MH_dev_186

DB00144 MEN synthase - 1 and - 2 are localized to mitochondria-associated membranes . We report the subcellular localization of enzymes involved in phosphatidylserine biosynthesis in mammalian cells . Several lines of evidence suggest that phosphatidylserine synthase - 1 ( PSS 1 ) is highly enriched in mitochondria-associated membranes ( MAM ) and is largely excluded from the bulk of the endoplasmic reticulum ( ER ) . Taking advantage of the substrate specificity of PSS 1 , we showed that ( i ) MAM contain choline exchange activity , whereas this activity is very low in the bulk of the ER , ( ii ) serine exchange activity is inhibited by choline to a much greater extent in MAM than in ER , and ( iii ) MAM use phosphatidylcholine and phosphatidylethanolamine as substrates for phosphatidylserine biosynthesis , whereas the ER utilizes only phosphatidylethanolamine . According to immunoblotting of proteins from both CHO - P04264 REA cells and murine liver , PSS 1 is localized to MAM , and in hepatoma cells stably expressing PSS 1 this protein is highly enriched in MAM . Since the ER contains serine and ethanolamine exchange activities , we had predicted that Q9BVG9 would account for the serine exchange activity in the ER . Unexpectedly , using immunoblotting experiments , we found that ( i ) Q9BVG9 of CHO - P04264 REA cells is present only in MAM and ( ii ) Q9BVG9 is restricted to MAM of McArdle cells expressing recombinant Q9BVG9 . These data leave open the question of which enzyme imparts PSS activity to the ER and suggest that a third isoform of PSS might be located in the ER .

In P11274 REA - P00519 REA - positive cells , P35610 REA - 5 tyrosine-phosphorylation integrates signals induced by imatinib mesylate and DB00987 . In P11274 REA - P00519 REA - positive cells , the transcription factor P35610 REA - 5 is constitutively activated by tyrosine phosphorylation . P35610 REA - 5 activation results in upregulation of bcl-X ( L ) and increased resistance to induction of apoptosis . Here , we investigated the effects of imatinib mesylate and cytosine arabinoside ( DB00987 ) on P35610 REA - 5 tyrosine-phosphorylation , cellular proliferation and induction of apoptosis in cell lines and primary hematopoietic cells . Imatinib mesylate treatment strongly suppressed P35610 REA - 5 tyrosine-phosphorylation in K562 and primary CML blasts . In contrast to O60674 REA and P19957 REA - kinase inhibition , exposure of K562 cells to imatinib mesylate resulted in obvious suppression of proliferation . Reduced cell growth was due to specific induction of caspase activation followed by apoptotic cell death . In addition , we investigated the effects of DB00987 on P35610 REA - 5 tyrosine-phosphorylation . Exposure to DB00987 resulted in significant downregulation of P35610 REA - 5 tyrosine-phosphorylation and inhibition of DNA binding . Treatment of K562 cells with DB00987 in combination with imatinib mesylate revealed synergistic effects at the level of P35610 REA - 5 tyrosine-phosphorylation and DNA binding , Hck tyrosine-phosphorylation , cell growth and induction of apoptosis . Overall , in this report we demonstrate that P35610 REA - 5 tyrosine-phosphorylation is a specific target of imatinib mesylate and DB00987 . Our results suggest that , in combination therapy , inhibition of P35610 REA - 5 tyrosine-phosphorylation may be responsible for synergistic or additive effects on P11274 REA - P00519 REA - positive cells .

