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Sample records for hgf receptor met

  1. The tyrosine kinase receptor c-met, its cognate ligand HGF and the tyrosine kinase receptor trasducers STAT3, PI3K and RHO in thyroid nodules associated with Hashimoto's thyroiditis: an immunohistochemical characterization

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    R. M. Ruggeri

    2010-06-01

    Full Text Available Hepatocyte growth factor (HGF exerts proliferative activities in thyrocytes upon binding to its tyrosine kinase receptor c-met and is also expressed in benign thyroid nodules as well as in Hashimoto’s thyroiditis (HT. The simultaneous expression of HGF/c-met and three trasducers of tyrosine kinase receptors (STAT3, PI3K, RHO in both the nodular and extranodular tissues were studied by immunohistochemistry in 50 benign thyroid nodules (NGs, 25 of which associated with HT. The ligand/tyrosine kinase receptor pair HGF/c-met and the two trasducers PI3K and RHO were expressed in NGs, regardless of association with HT, with a higher positive cases percentage in HT-associated NGs compared to not HT-associated NGs (25/25 or 100% vs 7/25 or 28%; P<0.001. HGF, PI3K and RHO expression was only stromal (fibroblasts and endothelial cells, in all 32 reactive NGs, while c-met localization was consistently epithelial (thyrocyes. Immu­noreactions for HGF, c-met, PI3K and RHO were also apparent in the extra-nodular tissue of HT specimens, where HGF and PI3K were expressed not only in stromal cells but also in thyrocyes along with the c-met. Finally, a positive correlation was observed between the proportion of HGF, c-met, PI3K follicular cells and the grade of lymphoid aggregates in HT. In conclusion, HGF, c-met, PI3K are much more frequently and highly expressed in HT compared to NGs, and among all NGs in those present in the context of HT. A paracrine effect of HFG/c-met on nodule development, based on the prevalent stromal expression, may be suggested along with a major role of HGF/c-met and PI3K in HT. Finally, the expression of such molecules in HT may be regulated by lymphoid infiltrate.

  2. Cellular and molecular mechanisms of HGF/Met in the cardiovascular system.

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    Gallo, Simona; Sala, Valentina; Gatti, Stefano; Crepaldi, Tiziana

    2015-12-01

    Met tyrosine kinase receptor, also known as c-Met, is the HGF (hepatocyte growth factor) receptor. The HGF/Met pathway has a prominent role in cardiovascular remodelling after tissue injury. The present review provides a synopsis of the cellular and molecular mechanisms underlying the effects of HGF/Met in the heart and blood vessels. In vivo, HGF/Met function is particularly important for the protection of the heart in response to both acute and chronic insults, including ischaemic injury and doxorubicin-induced cardiotoxicity. Accordingly, conditional deletion of Met in cardiomyocytes results in impaired organ defence against oxidative stress. After ischaemic injury, activation of Met provides strong anti-apoptotic stimuli for cardiomyocytes through PI3K (phosphoinositide 3-kinase)/Akt and MAPK (mitogen-activated protein kinase) cascades. Recently, we found that HGF/Met is also important for autophagy regulation in cardiomyocytes via the mTOR (mammalian target of rapamycin) pathway. HGF/Met induces proliferation and migration of endothelial cells through Rac1 (Ras-related C3 botulinum toxin substrate 1) activation. In fibroblasts, HGF/Met antagonizes the actions of TGFβ1 (transforming growth factor β1) and AngII (angiotensin II), thus preventing fibrosis. Moreover, HGF/Met influences the inflammatory response of macrophages and the immune response of dendritic cells, indicating its protective function against atherosclerotic and autoimmune diseases. The HGF/Met axis also plays an important role in regulating self-renewal and myocardial regeneration through the enhancement of cardiac progenitor cells. HGF/Met has beneficial effects against myocardial infarction and endothelial dysfunction: the cellular and molecular mechanisms underlying repair function in the heart and blood vessels are common and include pro-angiogenic, anti-inflammatory and anti-fibrotic actions. Thus administration of HGF or HGF mimetics may represent a promising therapeutic agent for the

  3. Recent Progress and Advances in HGF/MET-Targeted Therapeutic Agents for Cancer Treatment

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    Yilong Zhang

    2015-03-01

    Full Text Available The hepatocyte growth factor (HGF: MET axis is a ligand-mediated receptor tyrosine kinase pathway that is involved in multiple cellular functions, including proliferation, survival, motility, and morphogenesis. Aberrancy in the HGF/MET pathway has been reported in multiple tumor types and is associated with tumor stage and prognosis. Thus, targeting the HGF/MET pathway has become a potential therapeutic strategy in oncology development in the last two decades. A number of novel therapeutic agents—either as therapeutic proteins or small molecules that target the HGF/MET pathway—have been tested in patients with different tumor types in clinical studies. In this review, recent progress in HGF/MET pathway-targeted therapy for cancer treatment, the therapeutic potential of HGF/MET-targeted agents, and challenges in the development of such agents will be discussed.

  4. Antifolate/folate-activated HGF/c-Met signalling pathways in mouse kidneys-the putative role of their downstream effectors in cross-talk with androgen receptor.

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    Dudkowska, Magdalena; Bajer, Seweryn; Jaworski, Tomasz; Zielińska, Joanna; Manteuffel-Cymborowska, Małgorzata; Grzelakowska-Sztabert, Barbara

    2009-03-01

    This in vivo study of mouse kidneys was focused on the identification of protein mediators involved in the cross-talk between two signalling pathways. One pathway was triggered by testosterone via an androgen receptor, AR, and the other induced by CB 3717/folate via HGF, and its membrane receptor c-Met. Sequential activation of these pathways leads to a drastic decrease of testosterone-induced ornithine decarboxylase, ODC, expression. We proved that CB 3717/folate-induced ODC expression is Akt-dependent. CB 3717/folate activates Akt and ERK1/2 kinases, PTEN phosphatase and also up-regulates cyclin D2 and PCNA, but decreases GSK3beta and cyclin D1 protein levels. Testosterone activation of AR induces GSK3beta and PTEN. Results of the sequential activation of the studied signalling pathways suggest that Akt, GSK3beta and possibly ERK1/2 kinases may participate in the negative cross-talk and attenuation of AR transactivity, while the involvement of PTEN and cyclin D1 seems to be doubtful.

