soluble receptor forms P17948 REA and P35968 REA , placenta growth factor , and stromal cell-derived factor - 1 . We also quantified soluble P16581 REA and P04275 REA to evaluate endothelial activation . Blood samples were drawn just before the first clopidogrel intake on day 1 , and after the last dosing ( day 7 ) . As expected , we observed a decrease in platelet reactivity in response to clopidogrel , confirmed by vasodilator-stimulated phosphoprotein phosphorylation assay . However , the 7 - day intake of clopidogrel did not significantly modify the levels of the selected angiogenic factors or biomarkers of endothelial activation . These results show that circulating angiogenic factor level in healthy subjects is not driven by Q9H244 REA platelet receptor-induced activation and clopidogrel does not modify in a significant way the endothelial activation level .

A phase II trial of sorafenib in metastatic melanoma with tissue correlates . BACKGROUND : DB00398 SUB monotherapy in patients with metastatic melanoma was explored in this multi-institutional phase II study . In correlative studies the impact of sorafenib on cyclin D1 and Ki67 was assessed . METHODOLOGY / PRINCIPAL FINDINGS : Thirty-six patients treatment-naïve advanced melanoma patients received sorafenib 400 mg p . o . twice daily continuously . Tumor P15056 REA ( V600E ) mutational status was determined by routine DNA sequencing and mutation-specific PCR ( MSPCR ) . Immunohistochemistry ( IHC ) staining for cyclin D1 and Ki67 was performed on available pre - and post treatment tumor samples . The main toxicities included diarrhea , alopecia , rash , mucositis , nausea , hand-foot syndrome , and intestinal perforation . One patient had a RECIST partial response ( PR ) lasting 175 days . Three patients experienced stable disease ( SD ) with a mean duration of 37 weeks . Routine P15056 REA ( V600E ) sequencing yielded 27 wild-type ( wt ) and 6 mutant tumors , whereas MSPCR identified 12 wt and 18 mutant tumors . No correlation was seen between P15056 REA ( V600E ) mutational status and clinical activity . No significant changes in expression of cyclin D1 or Ki67 with sorafenib treatment were demonstrable in the 15 patients with pre-and post-treatment tumor samples . CONCLUSIONS / SIGNIFICANCE : DB00398 SUB monotherapy has limited activity in advanced melanoma patients . P15056 REA ( V600E ) mutational status of the tumor was not associated with clinical activity and no significant effect of sorafenib on cyclin D1 or Ki67 was seen , suggesting that sorafenib is not an effective P15056 REA inhibitor or that additional signaling pathways are equally important in the patients who benefit from sorafenib . TRIAL REGISTRATION : Clinical Trials.gov NCT 00119249 .

P00797 REA inhibition reduces atherosclerotic plaque neovessel formation and regresses advanced atherosclerotic plaques . OBJECTIVE : The interaction between the renin-angiotensin system and toll-like receptors ( TLRs ) in the pathogenesis of advanced atherosclerotic plaques is not well understood . We studied the effects of the renin inhibitor aliskiren on the progression of advanced atherosclerotic plaque in apolipoprotein E-deficient ( ApoE ( - / - ) ) mice with a special focus on plaque neovessel formation . METHODS AND RESULTS : Four-wk-old ApoE ( - / - ) mice were fed a high-fat diet for 8 wks , and the mice were randomly assigned to one of three groups and administered a vehicle , hydralazine , or aliskiren for an additional 12 wks . DB09026 MEN reduced the atherosclerotic plaque area and plaque neovessel density . It increased the plaque collagen and elastin contents , and reduced plasma angiotensin II levels and plaque macrophage infiltration and cathepsin S ( CatS ) protein . DB09026 MEN also decreased the levels of AT1R , gp91phox , O60603 REA , monocyte chemotactic protein - 1 , and CatS mRNAs in the aortic roots . DB01275 had no beneficial vascular effects , although its administration resulted in the same degree of blood pressure reduction as aliskiren . CatS deficiency mimicked the aliskiren-mediated vasculoprotective effect in the ApoE ( - / - ) mice , but aliskiren showed no further benefits in ApoE ( - / - ) CatS ( - / - ) mice . In vitro , O60603 REA silencing reduced CatS expression induced by angiotensin II . Moreover , aliskiren or the inhibition of CatS impaired the endothelial cell angiogenic action in vitro or / and ex vivo . CONCLUSION : P00797 REA inhibition appears to inhibit advanced plaque neovessel formation in ApoE ( - / - ) mice and to decrease the vascular inflammatory action and extracellular matrix degradation , partly by reducing AT1R / O60603 REA - mediated CatS activation and activity , thus regressing advanced atherosclerosis .

Temporal and pharmacological characterization of angiostatin release and generation by human platelets : implications for endothelial cell migration . Platelets play an important role in thrombosis and in neo-vascularisation as they release and produce factors that both promote and suppress angiogenesis . Amongst these factors is the angiogenesis inhibitor angiostatin , which is released during thrombus formation . The impact of anti-thrombotic agents and the kinetics of platelet angiostatin release are unknown . Hence , our objectives were to characterize platelet angiostatin release temporally and pharmacologically and to determine how angiostatin release influences endothelial cell migration , an early stage of angiogenesis . We hypothesized anti-platelet agents would suppress angiostatin release but not generation by platelets . Human platelets were aggregated and temporal angiostatin release was compared to vascular endothelial growth factor ( P15692 REA ) . Immuno-gold electron microscopy and immunofluorescence microscopy identified α-granules as storage organelles of platelet angiostatin . Acetylsalicylic acid , MRS 2395 , P08514 REA / IIIa blocking peptide , and aprotinin were used to characterize platelet angiostatin release and generation . An endothelial cell migration assay was performed under hypoxic conditions to determine the effects of pharmacological platelet and angiostatin inhibition . Compared to P15692 REA , angiostatin generation and release from α-granules occurred later temporally during platelet aggregation . Consequently , collagen-activated platelet releasates stimulated endothelial cell migration more potently than maximally-aggregated platelets . Platelet inhibitors prostacyclin , S-nitroso-glutathione , acetylsalicylic acid , and P08514 REA / IIIa blocking peptide , but not a Q9H244 REA inhibitor , suppressed angiostatin release but not generation . Suppression of angiostatin generation in the presence of acetylsalicylic acid enhanced platelet-stimulated endothelial migration . Hence , the temporal and pharmacological modulation of platelet angiostatin release may have significant consequences for neo-vascularization following thrombus formation .