Dual inhibition of PI3K and P42345 REA signaling pathways decreases human pancreatic neuroendocrine tumor metastatic progression . OBJECTIVES : Patients with advanced pancreatic neuroendocrine tumors have limited therapeutic options . DB01590 MENMAX DB01590 MEN ( RAD 001 ) , an inhibitor of the mammalian target of rapamycin ( P42345 REA ) pathway , has been shown to increase progression-free survival , but not overall survival , indicating a need to identify additional therapeutic targets . Inhibition of P42345 REA complex 1 by RAD 001 may induce upstream AKT upregulation . We hypothesized that dual inhibition of AKT along with P42345 REA will overcome the limited activity of RAD 001 alone . METHODS : The BON cell line has been used as a model to study pancreatic neuroendocrine tumor cell biology . Western blots and cell growth assays were performed with P42345 REA inhibitor RAD 001 ( 50 nM ) , mitogen-activated protein kinase inhibitor PD0325901 ( 50 nM ) , PI3K ( phosphatidylinositol 3 - kinase ) inhibitor LY294002 ( 25 μM ) , or vehicle control . Nude mice were treated daily for 6 weeks with RAD 001 ( oral gavage ) and with LY29400 ( subcutaneous ) 1 week after intrasplenic injection of BON cells . RESULTS : Cellular proliferation was most attenuated with the combination therapy of LY29400 and RAD 001 . Similarly , the volume of liver metastasis was lowest in the group treated with both LY29400 ( 100 mg / kg per week , subcutaneous ) and RAD 001 ( 2.5 mg / kg per day ) compared with that in the vehicle group ( P = 0.04 ) . CONCLUSION : The combination therapy of LY29400 and RAD 001 decreased the cell growth in vitro and progression of liver metastasis in vivo compared with vehicle or with single-drug therapy .

Combination of rapamycin and protein tyrosine kinase ( PTK ) inhibitors for the treatment of leukemias caused by oncogenic PTKs . Abnormal protein tyrosine kinases ( PTKs ) cause many human leukemias . For example , P11274 REA / P00519 REA causes chronic myelogenous leukemia ( CML ) , whereas P36888 REA mutations contribute to the pathogenesis of acute myelogenous leukemia . The P00519 REA inhibitor Imatinib ( Gleevec , STI 571 ) has remarkable efficacy for treating chronic phase CML , and P36888 REA inhibitors ( e . g . , PKC 412 ) show similar promise in preclinical studies . However , resistance to PTK inhibitors is a major emerging problem that may limit long-term therapeutic efficacy . Development of rational combination therapies will probably be required to effect cures of these and other neoplastic disorders . Here , we report that the P42345 REA inhibitor rapamycin synergizes with Imatinib against P11274 REA / P00519 REA - transformed myeloid and lymphoid cells and increases survival in a murine CML model . DB00877 / Imatinib combinations also inhibit Imatinib-resistant mutants of P11274 REA / P00519 REA , and rapamycin plus PKC 412 synergistically inhibits cells expressing PKC 412 - sensitive or - resistant leukemogenic P36888 REA mutants . Biochemical analyses raise the possibility that inhibition of Q13541 REA phosphorylation may be particularly important for the synergistic effects of PTK inhibitor / rapamycin combinations . Addition of a mitogen-activated protein kinase kinase inhibitor to rapamycin or rapamycin plus PTK inhibitor further increases efficacy . Our results suggest that simultaneous targeting of more than one signaling pathway required by leukemogenic PTKs may improve the treatment of primary and relapsed CML and / or acute myelogenous leukemia caused by P36888 REA mutations . Similar strategies may be useful for treating solid tumors associated with mutant and / or overexpressed PTKs .

Phosphorylation of the P8 1877 and P00519 REA proteins by the Q9UBW7 - P11362 REA fusion kinase seen in atypical myeloproliferative disorders as revealed by phosphopeptide-specific MS . The Q9UBW7 - fibroblast growth factor receptor - 1 ( P11362 REA ) fusion kinase is a constitutively activated tyrosine kinase associated with a specific atypical myeloproliferative disease . The chimeric protein localizes to the cytoplasm , unlike the wild type P11362 REA receptor kinase , and presumably inappropriately phosphorylates specific targets as part of the oncogenic signaling cascade . Other than known targets of the P11362 REA kinase itself , few specific targets of Q9UBW7 - P11362 REA have been identified . Using a genetically engineered P29320 REA 293 cell system , we have identified proteins that are specifically phosphorylated in the presence of the fusion kinase using anti-phosphotyrosine immunoprecipitation and MS . Compared with 293 cells expressing exongenous wild type P11362 REA , Q9UBW7 - P11362 REA is associated with phosphorylation of several proteins including P8 1877 , P00519 REA , FLJ 14235 , CALM and Q9C037 REA proteins . The specificity of the phosphorylation events in the P8 1877 and P00519 REA proteins , which have previously been implicated in leukemogenesis , was further confirmed independently using immunoprecipitation with protein-specific antibodies and Western blotting . The MS analysis also identified the phosphorylation events in the Q9UBW7 moiety in the chimeric protein that might be related to its function . These studies identify the intersection of several different leukemia-related pathways in the development of this myeloproliferative disorder and provide new insights into the substrates of P11362 REA under defined conditions .