  5. HGF/Met Signaling Is a Key Player in Malignant Mesothelioma Carcinogenesis

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    Giovanni Gaudino

    2014-11-01

    Full Text Available Malignant mesothelioma (MM is a highly aggressive cancer related to asbestos or erionite exposure and resistant to current therapies. Hepatocyte Growth Factor (HGF and its tyrosine kinase receptor Met regulate cell growth, survival, motility/migration, and invasion. HGF and Met are expressed in MM cells, suggesting that the HGF/Met signaling plays a role in development and progression of this tumor, by autocrine and/or paracrine mechanisms. Upregulation and ligand-independent activation of Met, which is under suppressive control of miR-34 family members, correlate with enhanced invasion, migration and metastatic potential in several cancers, including MM. Moreover, Simian Virus 40 (SV40 Tag expression also induces a HGF autocrine circuit in an Rb-dependent manner in human mesothelial cells (HM and possibly other cell types, enhancing cell adhesion, invasion and angiogenesis. The resulting activation of Met causes HM transformation and cell cycle progression, and contributes to virus particle assembling and infection of adjacent cells. The constitutive activation of Met, frequently occurring in MM, has been successfully targeted in preclinical models of MM. In conclusion, Met expression, activation state, subcellular localization and also HGF co-receptors expression, such as CD44, have clinical relevance for novel targeted therapies in a cancer for which no effective treatment is currently available.

  6. The Hepatocyte Growth Factor (HGF)/Met Axis: A Neglected Target in the Treatment of Chronic Myeloproliferative Neoplasms?

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    Boissinot, Marjorie [Translational Neuro-Oncology Group, Leeds Institute of Cancer and Pathology, University of Leeds, Level 5 Wellcome Trust Brenner Building, St James’s Hospital, Leeds LS9 7TF (United Kingdom); Vilaine, Mathias [Institute of Research on Cancer and Aging (IRCAN), CNRS-Inserm-UNS UMR 7284, U 1081, Centre A. Lacassagne, 33 Avenue Valombrose, Nice 06189 (France); Hermouet, Sylvie, E-mail: sylvie.hermouet@univ-nantes.fr [Centre Hospitalier Universitaire (CHU), Place Alexis Ricordeau, Nantes 44093 (France); Inserm UMR892, Centre de Recherche en Cancérologie Nantes-Angers, Institut de Recherche en Santé, Université de Nantes, 8 quai Moncousu, Nantes cedex 44007 (France)

    2014-08-12

    Met is the receptor of hepatocyte growth factor (HGF), a cytoprotective cytokine. Disturbing the equilibrium between Met and its ligand may lead to inappropriate cell survival, accumulation of genetic abnormalities and eventually, malignancy. Abnormal activation of the HGF/Met axis is established in solid tumours and in chronic haematological malignancies, including myeloma, acute myeloid leukaemia, chronic myelogenous leukaemia (CML), and myeloproliferative neoplasms (MPNs). The molecular mechanisms potentially responsible for the abnormal activation of HGF/Met pathways are described and discussed. Importantly, inCML and in MPNs, the production of HGF is independent of Bcr-Abl and JAK2V617F, the main molecular markers of these diseases. In vitro studies showed that blocking HGF/Met function with neutralizing antibodies or Met inhibitors significantly impairs the growth of JAK2V617F-mutated cells. With personalised medicine and curative treatment in view, blocking activation of HGF/Met could be a useful addition in the treatment of CML and MPNs for those patients with high HGF/MET expression not controlled by current treatments (Bcr-Abl inhibitors in CML; phlebotomy, hydroxurea, JAK inhibitors in MPNs)

  7. Characterization of HGF/Met Signaling in Cell Lines Derived From Urothelial Carcinoma of the Bladder

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    Lee, Young H. [Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892 (United States); Apolo, Andrea B. [Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892 (United States); Agarwal, Piyush K.; Bottaro, Donald P., E-mail: dbottaro@helix.nih.gov [Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892 (United States)

    2014-11-25

    There is mounting evidence of oncogenic hepatocyte growth factor (HGF)/Met signaling in urothelial carcinoma (UC) of the bladder. The effects of three kinase inhibitors, cabozantinib, crizotinib and EMD1214063, on HGF-driven signaling and cell growth, invasion and tumorigenicity were analyzed in cultured UC cell lines. SW780 xenograft growth in SCID and human HGF knock-in SCID (hHGF/SCID) mice treated with cabozantinib or vehicle, as well as tumor levels of Met and pMet, were also determined. Met content was robust in most UC-derived cell lines. Basal pMet content and effector activation state in quiescent cells were low, but significantly enhanced by added HGF, as were cell invasion, proliferation and anchorage independent growth. These HGF-driven effects were reversed by Met inhibitor treatment. Tumor xenograft growth was significantly higher in hHGF/SCID mice vs. SCID mice and significantly inhibited by cabozantinib, as was tumor phospho-Met content. These studies indicate the prevalence and functionality of the HGF/Met signaling pathway in UC cells, suggest that paracrine HGF may contribute to UC tumor growth and progression, and that support further preclinical investigation of Met inhibitors for the treatment of UC is warranted.

  8. Characterization of HGF/Met Signaling in Cell Lines Derived From Urothelial Carcinoma of the Bladder

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    Young H. Lee

    2014-11-01

    Full Text Available There is mounting evidence of oncogenic hepatocyte growth factor (HGF/Met signaling in urothelial carcinoma (UC of the bladder. The effects of three kinase inhibitors, cabozantinib, crizotinib and EMD1214063, on HGF-driven signaling and cell growth, invasion and tumorigenicity were analyzed in cultured UC cell lines. SW780 xenograft growth in SCID and human HGF knock-in SCID (hHGF/SCID mice treated with cabozantinib or vehicle, as well as tumor levels of Met and pMet, were also determined. Met content was robust in most UC-derived cell lines. Basal pMet content and effector activation state in quiescent cells were low, but significantly enhanced by added HGF, as were cell invasion, proliferation and anchorage independent growth. These HGF-driven effects were reversed by Met inhibitor treatment. Tumor xenograft growth was significantly higher in hHGF/SCID mice vs. SCID mice and significantly inhibited by cabozantinib, as was tumor phospho-Met content. These studies indicate the prevalence and functionality of the HGF/Met signaling pathway in UC cells, suggest that paracrine HGF may contribute to UC tumor growth and progression, and that support further preclinical investigation of Met inhibitors for the treatment of UC is warranted.