Influence of a 3 - day regimen of azithromycin on the disposition kinetics of cyclosporine A in stable renal transplant patients . Some macrolide antibiotics have been shown to produce significant drug-drug interactions through the inhibition of cytochrome P450 ( CYP ) enzymes . In renal transplant patients these interactions pose potentially serious problems for the safe administration of cyclosporine A ( Q13216 REA ) , a substrate of P08684 REA . The effects of azithromycin on Q13216 REA disposition kinetics were evaluated in eight stable renal transplant patients . Patients had been stabilized on individualized doses of Q13216 REA which remained unchanged throughout the study . DB00207 MEN was administered for 3 days . Baseline measurements of Q13216 REA disposition kinetics were taken prior to azithromycin treatment ( study day 2 ) and after 3 days ( study day 5 ) of azithromycin treatment ( 500mg / day , orally ) . The key parameters of interest were the area under the Q13216 REA blood concentration versus time curve ( AUC ) measured for 24h after the morning dose of Q13216 REA on both days 2 and 5 , and the C ( max ) values of Q13216 REA . The geometric mean ratios ( GMRs ) of those parameters ( day 5 / day 2 ) and their 90 % confidence intervals ( 90 % CI ) were 107 ( 98,116 ) and 119 ( 104,136 ) , respectively . The 7 % increase in exposure level and 19 % increase in peak plasma concentration are not likely to be clinically significant . It is concluded that azithromycin ( 500mg / dayx 3 days ) does not alter the disposition kinetics of Q13216 REA in a clinically significant way , and that Q13216 REA dosage adjustments are not warranted in renal transplant patients taking these two drugs together .

Changes in skeletal muscle size and glucose tolerance with electrically stimulated resistance training in subjects with chronic spinal cord injury . OBJECTIVE : To determine the effect of residence-based , resistance exercise training ( P07949 REA ) on affected skeletal muscle size and glucose tolerance after long-standing , complete spinal cord injury ( SCI ) . DESIGN : Before-after trial . SETTING : University laboratory trial . PARTICIPANTS : Five men with chronic , complete SCI ( P01031 REA - P02786 REA ) . INTERVENTION : Magnetic resonance images of the thighs and an oral glucose tolerance test were performed before and after P07949 REA . Subjects performed P07949 REA with both thighs , 2 d / wk for 4 sets of 10 unilateral , dynamic knee extensions for 12 weeks . Neuromuscular electric stimulation induced P07949 REA by activating the knee extensors . MAIN OUTCOME MEASURES : Quadriceps femoris muscle cross-sectional area ( Q13216 REA ) , plasma glucose , and insulin concentrations were measured before and after P07949 REA . Results Skeletal muscle Q13216 REA increased by 35 % in the right quadriceps femoris ( from 32.6 cm2 to 44.0 cm2 ) and by 39 % in the left quadriceps femoris ( from 34.6 cm2 to 47.9 cm2 ) as a result of training ( P < . 05 ) . There were no significant changes in blood glucose or insulin after training . However , a trend for a reduction in plasma glucose levels was observed ( P = . 074 ) . Conclusions Affected skeletal muscle can achieve substantial hypertrophy years after SCI with resistance exercise . Furthermore , our results suggest that this type of training may enhance glucose disposal .

DB00398 SUB is tolerable and improves clinical outcomes in patients with P36888 REA - ITD acute myeloid leukemia prior to stem cell transplant and after relapse post-transplant .

P2Y receptor antagonists in thrombosis . The dual role of P47900 REA and Q9H244 REA receptors in platelet aggregation by ADP has been firmly established , based on the action of selective inhibitors , gene targeting in mice and human genetic evidence . Both of these receptor subtypes constitute targets for antithrombotic agents , and compounds with a dual action might also be of interest . However , the agents currently on the market ( ticlopidine and clopidogrel ) , or known to be in development ( cangrelor , DB08816 MEN and prasugrel ) , all target the Q9H244 REA receptor . The thienopyridines ( ticlopidine , clopidogrel and prasugrel ) irreversibly inactivate the Q9H244 REA receptor via the covalent binding of an active metabolite generated in the liver , while the other compounds are competitive antagonists . DB06441 , an DB00171 derivative , is suitable for intravenous perfusion , whereas DB08816 MEN is in clinical development as an orally active agent .

Complementary and alternative medicine use and quality of life in patients with primary brain tumors . This study explored the use of complementary and alternative medicine ( P62158 ) approaches and their relationship with demographic and disease characteristics and quality of life ( QOL ) in the primary brain tumor ( P10721 REA ) population . One hundred one P10721 REA patients were enrolled in this study . The results showed that 34 % of patients reported using P62158 . Forty-one percent reported using more than one type of P62158 . The average cost of each P62158 used per month was 69 dollars , with 20 % of patients spending more than 100 dollars per month . The majority ( 74 % ) reported that their physicians were unaware of their use of P62158 . Data analysis found a higher performance status to be the only factor significantly related to use of P62158 therapy ( P < 0.005 ) . There was no difference in patient report of QOL between users and nonusers of P62158 therapies . The high number of patients who do not report P62158 use has potential implications for evaluation of symptoms and response to therapy in this population . This may be especially relevant in those patients with higher functional status participating in clinical trials .

Predictive factors in patients with advanced and metastatic squamous cell carcinoma of the head and neck : a study based on SWOG protocol S0420 . To evaluate the prognostic values of different protein expression in the progression of squamous cell carcinoma of the head and neck ( SCCHN ) patients , we conducted immunohistochemical ( IHC ) analysis in tissue samples of different patients enrolled on SWOG protocol S0420 . S0420 was a phase II trial to evaluate the efficacy and safety of single-agent sorafenib in chemotherapy-naïve patients with metastatic or recurrent SCCHN . The primary end point was response probability , i . e . , confirmed complete ( CR ) and partial response ( PR ) . DB00398 SUB was administered orally at 400 mg twice daily on a continuous basis in 28 - day cycles to eligible patients . Responses were evaluated according to RECIST ( Response Evaluation Criteria in Solid Tumors ) criteria . IHC analysis was performed for various markers and data were analyzed statistically . IHC data were obtained from 19 patients enrolled on S0420 . There was a high frequency of cases with expression of the angiogenesis markers SMA , HIF - 1α , P04049 REA , P15692 REA and P15692 REA - R . None of the markers were significantly associated with response . Negative HER - 2 status was associated with longer progression-free survival ( PFS ) , P= 0.04 . Negative NRP - 1 status was associated with longer overall survival ( OS ) , P= 0.04 . There were no other significant associations . An almost universal overexpression of angiogenesis markers in the samples analyzed supports the evaluation of angiogenesis inhibition as a potential target for therapy . High levels of NRP - 1 and HER - 2 in SCCHN samples appear to be associated with decreased survival and earlier progression of disease , respectively , in SCCHN patients and may represent targets for therapy .