[ Late appearance of Philadelphia chromosome with the P78357 REA P11274 REA / P00519 REA chimeric transcript in acute myelogenous leukemia progressing from myelodysplastic syndrome ] . We report a late appearance of the Philadelphia chromosome ( Ph ) with the P78357 REA P11274 REA / P00519 REA chimeric transcript in a 69 - year-old patient with acute myelogenous leukemia ( AML ) that had evolved from myelodysplastic syndrome ( P43034 REA ) . In July 1997 , the patient was found to have pancytopenia caused by refractory anemia with excess of blasts , which evolved into AML in 4 months . The leukemic cells were positive for P15144 REA , P08571 REA , P20138 REA , and HLA-DR and had a normal karyotype . The patient achieved a complete remission after combination chemotherapy . However , his leukemia relapsed in November 1999 , with the appearance of leukemic cells positive for P09564 , P15144 REA , P28906 REA , and HLA-DR with a 46 , XY , add ( 18 ) ( p11 ) karyotype . The patient failed to achieve the second remission after several courses of intensive chemotherapy . When the number of blastic cells , showing the same surface phenotypes , in the peripheral blood increased drastically in April 2000 , chromosomal analysis of leukemic cells revealed a 46 , XY , t ( 9 ; 22 ) ( q34 ; q11 ) , add ( 18 ) ( p11 ) karyotype . The fusion of the P11274 REA and P00519 REA genes was confirmed by fluorescence in situ hybridization analysis , and the reverse transcription-polymerase chain reaction analysis further revealed the presence of the P78357 REA P11274 REA / P00519 REA chimeric transcript . The appearance of the Ph chromosome in the course of P43034 REA transforming to AML is very rare and may be correlated to the disease progression .

Transcriptional regulation of the P04264 REA gene product of Kaposi ' s sarcoma-associated herpesvirus . The P04264 REA protein of Kaposi ' s sarcoma-associated herpesvirus ( KSHV ) has been shown to be a transforming protein capable of inducing morphological changes and focus formation in rodent fibroblasts . P04264 REA can activate B-cell receptor ( P11274 REA ) signaling and upregulate activity of the NFAT and NF-kappaB transcription factors . In order to understand the regulation of P04264 REA gene expression , we have analyzed sequences upstream of the P04264 REA gene to identify the P04264 REA promoter element . We have performed 5 ' rapid amplification of cDNA ends as well as a nuclease protection assay to map the transcriptional start site of the KSHV P04264 REA transcript . The P04264 REA transcriptional start site lies 75 bp upstream of the translation start site . Sequences upstream of the P04264 REA gene were characterized for their ability to activate a luciferase reporter gene in 293 epithelial cells , KSHV-negative B cells ( BJAB ) , KSHV-positive B cells ( BCBL - 1 ) , and KS tumor-derived endothelial cells ( SLK-KS ( - ) ) . We found that a 125 - bp sequence upstream of the P04264 REA transcript start site was sufficient to fully activate the luciferase reporter gene in all cell types tested . In addition , the viral transcription factor KSHV Orf 50 / Rta was capable of further activating this promoter element in 293 , BJAB , and BCBL - 1 cells but not in SLK-KS ( - ) cells . Promoter constructs containing additional sequences upstream of the 125 - bp element did not show further augmentation of transcription in the presence or absence of KSHV Orf 50 .