  9. Characterization of HGF/Met Signaling in Cell Lines Derived From Urothelial Carcinoma of the Bladder.

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    Lee, Young H; Apolo, Andrea B; Agarwal, Piyush K; Bottaro, Donald P

    2014-11-25

    There is mounting evidence of oncogenic hepatocyte growth factor (HGF)/Met signaling in urothelial carcinoma (UC) of the bladder. The effects of three kinase inhibitors, cabozantinib, crizotinib and EMD1214063, on HGF-driven signaling and cell growth, invasion and tumorigenicity were analyzed in cultured UC cell lines. SW780 xenograft growth in SCID and human HGF knock-in SCID (hHGF/SCID) mice treated with cabozantinib or vehicle, as well as tumor levels of Met and pMet, were also determined. Met content was robust in most UC-derived cell lines. Basal pMet content and effector activation state in quiescent cells were low, but significantly enhanced by added HGF, as were cell invasion, proliferation and anchorage independent growth. These HGF-driven effects were reversed by Met inhibitor treatment. Tumor xenograft growth was significantly higher in hHGF/SCID mice vs. SCID mice and significantly inhibited by cabozantinib, as was tumor phospho-Met content. These studies indicate the prevalence and functionality of the HGF/Met signaling pathway in UC cells, suggest that paracrine HGF may contribute to UC tumor growth and progression, and that support further preclinical investigation of Met inhibitors for the treatment of UC is warranted.

  10. Met and its ligand HGF are associated with clinical outcome in breast cancer

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    Veenstra, Cynthia; Pérez-Tenorio, Gizeh; Stelling, Anna; Karlsson, Elin; Mirwani, Sanam Mirwani; Nordensköljd, Bo; Fornander, Tommy; Stål, Olle

    2016-01-01

    Few biomarkers exist to predict radiotherapy response in breast cancer. In vitro studies suggest a role for Met and its ligand HGF. To study this suggested role, MET and HGF gene copy numbers were determined by droplet digital PCR in tumours from 205 pre-menopausal and 184 post-menopausal patients, both cohorts randomised to receive either chemo- or radiotherapy. MET amplification was found in 8% of the patients in both cohorts and HGF amplification in 7% and 6% of the patients in the pre- and post-menopausal cohort, respectively. Met, phosphorylated Met (pMet), and HGF protein expression was determined by immunohistochemistry in the pre-menopausal cohort. Met, pMet, and HGF was expressed in 33%, 53%, and 49% of the tumours, respectively. MET amplification was associated with increased risk of distant recurrence for patients receiving chemotherapy. For the pre-menopausal patients, expression of cytoplasmic pMet and HGF significantly predicted benefit from radiotherapy in terms of loco-regional recurrence. Similar trends were seen for MET and HGF copy gain. In the post-menopausal cohort, no significant association of benefit from radiotherapy with neither genes nor proteins was found. The present results do not support that inhibition of Met prior to radiotherapy would be favourable for pre-menopausal breast cancer, as previously suggested. PMID:27175600

  11. SF/HGF-c-Met autocrine and paracrine promote metastasis of hepatocellular carcinoma

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    Qian Xie; Kang-Da Liu; Mei-Yu Hu; Kang Zhou

    2001-01-01

    AIM: To explore the role of SF/HGF-Met autocrine and parscrine in metastasis of hepatocellular carcinoma (HCC). METHODS: SF/HGF and c-met transcription and protein expression in HCC were examined by RT-PCR and Western Blot in 4 HCC cell lines, including HepG2, Hep3B,SMMC7721 and MHCC-1, the last cell line had a higher potential of metastasis. Sf/hgf cDNA was transfected by the method of Lipofectin into SMMC7721. SF/HGF and c-met antibody were used to stimulate and block SF/HGF-c-met signal transduction. Cell morphology, mobility, and proliferation were respectively compared by microscopic observation, wound healing assay and cell growth curve. RESULTS: HCC malignancy appeared to be relative to its met-SF/HGF expression. In MHCC-1, c-met expression was much stronger than that in other cell lines with lower potential of metastasis and only SF/HGF autocrine existed in MHCC-1. After sf/hgf cDNA transfection or conditioned medium of MHCC-1 stimulation, SMMC7721 changed into elongated morphology, and the abilities of proliferation ( P < 0.05) and mobility increased. Such bio-activity could he blocked by c-met antibody ( P< 0.05). CONCLUSION: The system of SF/HGF-c-met autocrine and paracrine played an important role in development and metastasis potential of HCC. Inhibition of SF/HGF-c-met signal transduction system may reduce the growth and metastasis of HCC.

  12. Cooperative interaction of MUC1 with the HGF/c-Met pathway during hepatocarcinogenesis

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    Bozkaya Giray

    2012-09-01

    Full Text Available Abstract Background Hepatocyte growth factor (HGF induced c-Met activation is known as the main stimulus for hepatocyte proliferation and is essential for liver development and regeneration. Activation of HGF/c-Met signaling has been correlated with aggressive phenotype and poor prognosis in hepatocellular carcinoma (HCC. MUC1 is a transmembrane mucin, whose over-expression is reported in most cancers. Many of the oncogenic effects of MUC1 are believed to occur through the interaction of MUC1 with signaling molecules. To clarify the role of MUC1 in HGF/c-Met signaling, we determined whether MUC1 and c-Met interact cooperatively and what their role(s is in hepatocarcinogenesis. Results MUC1 and c-Met over-expression levels were determined in highly motile and invasive, mesenchymal-like HCC cell lines, and in serial sections of cirrhotic and HCC tissues, and these levels were compared to those in normal liver tissues. Co-expression of both c-Met and MUC1 was found to be associated with the differentiation status of HCC. We further demonstrated an interaction between c-Met and MUC1 in HCC cells. HGF-induced c-Met phosphorylation decreased this interaction, and down-regulated MUC1 expression. Inhibition of c-Met activation restored HGF-mediated MUC1 down-regulation, and decreased the migratory and invasive abilities of HCC cells via inhibition of β-catenin activation and c-Myc expression. In contrast, siRNA silencing of MUC1 increased HGF-induced c-Met activation and HGF-induced cell motility and invasion. Conclusions These findings indicate that the crosstalk between MUC1 and c-Met in HCC could provide an advantage for invasion to HCC cells through the β-catenin/c-Myc pathway. Thus, MUC1 and c-Met could serve as potential therapeutic targets in HCC.