DB00398 SUB inhibits many kinase mutations associated with drug-resistant gastrointestinal stromal tumors . DB00398 SUB has substantial clinical activity as third - or fourth-line treatment of imatinib - and sunitinib-resistant gastrointestinal stromal tumors ( GIST ) . Because sorafenib targets both angiogenesis-related kinases ( VEGFR ) and the pathogenetic kinases found in GIST ( P10721 REA or P16234 REA ) , the molecular basis for sorafenib efficacy in this setting remains unknown . We sought to determine the spectrum of activity of sorafenib against different mutant kinases associated with drug-sensitive and drug-resistant GIST . We compared the activity of imatinib and sorafenib against transiently expressed mutant forms of P10721 REA and P16234 REA , including various secondary mutations that have been identified in imatinib-resistant or sunitinib-resistant GISTs . We also examined these drugs against four GIST cell lines , three of which are imatinib resistant . In our in vitro studies , we determined that sorafenib inhibited imatinib-resistant mutations in exons encoding the DB00171 / drug-binding pocket and in exons encoding the activation loop , with the exception of substitutions at P10721 REA codon D8 16 and P16234 REA codon 842 . Notably our data indicate that sorafenib is more effective than imatinib or sunitinib for inhibiting the kinase activity of drug-resistant P10721 REA mutants ( as assessed by biochemical IC ( 50 ) ) . We hypothesize that a major determinant of the efficacy of sorafenib for treatment of advanced GIST is the activity of this agent against P10721 REA or P16234 REA - mutant kinases . These results have implications for the further development of treatments for drug-resistant GIST .

Increased expression of nucleophosmin / B23 in hepatocellular carcinoma and correlation with clinicopathological parameters . P06748 REA ( P06748 REA , B23 , numatrin , NO38 ) is an abundant nucleolar phosphoprotein involved in multiple cellular functions . Previous evidence indicates that high-level expression of P06748 REA causes uncontrolled cell growth and suggests that P06748 REA may have oncogenic potential . In this study , we examined P06748 REA expression in 103 paired cases of hepatocellular carcinoma ( HCC ) , 12 cases of hepatic focal nodular hyperplasia , 17 cases of liver tissue adjacent to a hepatic haemangioma , and series of array tissues from normal human organs and malignancies using a monoclonal antibody against P06748 REA and reverse transcription-PCR techniques , Western blot analysis , immunohistochemistry , and immunocytofluorescence . Our data indicated that P06748 REA expression was significantly higher in HCC than in the non-malignant hepatocytes ( P < 0.001 ) . P06748 REA was weakly expressed in hepatocytes from a 5 - month-old embryo and in stationary hepatocytes of healthy adults . Moreover , enhanced expression of P06748 REA in HCC correlated with the level of P12004 REA ( R ( 2 )= 0.5639 ) and with the clinical prognostic parameters such as serum alpha fetal protein level , tumour pathological grading , and liver cirrhosis ( P < 0.05 ) . Our results suggest that P06748 REA may play an important role in the progression of tumorigenesis and that P06748 REA may serve as a potential marker for HCC .

DB00107 alleviates the neuroendocrine and cytokine response to bacterial endotoxin in healthy men . DB00107 is a hormone and neurotransmitter found to have anti-inflammatory functions in rodents . Here we used experimental bacterial endotoxinemia to examine the role of exogenous oxytocin administration on innate immune responses in humans . Ten healthy men received , in a randomized , placebo-controlled , crossover design , placebo , oxytocin , LPS , and LPS + oxytocin . DB00107 treatment resulted in a transient or prolonged reduction of endotoxin-induced increases in plasma DB01285 , cortisol , procalcitonin , P01375 REA , IL - 1 receptor antagonist , P05112 REA , P05231 REA , macrophage inflammatory protein - 1alpha , macrophage inflammatory protein - 1beta , monocyte chemoattractant protein - 1 ( P13500 REA ) , interferon-inducible protein 10 , and P15692 REA . In vitro , oxytocin had no impact on LPS effects in releasing P01375 REA , P05231 REA , and P13500 REA in monocytes and peripheral blood mononuclear cells from healthy human donors . In summary , oxytocin decreases the neuroendocrine and cytokine activation caused by bacterial endotoxin in men , possibly due to the pharmacological modulation of the cholinergic anti-inflammatory pathway . DB00107 might be a candidate for the therapy of inflammatory diseases and conditions associated with high cytokine and P15692 REA levels .

Synergistic cytotoxicity of radiation and oncolytic Lister strain vaccinia in ( V600D / E ) P15056 REA mutant melanoma depends on JNK and P01375 REA - α signaling . Melanoma is an aggressive skin cancer that carries an extremely poor prognosis when local invasion , nodal spread or systemic metastasis has occurred . Recent advances in melanoma biology have revealed that DB01367 - RAF-MEK - P29323 REA signaling has a pivotal role in governing disease progression and treatment resistance . Proof-of-concept clinical studies have shown that direct P15056 REA inhibition yields impressive responses in advanced disease but these are short-lived as treatment resistance rapidly emerges . Therefore , there is a pressing need to develop new targeted strategies for P15056 REA mutant melanoma . As such , oncolytic viruses represent a promising cancer-specific approach with significant activity in melanoma . This study investigated interactions between genetically-modified vaccinia virus ( GLV - 1h68 ) and radiotherapy in melanoma cell lines with P15056 REA mutant , Ras mutant or wild-type genotype . Preclinical studies revealed that GLV - 1h68 combined with radiotherapy significantly increased cytotoxicity and apoptosis relative to either single agent in ( V600D ) P15056 REA / ( V600E ) P15056 REA mutant melanoma in vitro and in vivo . The mechanism of enhanced cytotoxicity with GLV - 1h68 / radiation ( RT ) was independent of viral replication and due to attenuation of JNK , p38 and P29323 REA MAPK phosphorylation specifically in P15056 REA mutant cells . Further studies showed that JNK pathway inhibition sensitized P15056 REA mutant cells to GLV - 1h68 - mediated cell death , mimicking the effect of RT . GLV - 1h68 infection activated MAPK signaling in ( V600D ) P15056 REA / ( V600E ) P15056 REA mutant cell lines and this was associated with P01375 REA - α secretion which , in turn , provided a prosurvival signal . Combination GLV - 1h68 / RT ( or GLV - 1h68 / JNK inhibition ) caused abrogation of P01375 REA - α secretion . These data provide a strong rationale for combining GLV - 1h68 with irradiation in ( V600D / E ) P15056 REA mutant tumors .