Polyamines and membrane transporters . In recent years , our understanding of the importance of membrane transporters ( MTs ) in the disposition of and response to drugs has increased significantly . MTs are proteins that regulate the transport of endogenous molecules and xenobiotics across the cell membrane . In mammals , two super-families have been identified : DB00171 - binding cassette ( DB01048 ) and solute carrier ( O00585 REA ) transporters . There is evidence that MTs might mediate polyamines ( PA ) transport . PA are ubiquitous polycations which are found in all living cells . In mammalian cells , three major PA are synthesised : putrescine , spermidine and spermine ; whilst the decarboxylated arginine ( agmatine ) is not produced by mammals but is synthesised by plants and bacteria . In addition , research in the PA field suggests that PA are transported into cells via a specific transporter , the polyamine transport system ( s ) ( Q03393 REA ) . Although the Q03393 REA has not been fully defined , there is evidence that some of the known MTs might be involved in PA transport . In this mini review , eight O00585 REA transporters will be reviewed and their potential to mediate PA transport in human cells discussed . These transporters are O15245 REA , O15244 REA , O75751 REA , Q96FL8 , P30825 REA , P08195 REA , SLC 12A8A , and Q86VW1 . Preliminary data from our laboratory have revealed that O15245 REA might be involved in the PA uptake ; in addition to one member of ABC superfamily ( P08183 REA protein ) might also mediate the efflux of polyamine like molecules .

Effects of mitiglinide ( S 21403 ) on Kir 6.2 / Q09428 REA , Kir 6.2 / SUR 2A and Kir 6.2 / SUR 2B types of DB00171 - sensitive potassium channel . 1 . We have investigated the mechanism of action of the novel anti-diabetic agent mitiglinide ( S 21403 ) on Kir 6.2 / Q09428 REA , Kir 6.2 / SUR 2A and Kir 6.2 / SUR 2B types of DB00171 - sensitive potassium ( K ( DB00171 ) ) channel . These possess a common pore-forming subunit , Kir 6.2 , and different regulatory sulphonylurea receptor ( Q09428 REA ) subunits . It is believed that they correspond to native K ( DB00171 ) channels in pancreatic beta-cells , heart and non-vascular smooth muscle , respectively . 2 . Kir 6.2 was coexpressed with Q09428 REA , SUR 2A or SUR 2B in Xenopus oocytes and macroscopic currents were recorded in giant inside-out membrane patches . DB01252 MEN was added to the intracellular membrane surface . 3 . DB01252 MEN inhibited Kir 6.2 / Q09428 REA currents at two sites : a low-affinity site on Kir 6.2 and a high-affinity site on Q09428 REA . Low-affinity inhibition was similar for all three types of K ( DB00171 ) channel but high-affinity inhibition was greater for Kir 6.2 / Q09428 REA currents ( IC ( 50 ) , 4 nM ) than for Kir 6.2 / SUR 2A or Kir 6.2 / SUR 2B currents ( IC ( 50 ) , 3 and 5 microM , respectively ) . 4 . Inhibition of Kir 6.2 / Q09428 REA currents was only slowly reversible on the time scale of electrophysiological experiments . 5 . Kir 6.2 / Q09428 REA - S1237Y currents , which previously have been shown to lack high affinity tolbutamide inhibition , resembled Kir 6.2 / SUR 2 currents in being unaffected by 100 nM but blocked by 10 microM mitiglinide . 6 . Our results show that mitiglinide is a high-affinity drug that shows a 1000 fold greater affinity for the beta-cell type than the cardiac and smooth muscle types of K ( DB00171 ) channel , when measured in excised patches .

Personalized medicine and pharmacogenetic biomarkers : progress in molecular oncology testing . In the field of oncology , clinical molecular diagnostics and biomarker discoveries are constantly advancing as the intricate molecular mechanisms that transform a normal cell into an aberrant state in concert with the dysregulation of alternative complementary pathways are increasingly understood . Progress in biomarker technology , coupled with the companion clinical diagnostic laboratory tests , continue to advance this field , where individualized and customized treatment appropriate for each individual patient define the standard of care . Here , we discuss the current commonly used predictive pharmacogenetic biomarkers in clinical oncology molecular testing : P15056 REA V600E for vemurafenib in melanoma ; Q9HC35 - Q9UM73 for crizotinib and P00533 REA for erlotinib and gefitinib in non-small-cell lung cancer ; P01116 REA against the use of cetuximab and panitumumab in colorectal cancer ; P04626 REA ( P04626 REA / neu ) for trastuzumab in breast cancer ; P11274 REA - P00519 REA for tyrosine kinase inhibitors in chronic myeloid leukemia ; and P29590 REA / RARα for all-trans-retinoic acid and arsenic trioxide treatment for acute promyelocytic leukemia .