  13. Research Progress of HGF/c-MET Inhibitor in the Treatment 
of Non-small Cell Lung Cancer

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    Tao JIANG

    2015-04-01

    Full Text Available Molecular targeted therapy has become more and more important in the treatment of non-small cell lung cancer (NSCLC. HGF/c-MET plays the pivotal role in the growth, development and tolerance to epidermal growth factor receptor tyrosine kinase inhibitor of NSCLC. Moreover it has become another heat point in the molecular targeted therapy of NSCLC. c-MET amplification or high expression was deemed to another significant gene modification beyond EGFR and ALK. In the preclinical studies, HGF/c-MET inhibitors have showed the promising anti-tumor effect. Recently, some phase II/III clinical trials have proved that these inhibitors could improve the survival of patients with NSCLC. Hence we performed this review to elaborate the research progress of c-MET inhibitor in the treatment of NSCLC.

  14. Evaluation of c-Met, HGF, and HER-2 expressions in gastric carcinoma and their association with other clinicopathological factors

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    Yıldız Y

    2016-09-01

    Full Text Available Yetkin Yıldız,1 Cenk Sokmensuer,2 Suayib Yalcin1 1Department of Medical Oncology, 2Department of Pathology, Hacettepe University, Ankara, Turkey Background: Met and HER-2 are proto-oncogenes encoding receptor tyrosine kinase c-Met and HER-2, respectively. Hepatocyte growth factor (HGF is a ligand of c-Met. The frequency of c-Met, HGF, and HER-2 expressions in gastric cancer and their association with other clinicopathological factors have not been fully understood. Patients and methods: Patients with stage 1–4 disease were analyzed. Expressions of c-Met, HGF, and HER-2 were examined using immunohistochemistry. Results: A total of 143 patients, 97 males and 46 females, were included. C-Met scores were 3(+ in 31.5%, 2(+ in 27.3%, and 1(+ in 10.5% of the patients. There was no statistically significant difference in age, sex, tumor location, differentiation, Lauren classification, TNM staging, presence of distant metastasis, depth of tumor invasion (T, lymphovascular invasion, and survival between c-Met subgroups. Overall HGF positivity was 20.6%. HER-2 scores were 3(+ in 9.1%, 2(+ in 9.8%, and 1(+ in 16.1% of the patients. HER-2 overexpression was associated with better differentiation, intestinal subtype, and advanced stage. C-Met overexpressions were 84.6% in the HER-2-overexpression-positive group and 56.2% in the HER-2-overexpression-negative group. There were no statistically significant differences in survival between the high c-Met-expression-positive and -negative stage 3 and stage 4 patients and between the HGF-positive and -negative groups. The mean survival was 11.6±6.3 months in the HER-2-overexpression-positive stage 4 group and 11.9±6.8 months in the HER-2-overexpression-negative stage 4 group. There were no statistically significant differences in survival between the two groups. Conclusion: c-Met was not associated with any prognostic factors in gastric cancer. HER-2 was associated with better differentiation, intestinal

  15. Telmisartan prevents angiotensin II-induced endothelial dysfunction in rabbit aorta via activating HGF/Met system and PPARγ pathway.

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    Hu, Ze-Ping; Fang, Xiao-Ling; Qian, Hai-Yan; Fang, Nan; Wang, Bang-Ning; Wang, Yuan

    2014-10-01

    Telmisartan with partial activation of peroxisome proliferator-activated receptor γ (PPARγ) powerfully reduces blood pressure, improves endothelial function and lipid metabolism. Hepatocyte growth factor/mesenchymal-epithelial transition factor (HGF/Met) system in the local vasculature plays a pivotal role in maintaining normal endothelial function. This study is aimed to evaluate whether telmisartan directly prevents angiotensin II (Ang II)-induced endothelial dysfunction (ED) via activating HGF/Met system and/or PPARγ pathway. The isolated aortic rings of rabbits were incubated with Ang II (0.01-1 μM), telmisartan (0.1-10 μM), SU11274 (5 μM) as a specific Met inhibitor, GW9662 (10 μM) as a PPARγ antagonist alone or a combination for 6 h. Ang II obviously inhibited the mRNA and protein expression of HGF, Met and PPARγ, and the accumulative concentration-relaxation of the aortic rings to acetylcholine, among which the inhibitory effect of 1 μM Ang II was most significant. By contrast, telmisartan significantly increased the mRNA and protein expression of HGF, Met, and PPARγ, thus preventing Ang II-induced ED in a dose-dependent pattern. However, SU11274, GW9662 or a combination of both partially abolished the protective effects derived from telmisartan, with the effect of SU11274 exceeding that of GW9662. These results demonstrate that Ang II-induced ED in rabbit aortic rings in vitro can be prevented by telmisartan through selective PPARγ-modulating pathway. Moreover, this study indicates for the first time that activating HGF/Met system in the local vasculature is involved in the protective mechanism of telmisartan. © 2013 Société Française de Pharmacologie et de Thérapeutique. Published by John Wiley & Sons Ltd.

  16. Evaluation of c-Met, HGF, and HER-2 expressions in gastric carcinoma and their association with other clinicopathological factors

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    Yıldız, Yetkin; Sokmensuer, Cenk; Yalcin, Suayib

    2016-01-01

    Background Met and HER-2 are proto-oncogenes encoding receptor tyrosine kinase c-Met and HER-2, respectively. Hepatocyte growth factor (HGF) is a ligand of c-Met. The frequency of c-Met, HGF, and HER-2 expressions in gastric cancer and their association with other clinicopathological factors have not been fully understood. Patients and methods Patients with stage 1–4 disease were analyzed. Expressions of c-Met, HGF, and HER-2 were examined using immunohistochemistry. Results A total of 143 patients, 97 males and 46 females, were included. C-Met scores were 3(+) in 31.5%, 2(+) in 27.3%, and 1(+) in 10.5% of the patients. There was no statistically significant difference in age, sex, tumor location, differentiation, Lauren classification, TNM staging, presence of distant metastasis, depth of tumor invasion (T), lymphovascular invasion, and survival between c-Met subgroups. Overall HGF positivity was 20.6%. HER-2 scores were 3(+) in 9.1%, 2(+) in 9.8%, and 1(+) in 16.1% of the patients. HER-2 overexpression was associated with better differentiation, intestinal subtype, and advanced stage. C-Met overexpressions were 84.6% in the HER-2-overexpression-positive group and 56.2% in the HER-2-overexpression-negative group. There were no statistically significant differences in survival between the high c-Met-expression-positive and -negative stage 3 and stage 4 patients and between the HGF-positive and -negative groups. The mean survival was 11.6±6.3 months in the HER-2-overexpression-positive stage 4 group and 11.9±6.8 months in the HER-2-overexpression-negative stage 4 group. There were no statistically significant differences in survival between the two groups. Conclusion c-Met was not associated with any prognostic factors in gastric cancer. HER-2 was associated with better differentiation, intestinal subtype, advanced stage, and c-Met overexpression. PMID:27703380