Multi-kinase inhibition in ovarian cancer . DB00398 SUB ( Nexavar ) is a multi-kinase inhibitor that was developed as an inhibitor of RAF - 1 , in the P27361 REA / 2 pathway , but which was subsequently shown to inhibit class III tyrosine kinase receptors . ( 1 ) More recently regorafenib ( Stivarga ) has been developed , which is a further fluorinated version of sorafenib with greater bioavailability and similar inhibitory properties against RAF - 1 / class III RTKs . ( 2 ) Some of the anti-tumor effects of sorafenib have been ascribed to anti-angiogenic actions of this agent on endothelial associated kinases such as P35968 REA . Other effects of sorafenib clearly have to be due to its effects on the inherent biology of the tumor cells themselves . For example , through various mechanisms sorafenib has been shown in the laboratory and the clinic to suppress expression of the protective protein Q8WXI8 - 1 . ( 3 ) DB00398 SUB has also been linked to inhibition of P40763 REA , NFκB , and activation of the death receptor CD95 . ( 4 ) DB00398 SUB is routinely dosed daily ( 400 mg P55957 REA ) and 7 d after the start of dosing has a Cmax of ~ 21 μM with a nadir at 12 h of ~ 10 μM , and is a highly protein bound based on in vitro assays . ( 5 ) Despite this in vitro binding data sorafenib has profound in vivo effects on tumor cells in renal carcinoma and hepatocellular carcinoma patients ; cells which are not per se addicted to high activity oncogene signals that are targets of sorafenib / regorafenib . Thus the precise stable bioavailable level of sorafenib / regorafenib in patient plasma is not known .

Targeted therapeutic approach for an anaplastic thyroid cancer in vitro and in vivo . Anaplastic thyroid carcinoma ( ATC ) is among the most aggressive human malignancies , being responsible for the majority of thyroid cancer-related deaths . Despite multimodal therapy including surgery , chemotherapy , and radiotherapy , the outcome of ATC is poor . The human ATC cell line MB1 , derived from tumor tissue of a 57 - year-old man with thyroid cancer and pronounced neutrophilia , was established from surgically excised tumor tissue . The karyotype of the cell line shows many chromosomal abnormalities . Preclinical investigations have shown antitumor activity and effectiveness of the P15056 REA kinase inhibitor DB00398 SUB and the proteasome inhibitor DB00188 . After establishment of the MB1 cell line these agents were applied in vitro and , showing activity in a cell culture model , were also used for in vivo treatment . DB00398 SUB had some clinical effect , namely normalization of leucocytosis , but had no sustained impact on subsequent tumor growth and development of distant metastasis . Molecular diagnostics of the tumor demonstrated no P15056 REA mutations in exons 11 and 15 concordant with a rather modest effect of DB00398 SUB on MB1 cell growth . Clinical benefit was seen with subsequent bortezomib therapy inducing a temporary halt to lymph node growth and a progression-free interval of 7 weeks . Our observations together with previous data from preclinical models could serve as a rationale for selecting those patients suffering from ATC most likely to benefit from targeted therapy . A prospective controlled randomized trial integrating kinase and proteasome inhibitors into a therapeutic regime for ATC is warranted .

[ Angiogenesis and renal cell carcinoma ] . Developments in the knowledge of molecular biology of renal cell carcinoma ( RCC ) over the past 20 years have been identified . Angiogenesis is playing a key role in the physiopathology of RCC . Von Hippel-Lindau ( P40337 REA ) alterations , HIFalpha accumulation and vascular endothelial growth factor ( P15692 REA ) overexpression are important mediators of this process . Several stategies have been developped to target angiogenesis for the treatment of metastatic RCC . These include inhibition of P15692 REA receptors ( inhibition of the tyrosine kinase activity ) or binding to the P15692 REA protein . Several additional kinases inhibitions including PDGF receptors are also targeted . DB01268 ( SU11248 ) is an orally biovailable small molecule that has demonstrated superiority over interferon-alpha for the treatment of metastatic RCC . In a recent randomized phase III study conducted in 750 patients , the response rate to sunitinib was 31 % and to interferon 6 % . The median of progression free survival ( PFS ) was 11 months for sunitinib and 5 months for interferon ( p < 0.001 ) . DB00398 SUB ( BAY 43-9006 ) was found to inhibit Raf 1 , but also P35968 REA and 3 , Flt 3 , P09619 REA - a and b and c-kit , has been tested in a phase III study against placebo after one prior systemic therapy . The median of the time to progression ( TTP ) for sorafenib was 24 weeks versus 12 weeks for patients in the placebo arm ( p = 0,01 ) . Other molecules tested in metastatic RCC will be presented including axitinib , pazopanib and bevacizumab .

DB00091 modulates the response to hypoxia-reoxygenation in pulmonary artery endothelial cells . BACKGROUND : Depletion of macrophages , neutrophils , or lymphocytes confers only partial protection against experimental lung reperfusion injury , suggesting that inflammatory responses in other cell types contribute to tissue injury . Endothelial cell activation has previously been shown to be critical to the development of ischemia-reperfusion injury in other vascular beds . Furthermore , cyclosporine ( Q13216 REA ) reduces in vivo lung reperfusion injury through attenuated secretion of proinflammatory mediators . These studies determined whether pulmonary artery endothelial cells ( PAEC ) , subjected to hypoxia and reoxygenation , promote inflammation and whether Q13216 REA afforded any modulation of that response . METHODS : Isolated rat PAEC were subjected in vitro to 2 hours hypoxia followed by up to 4 hours reoxygenation . Cells were pretreated with Q13216 REA or a cremaphor vehicle . Differences in activation of signaling kinases and transcription factors were assessed , as was cytokine-chemokine protein secretion . RESULTS : There was significant signaling kinase ( extracellular signal regulated kinase [ P29323 REA 1/2 ] ) activation by 15 minutes reoxygenation , which was temporally associated with marked activation of the transcription factors nuclear factor kappa B ( NFkappaB ) and early growth response one ( P18146 REA ) . At 4 hours reoxygenation there were significant increases in chemokine protein secretion . The Q13216 REA decreased P29323 REA 1/2 phosphorylation and significantly attenuated transcription factor transactivation at 15 minutes reoxygenation . The Q13216 REA was found to be selective in reducing cytokine-chemokine elaboration at 4 hours reoxygenation . CONCLUSIONS : Hypoxia-reoxygenation induces P29323 REA 1/2 phosphorylation , as well as transactivation of the transcription factors NFkappaB and P18146 REA in PAEC . DB00091 selectively reduces proinflammatory mediator secretion , likely by transcriptional regulation through NFkappaB and P18146 REA . This is the first demonstration of P29323 REA 1/2 inhibition afforded by Q13216 REA .