Effective dasatinib uptake may occur without human organic cation transporter 1 ( O15245 REA ) : implications for the treatment of imatinib-resistant chronic myeloid leukemia . We have previously shown that imatinib uptake into chronic myeloid leukemia ( CML ) cells is dependent on human organic cation transporter 1 ( O15245 REA ; O15245 REA ) , and that low O15245 REA expression is an important determinant of clinical outcome to imatinib treatment . We hypothesized that dasatinib might be transported differently than imatinib , possibly accounting for its favorable effects in imatinib-resistant patients . ( 14 ) C-dasatinib uptake was greater in KCL 22 - transfected cells with pcDNA 3 - O15245 REA plasmid ( high O15245 REA - expressing cells ) than in control cells ( P = . 02 ) . However , hOCT inhibitors did not decrease dasatinib uptake into either control or primary cells , in contrast to their block on imatinib uptake . Dasa-tinib decreased the level of phosphorylated CrkL to 49.9 % in control and 40.3 % in high O15245 REA - expressing cells . Dasa-tinib efflux was investigated in confluent P08183 REA - transfected MDCKII cell monolayers . Both dasatinib and imatinib were transported from the basal to the apical layer , indicating that they were transported by P08183 REA , which was confirmed using the P08183 REA inhibitor PSC 833 ( P = . 001 and P < . 001 , respectively ) . Compared with imatinib , dasatinib achieved superior intracellular levels and P11274 REA - P00519 REA suppression even in cells with low or blocked O15245 REA . Efflux of dasatinib and imatinib appear similar via P08183 REA . Dasatinib may therefore offer an advantage over imatinib in patients with low O15245 REA expression .

DB01079 MEN inhibits the serotonin transporter P31645 REA . BACKGROUND : DB01079 MEN is a novel drug for the treatment of constipation-predominant irritable bowel syndrome . DB01079 MEN is thought to exert its prokinetic effect as a selective partial agonist of serotonin receptor type 4 ( Q13639 REA ) receptors located in the enteric nervous system . It is unknown , however , whether tegaserod interacts with the human serotonin reuptake transporter ( hSERT ) and the uptake transporters for dopamine ( hDAT ) and norepinephrine ( hNET ) . Therefore , the aim of the present study was to investigate whether tegaserod inhibits P31645 REA - , Q01959 REA - , and NET-mediated transport . METHODS : DB01079 MEN inhibition of P31645 REA - mediated [ 3H ] 5 - HT and NET - and Q01959 REA - mediated [ 3H ] dopamine uptake was measured in human embryonic kidney ( P29320 REA ) 293 cells stably expressing hSERT , hDAT , and hNET in comparison with untransfected control HEK 293 - FT cells . RESULTS : DB01079 MEN inhibited P31645 REA - , Q01959 REA - , and NET-mediated transport with IC50 - values of 11.7 , 20.7 , and 3.2 micromol / l , respectively , while 100 micromol / l estrone - 3 - sulfate or taurocholic acid , used as negative controls , failed to inhibit hSERT-mediated transport . Using Dixon plot analysis , inhibition kinetics yielded a non-competitive type of inhibition with an apparent inhibition constant ( Ki ) of 3.1 micromol / l for P31645 REA - mediated 5 - HT transport . CONCLUSION : In the present study we propose an additional mechanism of action for tegaserod as a serotonin uptake inhibitor . By inhibiting P31645 REA and increasing local 5 - HT concentrations in the gut wall , tegaserod might exert its prokinetic action via a synergism between Q13639 REA agonism and low-affinity P31645 REA inhibition .