  17. Transcriptional gene expression profiles of HGF/SF-met signaling pathway in colorectal carcinoma

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    Xue-Nong Li; Yan-Qing Ding; Guo-Bing Liu

    2003-01-01

    AIM: To explore the transcriptional gene expression profiles of HGF/SF-met signaling pathway in colorectal carcinoma to understand mechanisms of the signaling pathway at so gene level.METHODS: Total RNA was isolated from human colorectal carcinoma cell line LoVo treated with HGF/SF (80 ng/L)for 48 h. Fluorescent probes were prepared from RNA labeled with cy3-dUTP for the control groups and with cy5-dUTP for the HGF/SF-treated groups through reversetranscription. The probes were mixed and hybridized on the microarray at 60 ℃ for 15-20 h, then the microarray was scanned by laser scanner (GenePix 4000B). The intensity of each spot and ratios of Cy5/Cy3 were analyzed and finally the differentially expressed genes were selected by GenePix Pro 3.0 software. 6 differential expression genes (3 up-regulated genes and 3 down-regulated genes) were selected randomly and analyzed by β-actin semiquantitative RT-PCR.RESULTS: The fluorescent intensities of built-in negative control spots were less than 200, and the fluorescent intensities of positive control spots were more than 5000.Of the 4004 human genes analyzed by microarray, 129 genes (holding 3.22 % of the investigated genes) revealed differential expression in HGF/SF-treated groups compared with the control groups, of which 61 genes were up-regulated (holding 1.52 % of the investigated genes) and 68 genes were down-regulated (holding 1.70 % of the investigated genes), which supplied abundant information about target genes of HGF/SF-met signaling.CONCLUSION: HGF/SF-met signaling may up-regulate oncogenes, signal transduction genes, apoptosis-related genes, metastasis related genes, and down-regulate a number of genes. The complexity of HGF/SF-met signaling to control the gene expression is revealed as a whole by the gene chip technology.

  18. Pre-Osteoblasts Stimulate Migration of Breast Cancer Cells via the HGF/MET Pathway.

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    Sonia Vallet

    Full Text Available The occurrence of skeletal metastases in cancer, e.g. breast cancer (BC, deteriorates patient life expectancy and quality-of-life. Current treatment options against tumor-associated bone disease are limited to anti-resorptive therapies and aimed towards palliation. There remains a lack of therapeutic approaches, which reverse or even prevent the development of bone metastases. Recent studies demonstrate that not only osteoclasts (OCs, but also osteoblasts (OBs play a central role in the pathogenesis of skeletal metastases, partly by producing hepatocyte growth factor (HGF, which promotes tumor cell migration and seeding into the bone. OBs consist of a heterogeneous cell pool with respect to their maturation stage and function. Recent studies highlight the critical role of pre-OBs in hematopoiesis. Whether the development of bone metastases can be attributed to a particular OB maturation stage is currently unknown.Pre-OBs were generated from healthy donor (HD-derived bone marrow stromal cells (BMSC as well as the BMSC line KM105 and defined as ALPlow OPNlow RUNX2high OSX high CD166high. Conditioned media (CM of pre-OBs, but not of undifferentiated cells or mature OBs, enhanced migration of metastatic BC cells. Importantly, HGF mRNA was significantly up-regulated in pre-OBs versus mature OBs, and CM of pre-OBs activated the MET signaling pathway. Highlighting a key role for HGF, CM from HGF-negative pre-OBs derived from the BMSC line HS27A did not support migration of BC cells. Genetically (siMET or pharmacologically (INCB28060 targeting MET inhibited both HGF- and pre-OB CM- mediated BC cell migration.Our data demonstrate for the first time a role for pre-OBs in mediating HGF/MET- dependent migration of BC cells and strongly support the clinical evaluation of INCB28060 and other MET inhibitors to limit and/or prevent BC-associated bone metastases.

  19. Loss of HGF/c-Met signaling in pancreatic β-cells leads to incomplete maternal β-cell adaptation and gestational diabetes mellitus.

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    Demirci, Cem; Ernst, Sara; Alvarez-Perez, Juan C; Rosa, Taylor; Valle, Shelley; Shridhar, Varsha; Casinelli, Gabriella P; Alonso, Laura C; Vasavada, Rupangi C; García-Ocana, Adolfo

    2012-05-01

    Hepatocyte growth factor (HGF) is a mitogen and insulinotropic agent for the β-cell. However, whether HGF/c-Met has a role in maternal β-cell adaptation during pregnancy is unknown. To address this issue, we characterized glucose and β-cell homeostasis in pregnant mice lacking c-Met in the pancreas (PancMet KO mice). Circulating HGF and islet c-Met and HGF expression were increased in pregnant mice. Importantly, PancMet KO mice displayed decreased β-cell replication and increased β-cell apoptosis at gestational day (GD)15. The decreased β-cell replication was associated with reductions in islet prolactin receptor levels, STAT5 nuclear localization and forkhead box M1 mRNA, and upregulation of p27. Furthermore, PancMet KO mouse β-cells were more sensitive to dexamethasone-induced cytotoxicity, whereas HGF protected human β-cells against dexamethasone in vitro. These detrimental alterations in β-cell proliferation and death led to incomplete maternal β-cell mass expansion in PancMet KO mice at GD19 and early postpartum periods. The decreased β-cell mass was accompanied by increased blood glucose, decreased plasma insulin, and impaired glucose tolerance. PancMet KO mouse islets failed to upregulate GLUT2 and pancreatic duodenal homeobox-1 mRNA, insulin content, and glucose-stimulated insulin secretion during gestation. These studies indicate that HGF/c-Met signaling is essential for maternal β-cell adaptation during pregnancy and that its absence/attenuation leads to gestational diabetes mellitus.