Central role for hydrogen peroxide in P47900 REA ADP receptor-mediated cellular responses in vascular endothelium . ADP activates a family of cell surface receptors that modulate signaling pathways in a broad range of cells . ADP receptor antagonists are widely used to treat cardiovascular disease states . These studies identify a critical role for the stable reactive oxygen species hydrogen peroxide ( H2O2 ) in mediating cellular responses activated by the G protein-coupled P47900 REA receptor for ADP . We found that ADP-dependent phosphorylation of key endothelial signaling proteins - - including endothelial nitric oxide synthase , AMP-activated protein kinase , and the actin-binding P29966 REA protein - - was blocked by preincubation with PEG-catalase , which degrades H2O2 . ADP treatment promoted the H2O2 - dependent phosphorylation of c-Abl , a nonreceptor tyrosine kinase that modulates the actin cytoskeleton . Cellular imaging experiments using fluorescence resonance energy transfer-based biosensors revealed that ADP-stimulated activation of the cytoskeleton-associated small GTPase Rac 1 was independent of H2O2 . However , Rac 1 - dependent activation of AMP-activated protein kinase , the signaling phospholipid phosphatidylinositol - ( 4 , 5 ) - bisphosphate , and the c-Abl-interacting protein CrkII are mediated by H2O2 . We transfected endothelial cells with differentially targeted HyPer 2 H2O2 biosensors and found that ADP promoted a marked increase in H2O2 levels in the cytosol and caveolae , and a smaller increase in mitochondria . We performed a screen for P47900 REA receptor-mediated receptor tyrosine kinase transactivation and discovered that ADP transactivates P36888 REA ( Flt 3 ) , a receptor tyrosine kinase expressed in these cells . Our observation that P47900 REA receptor-mediated responses involve Flt 3 transactivation may identify a unique mechanism whereby cancer chemotherapy with receptor tyrosine kinase inhibitors promotes vascular dysfunction . Taken together , these findings establish a critical role for endogenous H2O2 in control of ADP-mediated signaling responses in the vascular wall .

Lipoteichoic acid induces matrix metalloproteinase - 9 expression via transactivation of PDGF receptors and NF-kappaB activation in rat brain astrocytes . Bacterial infections have been shown to be involved in several inflammatory diseases such as brain inflammation . A major factor for these findings is due to the secretion of pro-inflammatory mediators by host cells triggered by the components released from the bacteria . Among these components , lipoteichoic acid ( P01374 REA ) , a component of Gram-positive bacterial cell wall , has been found to be elevated in cerebrospinal fluid of patients suffering from meningitis . Moreover , increased plasma levels of matrix metalloproteinases ( MMPs ) , in particular P14780 REA , have been observed in patients with brain inflammatory diseases and may contribute to disease pathology . However , the molecular mechanisms underlying P01374 REA - induced P14780 REA expression in rat brain astrocytes ( RBA - 1 cells ) remain poorly defined . Here , the data with zymographic , Western blotting , RT-PCR , and immunofluorescent staining analyses showed that P01374 REA induced P14780 REA expression and activation via a O60603 REA - activated c-Src-dependent transactivation of P09619 REA pathway . Transactivation of P09619 REA led to activation of PI3K / Akt and Q8NFH3 / Q8TCB0 MAPK and then activated the IKK / NF-kappaB cascade . The activated-NF-kappaB translocated into nucleus which bound to kappaB-binding site of P14780 REA promoter , and thereby turned on transcription of P14780 REA . Eventually , upregulation of P14780 REA by P01374 REA enhanced cell migration of astrocytes . Taken together , these results suggested that in RBA - 1 cells , activation of NF-kappaB by a c-Src-dependent PI3K / Akt - Q8NFH3 / Q8TCB0 MAPK activation mediated through transactivation of P09619 REA is essential for P14780 REA gene upregulation induced by P01374 REA . Understanding the regulation of P14780 REA expression and functional changes by P01374 REA / TLR system on astrocytes may provide potential therapeutic targets of Gram-positive bacterial infection in brain disorders .

Proangiogenesis action of the thyroid hormone analog 3,5- diiodothyropropionic acid ( DITPA ) is initiated at the cell surface and is integrin mediated . We have recently described the proangiogenesis effects of thyroid hormone in the chick chorioallantoic membrane ( P62158 ) model . Generation of new blood vessels from existing vessels was promoted 2 - to 3 - fold by either T ( 4 ) or T ( 3 ) at 10 (-8 ) - 10 ( - 7 ) M total hormone concentrations . In the present studies , nanomolar concentrations of 3,5- diiodothyropropionic acid ( DITPA ) , a thyroid hormone analog with inotropic but not chronotropic properties , exhibited potent proangiogenic activity that was comparable to that obtained with T ( 3 ) and T ( 4 ) in both the P62158 model and in an in vitro three-dimensional human microvascular endothelial sprouting assay . The proangiogenesis effect of DITPA was inhibited by tetraiodothyroacetic acid , a thyroid hormone analog that competes with T ( 4 ) and T ( 3 ) for a novel cell surface hormone receptor site on integrin alphavbeta 3 . The thyroid hormone analogs DITPA , T ( 4 ) , and T ( 4 ) - agarose , as well as basic fibroblast growth factor ( b-FGF ) and vascular endothelial cell growth factor , demonstrated comparable proangiogenic effects in the P62158 model and in the three-dimensional human microvascular endothelial sprouting model . The proangiogenesis effect of either DITPA or b-FGF was blocked by PD 98059 , an inhibitor of the P27361 REA / 2 signal transduction cascade . Additionally , a specific integrin alphavbeta 3 small molecule antagonist , XT199 , effectively inhibited the proangiogenesis effect of DITPA and b-FGF . Thus , the proangiogenesis actions of thyroid hormone and its analog DITPA are initiated at the plasma membrane , apparently at integrin alphavbeta 3 , and are MAPK dependent .

Cbl-b is a negative regulator of inflammatory cytokines produced by IgE-activated mast cells . c-Cbl and Cbl-b E3 ubiquitin ligases are abundantly expressed in hemopoietic cells where they negatively regulate the activity and levels of many cell surface receptors and associated signaling molecules . By comparing bone marrow-derived mast cells from c-Cbl and Cbl-b-deficient mice it has recently been shown that Cbl-b is the dominant family member for negatively regulating signaling responses from high-affinity IgE receptors . In this study , we suggest that a possible reason for the greater enhancement of IgE receptor signaling in Cbl-b-deficient mice is the relatively higher levels of Cbl-b protein over c-Cbl in mast cells compared with other hemopoietic cells . We also directly compare mast cells from c-Cbl and Cbl-b-deficient mice and find that loss of Cbl-b , but not c-Cbl , increases cell growth , retards receptor internalization , and causes the sustained tyrosine phosphorylation of Syk and its substrates . However , loss of Cbl-b does not enhance the activation of P29323 REA or Akt , nor does it promote a greater calcium response . Furthermore , loss of Cbl-b or c-Cbl does not increase levels of the Syk or Lyn protein tyrosine kinases . Most notable , however , is the extremely large increase in the production of proinflammatory cytokines P01375 REA , P05231 REA , and P13500 REA by Cbl-b ( - / - ) mast cells compared with levels produced by c-Cbl ( - / - ) or wild-type cells . This marked induction , which appears to be restricted to these three cytokines , is dependent on IgE receptor activation and correlates with enhanced O15111 REA phosphorylation . Thus , Cbl-b functions as a potent negative regulator of cytokines that promote allergic and inflammatory reactions .