Enhancement of cytotoxicity of natural product drugs against multidrug resistant variant cell lines of human head and neck squamous cell carcinoma and breast carcinoma by tesmilifene . N , N-diethyl - 2 - [ 4 - ( phenylmethyl ) phenoxyl ] ethanamine ( tesmilifene ) , a tamoxifen derivative with antihistamine activity , greatly enhanced the survival of doxorubicin-treated , advanced stage breast cancer patients in a phase III trial . However , the molecular basis of tesmilifene action is not firmly established . The effects of tesmilifene on activity of several anticancer drugs was investigated using human head and neck squamous cell carcinoma ( HNSCC ) and breast carcinoma cell lines as a model system . Multidrug resistant ( MDR ) variants of an HNSCC cell line , HN - 5a / V15e , and a breast carcinoma cell line , MCF - 7 / V25a , both highly overexpressed mdr 1 ( P08183 REA ) mRNA and the proteins P-glycoprotein and glutathione transferase-pi . Drug sensitivities were measured by a vital stain after 4 days of continuous exposure to anticancer drug in the absence and presence of tesmilifene at a concentration that alone had no antiproliferative effect . DB04905 SUB had minimal effect on drug cytotoxicity against the parental cell lines . However , the same tesmilifene treatment enhanced cytotoxicity of docetaxel , paclitaxel , epirubicin , doxorubicin , and vinorelbine against both MDR cell lines by up to 50 % . Flow cytometric measurement of annexin V / propidium iodide staining demonstrated that tesmilifene increased the killing of HN - 5a / V15e cells caused by docetaxel after 24 and 48h exposure . DB04905 SUB increased accumulation of radiolabelled vincristine in HN - 5a / V15e cells , over 4h , by up to 100 % . The results suggest that tesmilifene might be effective in the treatment of tumors that are resistant to natural product drugs . The mechanism of enhancement appears to be related to expression of an ABC pump-dependent , MDR phenotype .

The anti-androgen drug dutasteride renders triple negative breast cancer cells more sensitive to chemotherapy via inhibition of HIF - 1α - / P15692 REA - signaling . BACKGROUND : Triple negative breast cancer ( TNBC ) is characterized by lack of expression of both estrogen and progesterone receptor as well as lack of amplification of P04626 REA . Patients with TNBC carry an unfavorable prognosis compared to other breast cancer subtypes given that endocrine or P04626 REA targeted therapies are not effective , rendering chemotherapy the sole effective treatment option to date . Therefore , there is a high demand for additional novel treatment options . FINDINGS : We previously published a list of genes showing both higher gene expression rates in TNBC and , in addition , are known to encode targets of non-oncologic drugs . P18405 REA , which encodes the type - 1 isoform of the steroid - 5alpha - reductase , which is involved in androgen metabolism , was found to be one of these genes . DB01126 MEN is a dual blocker of both the type - 1 and type - 2 isoform of P18405 REA and is indicated in the treatment of benign prostate hyperplasia . Treatment of TNBC cell lines with dutasteride was associated with a dose-dependent decrease in cell viability , altered protein expression of P15692 REA and HIF - 1α and increased chemosensitivity . CONCLUSION : Our results demonstrate that the P18405 REA - corresponding anti-androgenic drug dutasteride might act as a combinatorial therapeutic option besides standard chemotherapy in highly aggressive TNBC .

Inhibition of neuronal nitric oxide reduces anxiety-like responses to pair housing . Many psychological disorders are characterized by anxiety and alterations in social interactions . Recent studies demonstrate that the chemical messenger nitric oxide ( NO ) can regulate both anxiety and social behaviours . We tested whether an enzyme that produces NO in the brain , neuronal nitric oxide synthase ( P29475 REA ) , serves as an interface between social interactions and anxiety-like behaviour . Several investigators have observed that mice increase anxiety-like responses in the elevated plus-maze after pair housing . P29475 REA gene deletion and DB01997 MEN were used to inhibit the production of neuronal NO . Similar to previous studies , pair housing reduced open arm exploration in the elevated plus-maze . Pair housing also increased corticotropin-releasing hormone ( P06850 REA ) immunoreactive cells in the paraventricular nucleus ( PVN ) of the hypothalamus . Inhibition of NO production increased open arm exploration in pair-housed mice but decreased open arm exploration in individually housed mice . These results suggest that the effect of P29475 REA inhibition on anxiety-like responses is context dependent and that behavioural responses to social housing are altered after P29475 REA inhibition . This research suggests that NO may play an important role in mediating the effect social interactions have on anxiety .