  20. Signal transduction and downregulation of C-MET in HGF stimulated low and highly metastatic human osteosarcoma cells

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    Husmann, Knut, E-mail: khusmann@research.balgrist.ch [Laboratory for Orthopedic Research, Department of Orthopedics, Balgrist University Hospital, University of Zurich, Zurich (Switzerland); Ducommun, Pascal [Laboratory for Orthopedic Research, Department of Orthopedics, Balgrist University Hospital, University of Zurich, Zurich (Switzerland); Division of Plastic Surgery and Hand Surgery, Department of Surgery, University Hospital Zurich, Zurich (Switzerland); Sabile, Adam A.; Pedersen, Else-Marie; Born, Walter; Fuchs, Bruno [Laboratory for Orthopedic Research, Department of Orthopedics, Balgrist University Hospital, University of Zurich, Zurich (Switzerland)

    2015-09-04

    The poor outcome of osteosarcoma (OS), particularly in patients with metastatic disease and a five-year survival rate of only 20%, asks for more effective therapeutic strategies targeting malignancy-promoting mechanisms. Dysregulation of C-MET, its ligand hepatocyte growth factor (HGF) and the fusion oncogene product TPR-MET, first identified in human MNNG-HOS OS cells, have been described as cancer-causing factors in human cancers. Here, the expression of these molecules at the mRNA and the protein level and of HGF-stimulated signaling and downregulation of C-MET was compared in the parental low metastatic HOS and MG63 cell lines and the respective highly metastatic MNNG-HOS and 143B and the MG63-M6 and MG63-M8 sublines. Interestingly, expression of TPR-MET was only observed in MNNG-HOS cells. HGF stimulated the phosphorylation of Akt and Erk1/2 in all cell lines investigated, but phospho-Stat3 remained at basal levels. Downregulation of HGF-stimulated Akt and Erk1/2 phosphorylation was much faster in the HGF expressing MG63-M8 cells than in HOS cells. Degradation of HGF-activated C-MET occurred predominantly through the proteasomal and to a lesser extent the lysosomal pathway in the cell lines investigated. Thus, HGF-stimulated Akt and Erk1/2 signaling as well as proteasomal degradation of HGF activated C-MET are potential therapeutic targets in OS. - Highlights: • Expression of TPR-MET was only observed in MNNG-HOS cells. • HGF stimulated the phosphorylation of Akt and Erk1/2 but not of Stat3 in osteosarcoma cell lines. • Degradation of HGF-activated C-MET occurred predominantly through the proteasomal pathway.

  1. Targeting HGF/c-MET induces cell cycle arrest, DNA damage, and apoptosis for primary effusion lymphoma.

    Science.gov (United States)

    Dai, Lu; Trillo-Tinoco, Jimena; Cao, Yueyu; Bonstaff, Karlie; Doyle, Lisa; Del Valle, Luis; Whitby, Denise; Parsons, Chris; Reiss, Krzysztof; Zabaleta, Jovanny; Qin, Zhiqiang

    2015-12-24

    Kaposi sarcoma-associated herpesvirus (KSHV) is a principal causative agent of primary effusion lymphoma (PEL) with a poor prognosis in immunocompromised patients. However, it still lacks effective treatment which urgently requires the identification of novel therapeutic targets for PEL. Here, we report that the hepatocyte growth factor (HGF)/c-MET pathway is highly activated by KSHV in vitro and in vivo. The selective c-MET inhibitor, PF-2341066, can induce PEL apoptosis through cell cycle arrest and DNA damage, and suppress tumor progression in a xenograft murine model. By using microarray analysis, we identify many novel genes that are potentially controlled by HGF/c-MET within PEL cells. One of the downstream candidates, ribonucleoside-diphosphate reductase subunit M2 (RRM2), also displays the promising therapeutic value for PEL treatment. Our findings provide the framework for development of HGF/c-MET-focused therapy and implementation of clinical trials for PEL patients.

  2. Weight loss reversed obesity-induced HGF/c-Met pathway and basal-like breast cancer progression

    Directory of Open Access Journals (Sweden)

    Sneha eSundaram

    2014-07-01

    Full Text Available Epidemiologic studies demonstrate that obesity is associated with an aggressive subtype of breast cancer called basal-like breast cancer (BBC. Using the C3(1-TAg murine model of BBC, we previously demonstrated that mice displayed an early onset of tumors when fed obesogenic diets in the adult window of susceptibility. Obesity was also shown to elevate mammary gland expression and activation of hepatocyte growth factor (HGF/c-Met compared to lean controls, a pro-tumorigenic pathway associated with BBC in patients. Epidemiologic studies estimate that weight loss could prevent a large proportion of BBC. We sought to investigate whether weight loss in adulthood prior to tumor onset would protect mice from accelerated tumorigenesis observed in obese mice. Using a life-long model of obesity, C3(1-TAg mice were weaned onto and maintained on an obesogenic high fat diet. Obese mice displayed significant elevations in tumor progression, but not latency or burden. Tumor progression was significantly reversed when obese mice were induced to lose weight by switching to a control low fat diet prior to tumor onset compared to mice maintained on obesogenic diet. It is likely that other factors regulated tumor progression, hence we investigated the HGF/c-Met pathway known to regulate tumorigenesis. Importantly, HGF/c-Met expression in normal mammary glands and c-Met in tumors was elevated with obesity and was significantly reversed with weight loss. Changes in tumor growth could not be explained by measures of HGF action including phospho-AKT or phospho-S6. Other mediators associated with oncogenesis such as hyperinsulinemia and a high leptin/adiponectin ratio were elevated by obesity and reduced with weight loss. In sum, weight loss significantly blunted the obesity-responsive pro-tumorigenic HGF/c-Met pathway and improved several metabolic risk factors associated with BBC, which together may have contributed to the dramatic reversal of obesity-driven tumor

  3. TGF-β Negatively Regulates CXCL1 Chemokine Expression in Mammary Fibroblasts through Enhancement of Smad2/3 and Suppression of HGF/c-Met Signaling Mechanisms.

    Directory of Open Access Journals (Sweden)

    Wei Bin Fang

    Full Text Available Fibroblasts are major cellular components of the breast cancer stroma, and influence the growth, survival and invasion of epithelial cells. Compared to normal tissue fibroblasts, carcinoma associated fibroblasts (CAFs show increased expression of numerous soluble factors including growth factors and cytokines. However, the mechanisms regulating expression of these factors remain poorly understood. Recent studies have shown that breast CAFs overexpress the chemokine CXCL1, a key regulator of tumor invasion and chemo-resistance. Increased expression of CXCL1 in CAFs correlated with poor patient prognosis, and was associated with decreased expression of TGF-β signaling components. The goal of these studies was to understand the role of TGF-β in regulating CXCL1 expression in CAFs, using cell culture and biochemical approaches. We found that TGF-β treatment decreased CXCL1 expression in CAFs, through Smad2/3 dependent mechanisms. Chromatin immunoprecipitation and site-directed mutagenesis assays revealed two new binding sites in the CXCL1 promoter important for Smad2/3 modulation of CXCL1 expression. Smad2/3 proteins also negatively regulated expression of Hepatocyte Growth Factor (HGF, which was found to positively regulate CXCL1 expression in CAFs through c-Met receptor dependent mechanisms. HGF/c-Met signaling in CAFs was required for activity of NF-κB, a transcriptional activator of CXCL1 expression. These studies indicate that TGF-β negatively regulates CXCL1 expression in CAFs through Smad2/3 binding to the promoter, and through suppression of HGF/c-Met autocrine signaling. These studies reveal novel insight into how TGF-β and HGF, key tumor promoting factors modulate CXCL1 chemokine expression in CAFs.