First analysis of the relation between P33261 REA genotype and pharmacodynamics in patients treated with ticagrelor versus clopidogrel : the ONSET / OFFSET and RESPOND genotype studies . BACKGROUND : The influence of cytochrome P450 ( CYP ) 2C19 genotype on platelet function in patients treated with ticagrelor versus clopidogrel is unknown . METHODS AND RESULTS : P33261 REA ( * 1 , * 2 , * 3 , * 4 , * 5 , * 6 , * 7 , * 8 , * 17 ) genotyping was performed in patients with coronary artery disease treated with ticagrelor ( 180 - mg load , 90 mg P55957 REA ) ( n = 92 ) or clopidogrel ( 600 - mg load , 75 mg / d ) ( n = 82 ) . All patients received 75 to 100 mg / d aspirin . Platelet function was measured by aggregometry , VerifyNow Q9H244 REA assay , and vasodilator-stimulated phosphoprotein-phosphorylation assay at predose , 8 hours postloading , and maintenance . In each treatment group , patients were categorized according to 2C19 genotype carrier status ( loss-of-function , gain-of-function ) and metabolizer status . Kruskal-Wallis test was used to compare platelet function among these categories for each treatment , and Wilcoxon rank sum test was used to compare platelet function between the clopidogrel and ticagrelor groups for each category . There was no statistically significant influence of genotype on platelet function during aspirin therapy alone . DB08816 MEN exhibited lower platelet reactivity than clopidogrel by all assays irrespective of 2C19 genotype or metabolizer status ( P < 0.01 ) . Loss-of-function carriers had greater platelet reactivity during clopidogrel therapy . The influence of genotype on platelet reactivity was greatest during clopidogrel maintenance and best demonstrated by the VerifyNow Q9H244 REA assay . CONCLUSIONS : This report is the first to demonstrate the superior pharmacodynamic effect of ticagrelor compared with clopidogrel irrespective of P33261 REA genotype . Whereas P33261 REA genotype influenced the antiplatelet effect of clopidogrel , there was no effect of P33261 REA genotype during ticagrelor therapy .

Characterization of plant P18887 REA and its interaction with proliferating cell nuclear antigen . In plants , there are no P06746 REA ( Pol beta ) and P49916 REA ( Lig 3 ) genes . Thus , the plant short-patch base excision repair ( short-patch BER ) pathway must differ considerably from that in mammals . We characterized the rice ( Oryza Sativa L . cv . Nipponbare ) homologue of the mammalian X-ray repair cross complementing 1 ( P18887 REA ) , a well-known BER protein . The plant P18887 REA lacks the N-terminal domain ( NTD ) which is required for Pol beta binding and is essential for mammalian cell survival . The recombinant rice P18887 REA ( OsXRCC 1 ) protein binds single-stranded DNA ( ssDNA ) as well as double-stranded DNA ( dsDNA ) and also interacts with rice proliferating cell nuclear antigen ( OsPCNA ) in a pull-down assay . Through immunoprecipitation , we demonstrated that OsXRCC 1 forms a complex with P12004 REA in vivo . OsXRCC 1 mRNA was expressed in all rice organs and was induced by application of bleomycin , but not of MMS , H ( 2 ) O ( 2 ) or UV-B . DB00290 MEN also increased the fraction of OsXRCC 1 associated with chromatin . These results suggest that OsXRCC 1 contributes to DNA repair pathways that differ from the mammalian BER system .

[ DB00398 SUB monotherapy for P36888 REA - ITD positive acute myeloid leukemia : a case report ] .

Patterns of care , prognosis , and survival in patients with metastatic gastrointestinal stromal tumors ( GIST ) refractory to first-line imatinib and second-line sunitinib . BACKGROUND : Data regarding the management and outcome of patients with metastatic gastrointestinal stromal tumors ( GIST ) refractory to 1st - line imatinib and 2nd - line sunitinib are limited . METHODS : Medical records of 223 imatinib-resistant and sunitinib-resistant GIST who were treated in 11 major referral centers were reviewed . RESULTS : The three most frequent drugs used in the 3rd - line setting were : nilotinib n = 67 ( 29.5 % ) , sorafenib n = 55 ( 24.5 % ) , and imatinib n = 40 ( 17.5 % ) . There were 18 patients ( 8 % ) who received best supportive care ( BSC ) only . The median progression-free survival ( PFS ) and overall survival ( OS ) on 3rd - line treatment were 3.6 months [ 95 % confidence interval ( 95 % CI ) , 3.1- 4.1 ] and 9.2 months ( 95 % CI , 7.5- 10.9 ) , respectively . Multivariate analysis showed that , in the 3rd - line setting , albumin level and P10721 REA / P16234 REA mutational status were significantly associated with PFS , whereas performance status and albumin level were associated with OS . After adjustment for prognostic factors , nilotinib and sorafenib provided the best PFS and OS . Rechallenge with imatinib was also associated with improved OS in comparison with BSC . CONCLUSION : In the 3rd - line setting , rechallenge with imatinib provided limited clinical benefit but was superior to BSC . DB00398 SUB and nilotinib have significant clinical activity in imatinib-resistant and sunitinib-resistant GIST and may represent an alternative for rechallenge with imatinib .

Gene therapy for brain tumors : basic developments and clinical implementation . Glioblastoma multiforme ( GBM ) is the most common and deadliest of adult primary brain tumors . Due to its invasive nature and sensitive location , complete resection remains virtually impossible . The resistance of GBM against chemotherapy and radiotherapy necessitate the development of novel therapies . Gene therapy is proposed for the treatment of brain tumors and has demonstrated pre-clinical efficacy in animal models . Here we review the various experimental therapies that have been developed for GBM including both cytotoxic and immune stimulatory approaches . We also review the combined conditional cytotoxic immune stimulatory therapy that our lab has developed which is dependent on the adenovirus mediated expression of the conditional cytotoxic gene , Herpes Simplex Type 1 DB04485 Kinase ( TK ) and the powerful DC growth factor P36888 REA ligand ( P49771 REA ) . Combined delivery of these vectors elicits tumor cell death and an anti-tumor adaptive immune response that requires O60603 REA activation . The implications of our studies indicate that the combined cytotoxic and immunotherapeutic strategies are effective strategies to combat deadly brain tumors and warrant their implementation in human Phase I clinical trials for GBM .