Recent therapeutic strategy for sustained ventricular tachycardia in Japan . We investigated the therapeutic principles and strategies to treat sustained ventricular tachycardia ( SVT ) as five leading medical institutions in the Tokyo area and summarized the present situation of SVT treatment in Japan . Catheter ablation ( P00519 REA ) has been almost established to be effective in idiopathic ventricular tachycardia ( IVT ) and was used as the last treatment in 60.3 % of IVTs in this series . P00519 REA may be the first option of therapy for IVT . In patients with SVT who have underlying cardiac diseases , the last treatment was class I drugs in 8.3 % , class III drugs in 34.3 % , combination drug therapy in 24.0 % , P00519 REA in 33.3 % , surgical therapy ( Q09428 REA ) in 7.3 % , and implantable cardioverter defibrillator ( ICD ) in 12.5 % ( nonpharmacological therapy in combination with other therapy ) . The use of class I drugs was not common , whereas class III drugs were used more frequently in patients with a low left ventricular ejection fraction . In some patients with reduced cardiac function , a combination of class III drugs and non-pharmacological therapy is appropriate .

Imatinib inhibits P15692 REA - independent angiogenesis by targeting neuropilin 1 - dependent P00519 REA activation in endothelial cells . To enable new blood vessel growth , endothelial cells ( ECs ) express neuropilin 1 ( NRP 1 ) , and NRP 1 associates with the receptor tyrosine kinase P35968 REA after binding the vascular endothelial growth factor A ( P15692 REA ) to enhance arteriogenesis . We report that NRP 1 contributes to angiogenesis through a novel mechanism . In human and mouse ECs , the integrin ligand fibronectin ( FN ) stimulated actin remodeling and phosphorylation of the focal adhesion component paxillin ( P49023 REA ) in a P15692 REA / P35968 REA - independent but NRP 1 - dependent manner . NRP 1 formed a complex with P00519 REA that was responsible for FN-dependent P49023 REA activation and actin remodeling . This complex promoted EC motility in vitro and during angiogenesis on FN substrates in vivo . Accordingly , both physiological and pathological angiogenesis in the retina were inhibited by treatment with Imatinib , a small molecule inhibitor of P00519 REA which is widely used to prevent the proliferation of tumor cells that express P11274 REA - P00519 REA fusion proteins . The finding that NRP 1 regulates angiogenesis in a P15692 REA - and P35968 REA - independent fashion via P00519 REA suggests that P00519 REA inhibition provides a novel opportunity for anti-angiogenic therapy to complement P15692 REA or P35968 REA blockade in eye disease or solid tumor growth .

Bradykinin stimulates glutamate uptake via both P46663 REA and P30411 REA activation in a human retinal pigment epithelial cells . AIMS : We were to examine the effect of bradykinin ( BK ) in the regulation of glutamate transporter and its related signaling molecules in a human retinal pigment epithelial ( ARPE ) cells , which are important cells to support retina . MAIN METHODS : d - [ 2,3- ( 3 ) H ] - aspartate uptake , western immunoblotting , reverse transcription polymerase chain reaction , [ ( 3 ) H ] - arachidonic acid release , and siRNA transfection techniques were used . KEY FINDINGS : BK stimulated glutamate uptake as well as the mRNA expression of excitatory amino acid transporter 4 ( P48664 REA ) and excitatory amino acid carrier 1 ( P43005 REA ) , which was blocked by treatment with bradykinin 1 receptor ( P46663 REA ) and bradykinin 2 receptor ( P30411 REA ) siRNA , suggesting the role of P46663 REA and P30411 REA in this process . The BK-induced stimulation of glutamate uptake was also blocked by [ des - DB00125 ( 10 ) ] - DB06196 MEN , a P46663 REA antagonist , and DB06196 MEN , a P30411 REA antagonist , as well as by the tyrosine kinase inhibitors genistein and herbimycin A . In addition , the BK-induced stimulation of glutamate uptake was blocked by treatment with the phospholipase A ( 2 ) inhibitors mepacrine and AACOCF ( 3 ) , the cyclooxygenase ( P36551 REA ) inhibitor indomethacin , and the P35354 REA inhibitor Dup 697 . Furthermore , the BK-induced increase in P35354 REA expression was blocked by the P19957 REA kinase inhibitors wortmannin and LY294002 , Akt inhibitor , and the protein kinase C ( PKC ) inhibitors staurosporine and bisindolylmaleimide I , suggesting the role of P19957 REA kinase and PKC in this process . BK stimulated Akt activation and the translocation of PKC activation via the activation of P46663 REA and P30411 REA . SIGNIFICANCE : BK stimulates glutamate uptake through a PKC-Akt - P35354 REA signaling cascade in ARPE cells .