  4. Bufalin Reverses HGF-Induced Resistance to EGFR-TKIs in EGFR Mutant Lung Cancer Cells via Blockage of Met/PI3k/Akt Pathway and Induction of Apoptosis

    Directory of Open Access Journals (Sweden)

    Xiao-Hong Kang

    2013-01-01

    Full Text Available The epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs, such as gefitinib and erlotinib, have shown promising therapeutic efficacy in nonsmall cell lung cancer (NSCLC patients harboring epidermal growth factor receptor- (EGFR- activating mutation. However, the inevitable recurrence resulting from acquired resistance has limited the clinical improvement in therapy outcomes. Many studies demonstrate that hepatocyte growth factor- (HGF- Met axis plays an important role in tumor progression and drug sensitivity. HGF may induce resistance to EGFR-TKIs in EGFR mutant lung cancer cells by Met/PI3K/Akt signaling. The purpose of this study was to determine whether bufalin, a major bioactive component of Venenum Bufonis, could reverse HGF-induced resistance to reversible and irreversible EGFR-TKIs in mutant lung cancer cells PC-9, HCC827, and H1975. Our studies showed that bufalin could reverse resistance to reversible and irreversible EGFR-TKIs induced by exogenous HGF in EGFR mutant lung cancer cells by inhibiting the Met/PI3K/Akt pathway and inducing death signaling. These results suggested that bufalin might have a potential to overcome HGF-induced resistance to molecular-targeted drugs for lung cancer.

  5. Correlations of microvascular blood flow of contrast-enhanced ultrasound and HGF/c-Met signaling pathway with clinicopathological features and prognosis of patients with hepatocellular carcinoma

    Science.gov (United States)

    Zhuang, Peng-Hui; Xu, Lei; Gao, Lu; Lu, Wei; Ruan, Li-Tao; Yang, Jin

    2017-01-01

    The study is designed to explore the correlations of microvascular blood flow of contrast-enhanced ultrasound (CEUS) and hepatocyte growth factor (HGF)/c-Met signaling pathway with clinicopathological features and prognosis of patients with hepatocellular carcinoma (HCC). One hundred and eighteen patients pathologically diagnosed as primary HCC were selected. All HCC patients underwent CEUS examination before operation. HCC tissues and adjacent normal tissue specimens were obtained to detect the protein rates of HGF and c-Met expressions by immunohistochemistry. The mRNA expressions of HGF and c-Met were detected by quantitative real-time polymerase chase reaction assay. The microvessel density (MVD) was tested by CD34 immunohistochemistry. Compared with liver parenchyma, the HCC lesions had higher MVD, preoperative peak intensity (PI), area under the curve (AUC), lower preoperative time to peak (TTP), and washout time (WOT). Compared with adjacent normal tissues, the protein and mRNA expressions of HGF were reduced in HCC tissues, but the protein and mRNA expressions of c-Met and MVD were increased. The protein expressions of HGF and c-Met exhibited evident correlations with TNM stage, tumor size, vascular invasion, liver cirrhosis, and hepatitis B virus and hepatitis C virus infection of HCC patients. The tumor size and number, vascular invasion, the protein expressions of HGF and c-Met, and MVD were associated with the TTP, PI, WOT, and AUC of CEUS in HCC patients. The protein expressions of HGF and c-Met, MVD and preoperative PI revealed negative associations with the prognosis of HCC patients. In conclusion, quantitative parameters of CEUS and HGF/c-Met signaling pathway-related proteins may be helpful for early diagnosis and prognosis prediction of HCC patients.

  6. Blood vessel endothelium-directed tumor cell streaming in breast tumors requires the HGF/C-Met signaling pathway.

    Science.gov (United States)

    Leung, E; Xue, A; Wang, Y; Rougerie, P; Sharma, V P; Eddy, R; Cox, D; Condeelis, J

    2016-11-28

    During metastasis to distant sites, tumor cells migrate to blood vessels. In vivo, breast tumor cells utilize a specialized mode of migration known as streaming, where a linear assembly of tumor cells migrate directionally towards blood vessels on fibronectin-collagen I-containing extracellular matrix (ECM) fibers in response to chemotactic signals. We have successfully reconstructed tumor cell streaming in vitro by co-plating tumors cells, macrophages and endothelial cells on 2.5 μm thick ECM-coated micro-patterned substrates. We found that tumor cells and macrophages, when plated together on the micro-patterned substrates, do not demonstrate sustained directional migration in only one direction (sustained directionality) but show random bi-directional walking. Sustained directionality of tumor cells as seen in vivo was established in vitro when beads coated with human umbilical vein endothelial cells were placed at one end of the micro-patterned 'ECM fibers' within the assay. We demonstrated that these endothelial cells supply the hepatocyte growth factor (HGF) required for the chemotactic gradient responsible for sustained directionality. Using this in vitro reconstituted streaming system, we found that directional streaming is dependent on, and most effectively blocked, by inhibiting the HGF/C-Met signaling pathway between endothelial cells and tumor cells. Key observations made with the in vitro reconstituted system implicating C-Met signaling were confirmed in vivo in mammary tumors using the in vivo invasion assay and intravital multiphoton imaging of tumor cell streaming. These results establish HGF/C-Met as a central organizing signal in blood vessel-directed tumor cell migration in vivo and highlight a promising role for C-Met inhibitors in blocking tumor cell streaming and metastasis in vivo, and for use in human trials.Oncogene advance online publication, 28 November 2016; doi:10.1038/onc.2016.421.