[ Prominent features of management strategies in acute coronary syndromes with the new oral antiplatelet agents ] . The novel oral Q9H244 REA inhibitors ( prasugrel and ticagrelor ) have been incorporated into the recently updated acute coronary syndrome ( ACS ) guidelines , as an adjunct antiplatelet treatment to aspirin . The studies involving the use of new oral antiplatelet agents that are more potent , predictable and faster platelet inhibitors than clopidogrel have demonstrated superiority with respect to the primary composite endpoint ( cardiovascular death , non-lethal myocardial infarction , stroke ) for both prasugrel and ticagrelor compared to clopidogrel . The subgroup analysis of the relevant studies showed that these new agents differ in their level of efficacy in different ACS patient subgroups : ( 1 ) Mortality was reduced with ticagrelor ; ( 2 ) DB08816 MEN is especially more effective in intermediate-and high-risk non-ST elevation ACS patients in whom early invasive strategy is selected ; ( 3 ) Prasugrel should be especially preferred in patients with acute ST elevation myocardial infarction undergoing percutaneous coronary intervention ( P05154 REA ) after diagnostic angiography ; and ( 4 ) Prasugrel is more effective in diabetic patients . While clopidogrel is recommended for ACS patients who are followed with a non-invasive strategy or who have not undergone percutaneous revascularization , it is the last line choice or an alternative to the Q9H244 REA inhibitor therapy for patients undergoing invasive strategy .

[ Measurement of rifampicin and clarithromycin in serum by high-performance liquid chromatography with electrochemical detection ] . DB01045 ( RFP ) induces hepatic drug-metabolizing enzymes , making drug interactions a very important clinical problem . DB01211 MENMAX DB01211 MEN ( P62158 ) metabolism is reportedly enhanced by induction of hepatic drug-metabolizing enzymes ( P08684 REA ) by RFP , so that the blood lend of P62158 decreases when RFP is administered concurrently . We connected an electrochemical detector to a high-performance liquid chromatograph ( HPLC ) for simple , rapid , easy measurement of blood concentrations of RFP and P62158 . Using samples of patient serum , normal serum , and reference standards , we compared HPLC by an external laboratory and the results of LC / MS / MS analysis with those of this new assay . A strong correlation was seen between our HPLC results and those of the external laboratory in RFP levels ( r = 0.975 , p < 0.01 ) . A strong correlation was also seen between results we obtained for P62158 with the electrochemical detector in this assay and values measured by LC / MS / MS analysis ( r = 0.995 , p < 0.01 ) . Our method enabled simple , rapid measurement of RFP and P62158 by connecting the HPLC and electrochemical detector in tandem . This system was used to modulate dosage during combined therapy with RFP and P62158 . The therapeutic effect for nontuberculous mycobacteriosis is expected to improve , and our HPLC is expected to be useful for simple , rapid , easy measurement of blood concentrations .

P01344 REA Producing Hepatocellular Carcinoma Treated with DB00398 SUB : Metabolic Complications and a Foresight to Molecular Targeting Therapy to the IGF Signal . Hypoglycemia is a rare paraneoplastic manifestation of patients with neoplasms . Hypoglycemia can be induced by several causes , including an aberrant increase of hypoglycemic agents and adrenal insufficiency . DB00398 SUB is the first agent to demonstrate a survival benefit in the treatment of advanced hepatocellular carcinoma ( HCC ) . This small molecule inhibits serine / threonine kinase RAF in tumor cells and tyrosine kinases VEGFR / P09619 REA in tumor vasculature and decreases tumor growth and angiogenesis . In this paper , we report a case of HCC who was treated with sorafenib and showed severe hypoglycemia . This hypoglycemia might be induced by two causes , both adrenal insufficiency as an adverse effect of sorafenib and activation of the insulin-like growth factor ( IGF ) signal by excessive secretion of incompletely processed precursors of P01344 REA . Although the IGF signal is suggested to be involved in aberrant growth of HCC in some cases , there is no other report showing the influence of sorafenib on HCC with active IGF signal . Unfortunately , the effect of sorafenib was limited in the present case . However , emerging drugs that directly inhibit the IGF signal can be expected to be highly effective in the treatment of HCC with hypoglycemia .

P00797 REA angiotensin system modulates P42345 REA pathway through AT2R in HIVAN . P42345 REA ( P42345 REA ) has been reported to contribute to the development of HIV-associated nephropathy ( HIVAN ) . We hypothesized that HIV may be activating renal tissue P42345 REA pathway through renin angiotensin system ( DB01367 ) via Angiotensin Receptor Type II receptor ( AT2R ) . Renal tissues of Vpr transgenic and Tg26 ( HIVAN ) mice displayed enhanced phosphorylation of P42345 REA and p70S6K . DB09026 MEN , a renin inhibitor attenuated phosphorylation of both P42345 REA and p70S6K in renal tissues of HIVAN mice . Interestingly , Angiotensin Receptor Type I ( AT1R ) blockade did not modulate renal tissue phosphorylation of P42345 REA in HIVAN mice ; on the other hand , AT2R blockade attenuated renal tissue phosphorylation of P42345 REA in HIVAN mice . In vitro studies , both renin and Ang II displayed enhanced mouse tubular cell ( P04629 REA ) phosphorylation of p70S6K in a dose dependent manner . HIV / P04629 REA also displayed enhanced phosphorylation of both P42345 REA and p70S6K ; interestingly this effect of HIV was further enhanced by losartan ( an AT1R blocker ) . On the other hand , AT2R blockade attenuated HIV-induced tubular cell phosphorylation of P42345 REA and p70S6K , whereas , AT2R agonist enhanced phosphorylation of P42345 REA and p70S6K . These findings indicate that HIV stimulates P42345 REA pathway in HIVAN through the activation of renin angiotensin system via AT2R .

DB00398 SUB plus all-trans retinoic acid for AML patients with P36888 REA - ITD and P06748 REA mutations . Knowledge of the molecular basis of acute myeloid leukaemia has increased considerably in the past few years , and therapies targeting specific molecular defects of this disease are intensively investigated . Patients with both P06748 REA and P36888 REA - ITD mutations encompass 20 % of cytogenetically normal AML . The multikinase and P36888 REA inhibitor , sorafenib , has shown some efficacy in patients with relapsed P36888 REA - ITD ( + ) AML . In addition , it is suggested that all-trans retinoic acid ( DB00755 ) used in combination with chemotherapy has shown to improve outcome of patients harbouring P06748 REA mutations . We report here the clinical course of three patients with refractory or relapsed P36888 REA - ITD ( + ) / P06748 REA ( + ) AML who achieved significant response upon sorafenib and DB00755 combination .