Unbalanced placental expression of imprinted genes in human intrauterine growth restriction . Imprinted genes control fetal and placental growth in mice and in rare human syndromes , but the role of these genes in sporadic intrauterine growth restriction ( IUGR ) is less well-studied . We measured the ratio of mRNA from a maternally expressed imprinted gene , Q53GA4 , to that from a paternally expressed imprinted gene , Q5EB52 , by Northern blotting in 38 IUGR-associated placentae and 75 non-IUGR placentae and found an increase in the Q53GA4 / Q5EB52 mRNA ratio in IUGR ( p= 0.0001 ) . Altered expression of Q53GA4 and Q5EB52 was not accompanied by changes in DNA methylation within their imprinting centers , and immunohistochemistry showed Q53GA4 protein appropriately restricted to villous and intermediate cytotrophoblast in the IUGR placentae . We next did a genome-wide survey of mRNA expression in 14 IUGR placentae with maternal vascular under-perfusion compared to 15 non-IUGR placentae using Affymetrix U133A microarrays . In this series six imprinted genes were differentially expressed by Q9UNW9 with a Benjamini-Hochberg false discovery rate of 0.05 , with increased expression of Q53GA4 and decreased expression of Q5EB52 , Q9UI56 , P50440 REA , GNAS and Q9UM63 in IUGR placentae . At lower significance , we found P01344 REA mRNA decreased and P49918 REA mRNA increased in the IUGR cases . We confirmed the significant reduction in Q9UI56 non-translated RNA in IUGR placentae by Northern blotting . In addition to imprinted genes , the microarray data highlighted non-imprinted genes acting in endocrine signaling ( P41159 REA , P06850 REA , P15428 REA , P08476 REA ) , tissue growth ( IGF 1 ) , immune modulation ( P14902 REA , PSG-family genes ) , oxidative metabolism ( P35754 REA ) , vascular function ( P30556 REA , P53805 ) and metabolite transport ( O00585 REA - family solute carriers ) as differentially expressed in IUGR vs . non-IUGR placentae .

The O00206 REA antagonist DB04933 MEN protects mice from lethal influenza infection . There is a pressing need to develop alternatives to annual influenza vaccines and antiviral agents licensed for mitigating influenza infection . Previous studies reported that acute lung injury caused by chemical or microbial insults is secondary to the generation of host-derived , oxidized phospholipid that potently stimulates O00206 REA ( O00206 REA ) - dependent inflammation . Subsequently , we reported that Tlr 4 ( - / - ) mice are highly refractory to influenza-induced lethality , and proposed that therapeutic antagonism of O00206 REA signalling would protect against influenza-induced acute lung injury . Here we report that therapeutic administration of DB04933 MEN ( also known as E5564 ) - a potent , well-tolerated , synthetic O00206 REA antagonist-blocks influenza-induced lethality in mice , as well as lung pathology , clinical symptoms , cytokine and oxidized phospholipid expression , and decreases viral titres . P08571 REA and O60603 REA are also required for DB04933 MEN - mediated protection , and P08571 REA directly binds DB04933 MEN and inhibits ligand binding to Q9Y6Y9 REA . Thus , DB04933 MEN blockade of TLR signalling represents a novel therapeutic approach for inflammation associated with influenza , and possibly other infections .

DB05578 MEN : a novel antiangiogenic agent . DB05578 MEN ( IMC - 1121B ) is a fully humanized monoclonal antibody that binds to P35968 REA and can inhibit angiogenesis , a quintessential mechanism for promoting tumor growth and metastasis . Several antiangiogenesis agents are already approved for cancer therapy ; however , ramucirumab ' s selectivity for P35968 REA makes it interesting . The selectivity of an agent can improve safety and efficacy . This article describes the mechanism of action , pharmacokinetics , safety and clinical trial results of ramucirumab with particular emphasis on gastric cancer .