Raddeanin A , a triterpenoid saponin isolated from Anemone raddeana , suppresses the angiogenesis and growth of human colorectal tumor by inhibiting P35968 REA signaling . Raddeanin A ( RA ) is an active triterpenoid saponin from a traditional Chinese medicinal herb , Anemone raddeana Regel . It was previously reported that RA possessed attractive antitumor activity through inhibiting proliferation and inducing apoptosis of multiple cancer cells . However , whether RA can inhibit angiogenesis , an essential step in cancer development , remains unknown . In this study , we found that RA could significantly inhibit human umbilical vein endothelial cell ( HUVEC ) proliferation , motility , migration , and tube formation . RA also dramatically reduced angiogenesis in chick embryo chorioallantoic membrane ( P62158 ) , restrained the trunk angiogenesis in zebrafish , and suppressed angiogenesis and growth of human HCT - 15 colorectal cancer xenograft in mice . Western blot assay showed that RA suppressed P15692 REA - induced phosphorylation of P35968 REA and its downstream protein kinases including PLCγ 1 , O60674 REA , Q05397 REA , Src , and Akt . Molecular docking simulation indicated that RA formed hydrogen bonds and hydrophobic interactions within the DB00171 binding pocket of P35968 REA kinase domain . Our study firstly provides the evidence that RA has high antiangiogenic potency and explores its molecular basis , demonstrating that RA is a potential agent or lead candidate for antiangiogenic cancer therapy .

[ Strategy for patients with GIST after failure of imatinib ] . DB01268 malate ( SU11248 ) is an oral multitargeted receptor tyrosine kinase inhibitor ( MTI ) that has antitumor activities for patients with gastrointestinal stromal tumor ; GIST after failure of Imatinib . DB01268 has demonstrated significant clinical benefits , including PFS , RR and OS in the USA and Japan . However , cis-mutations in the activation loop of the P10721 REA gene tend to develop DB01268 - resistant GIST . Two clinical trials revealed that new multitargeted receptor tyrosine kinase inhibitors , DB00398 SUB and DB04868 , had antitumor activities for DB01268 - resistant GIST with longer PFS and a different spectrum . Now , clinical trials of several new MTIs are ongoing in Western countries . Inhibition of the P10721 REA gene cis-mutations and antiangiogenesis activities may be essential for the strategy for Imatinib / Sunitinibresistant GIST .

Imatinib mesylate : an innovation in treatment of autoimmune diseases . Imatinib mesylate is a selective protein tyrosine kinase inhibitor , which can inhibit P11274 REA / Abl , PDGF-R , c - P10721 REA , c-fms , TCR / Abl , Lck , P36888 REA and MAPKs activities on various cell types . On immune system , imatinib has antiproliferative activity and immunomodulatory effects in lymphocytes , macrophages , mast cells and dendritic cells with abrogating multiple signal transduction pathways involved in pathogenesis of autoimmune diseases e . g . inhibiting IFN-γ , P01375 REA - α , IL - 1β and Q16552 REA pro-inflammatory cytokines and MMPs secretion . To date , the efficacy of imatinib in numerous animal model of autoimmune diseases ( rheumatoid arthritis , multiple sclerosis , autoimmune diabetes and glomerulonephritis ) has been demonstrated , but application of this drug in human autoimmune diseases should be tested in future clinical trials . This review provides an update on the use of tyrosine kinase inhibitor imatinib mesylate in treatment of autoimmune diseases and its related recent patents that could be developed as a novel and available therapy for the management of the autoimmunity improvement .

Novel quinolinylaminoisoquinoline bioisosteres of sorafenib as selective P04049 REA kinase inhibitors : design , synthesis , and antiproliferative activity against melanoma cell line . Design and synthesis of a new series of quinolinylaminoisoquinoline derivatives as conformationally restricted bioisosteres of DB00398 SUB are described . Their in vitro antiproliferative activity against A375P melanoma cell line was tested . Compounds 1b , 1d , 1g , and 1j showed the highest potency against A375P cell line with IC50 values in sub-micromolar scale . In addition , compound 1d exerted high selectivity towards P04049 REA serine / threonine kinase with 96.47 % inhibition at 10 µM , and IC50 of 0.96 µM . This compound can possess antiproliferative activity against melanoma cells through inhibition of P04049 REA kinase .

Receptor tyrosine kinase pathway analysis sheds light on similarities between clear-cell sarcoma and metastatic melanoma . To highlight possible similarities and differences in receptor tyrosine kinase ( RTK ) and downstream signalling activation profiles between clear-cell sarcomas ( O14618 REA ) and metastatic melanomas ( MM ) , frozen , and paired-matched fixed samples of six O14618 REA with Q01844 rearrangement ( Q01844 + ) , five O14618 REA without Q01844 rearrangement ( Q01844 - ) , and seven MM were investigated by means of biochemical , immunohistochemical , Q5TCZ1 , molecular analyses , and immunofluorescence confocal microscopy . Fixed samples of a further 10 O14618 REA and 14 MM were investigated by means of sequencing for P15056 REA , P01111 REA , and P01116 REA mutations and Q5TCZ1 analyses for the gain of chromosomes 22 and 8 . RTK analysis of all O14618 REA / MM samples showed activation of short-form ( sf ) recepteur d'origine nantais ( Q04912 REA ) RTK and of P09619 REA , MET , and P21860 REA . Analysis of downstream signaling revealed consistent phosphorylation patterns of PI3K / AKT , RSK , and the P42345 REA targets S6 and 4EBP1 . Analysis of frozen and fixed material from 21 O14618 REA and 21 MM showed the presence of the V600E P15056 REA mutation in 2/12 Q01844 + and 3/9 Q01844 - O14618 REA and 9/21 MM and demonstrated a significant ( P < 0.001 ) correlation between the gain of chromosomes 22 and 8 and Q01844 - O14618 REA . Our results show that P15056 REA mutation can also be present in O14618 REA and support the proposed aberration of chromosomes 22 and 8 as a possibly useful nonrandom hallmark of Q01844 - O14618 REA . Besides , they broaden the spectrum of the similarities of RTK pathway activation between O14618 REA and MM , thus suggesting that new drugs found to be active in melanoma and Q04912 REA inhibitors could have a role in O14618 REA treatment . © 2011 Wiley Periodicals , Inc .