  7. Agonist antibodies activating the Met receptor protect cardiomyoblasts from cobalt chloride-induced apoptosis and autophagy

    Science.gov (United States)

    Gallo, S; Gatti, S; Sala, V; Albano, R; Costelli, P; Casanova, E; Comoglio, P M; Crepaldi, T

    2014-01-01

    Met, the tyrosine kinase receptor for hepatocyte growth factor (HGF), mainly activates prosurvival pathways, including protection from apoptosis. In this work, we investigated the cardioprotective mechanisms of Met activation by agonist monoclonal antibodies (mAbs). Cobalt chloride (CoCl2), a chemical mimetic of hypoxia, was used to induce cardiac damage in H9c2 cardiomyoblasts, which resulted in reduction of cell viability by (i) caspase-dependent apoptosis and (ii) – surprisingly – autophagy. Blocking either apoptosis with the caspase inhibitor benzyloxycarbonyl-VAD-fluoromethylketone or autophagosome formation with 3-methyladenine prevented loss of cell viability, which suggests that both processes contribute to cardiomyoblast injury. Concomitant treatment with Met-activating antibodies or HGF prevented apoptosis and autophagy. Pro-autophagic Redd1, Bnip3 and phospho-AMPK proteins, which are known to promote autophagy through inactivation of the mTOR pathway, were induced by CoCl2. Mechanistically, Met agonist antibodies or HGF prevented the inhibition of mTOR and reduced the flux of autophagosome formation. Accordingly, their anti-autophagic function was completely blunted by Temsirolimus, a specific mTOR inhibitor. Targeted Met activation was successful also in the setting of low oxygen conditions, in which Met agonist antibodies or HGF demonstrated anti-apoptotic and anti-autophagic effects. Activation of the Met pathway is thus a promising novel therapeutic tool for ischaemic injury. PMID:24743740

  8. Obesity-mediated regulation of HGF/c-Met is associated with reduced basal-like breast cancer latency in parous mice.

    Directory of Open Access Journals (Sweden)

    Sneha Sundaram

    Full Text Available It is widely thought that pregnancy reduces breast cancer risk, but this lacks consideration of breast cancer subtypes. While a full term pregnancy reduces risk for estrogen receptor positive (ER+ and luminal breast cancers, parity is associated with increased risk of basal-like breast cancer (BBC subtype. Basal-like subtypes represent less than 10% of breast cancers and are highly aggressive, affecting primarily young, African American women. Our previous work demonstrated that high fat diet-induced obesity in nulliparous mice significantly blunted latency in C3(1-TAg mice, a model of BBC, potentially through the hepatocyte growth factor (HGF/c-Met oncogenic pathway. Experimental studies have examined parity and obesity individually, but to date, the joint effects of parity and obesity have not been studied. We investigated the role of obesity in parous mice on BBC. Parity alone dramatically blunted tumor latency compared to nulliparous controls with no effects on tumor number or growth, while obesity had only a minor role in further reducing latency. Obesity-associated metabolic mediators and hormones such as insulin, estrogen, and progesterone were not significantly regulated by obesity. Plasma IL-6 was also significantly elevated by obesity in parous mice. We have previously reported a potential role for stromal-derived hepatocyte growth factor (HGF via its cognate receptor c-Met in the etiology of obesity-induced BBC tumor onset and in both human and murine primary coculture models of BBC-aggressiveness. Obesity-associated c-Met concentrations were 2.5-fold greater in normal mammary glands of parous mice. Taken together, our studies demonstrate that, parity in C3(1-TAg mice dramatically reduced BBC latency compared to nulliparous mice. In parous mice, c-Met is regulated by obesity in unaffected mammary gland and is associated with tumor onset. C3(1-TAg mice recapitulate epidemiologic findings such that parity drives increased BBC risk and

  9. Obesity-Mediated Regulation of HGF/c-Met Is Associated with Reduced Basal-Like Breast Cancer Latency in Parous Mice

    Science.gov (United States)

    Sundaram, Sneha; Freemerman, Alex J.; Galanko, Joseph A.; McNaughton, Kirk K.; Bendt, Katharine M.; Darr, David B.; Troester, Melissa A.; Makowski, Liza

    2014-01-01

    It is widely thought that pregnancy reduces breast cancer risk, but this lacks consideration of breast cancer subtypes. While a full term pregnancy reduces risk for estrogen receptor positive (ER+) and luminal breast cancers, parity is associated with increased risk of basal-like breast cancer (BBC) subtype. Basal-like subtypes represent less than 10% of breast cancers and are highly aggressive, affecting primarily young, African American women. Our previous work demonstrated that high fat diet-induced obesity in nulliparous mice significantly blunted latency in C3(1)-TAg mice, a model of BBC, potentially through the hepatocyte growth factor (HGF)/c-Met oncogenic pathway. Experimental studies have examined parity and obesity individually, but to date, the joint effects of parity and obesity have not been studied. We investigated the role of obesity in parous mice on BBC. Parity alone dramatically blunted tumor latency compared to nulliparous controls with no effects on tumor number or growth, while obesity had only a minor role in further reducing latency. Obesity-associated metabolic mediators and hormones such as insulin, estrogen, and progesterone were not significantly regulated by obesity. Plasma IL-6 was also significantly elevated by obesity in parous mice. We have previously reported a potential role for stromal-derived hepatocyte growth factor (HGF) via its cognate receptor c-Met in the etiology of obesity-induced BBC tumor onset and in both human and murine primary coculture models of BBC-aggressiveness. Obesity-associated c-Met concentrations were 2.5-fold greater in normal mammary glands of parous mice. Taken together, our studies demonstrate that, parity in C3(1)-TAg mice dramatically reduced BBC latency compared to nulliparous mice. In parous mice, c-Met is regulated by obesity in unaffected mammary gland and is associated with tumor onset. C3(1)-TAg mice recapitulate epidemiologic findings such that parity drives increased BBC risk and potential

  10. Obesity-mediated regulation of HGF/c-Met is associated with reduced basal-like breast cancer latency in parous mice.

    Science.gov (United States)

    Sundaram, Sneha; Freemerman, Alex J; Galanko, Joseph A; McNaughton, Kirk K; Bendt, Katharine M; Darr, David B; Troester, Melissa A; Makowski, Liza

    2014-01-01

    It is widely thought that pregnancy reduces breast cancer risk, but this lacks consideration of breast cancer subtypes. While a full term pregnancy reduces risk for estrogen receptor positive (ER+) and luminal breast cancers, parity is associated with increased risk of basal-like breast cancer (BBC) subtype. Basal-like subtypes represent less than 10% of breast cancers and are highly aggressive, affecting primarily young, African American women. Our previous work demonstrated that high fat diet-induced obesity in nulliparous mice significantly blunted latency in C3(1)-TAg mice, a model of BBC, potentially through the hepatocyte growth factor (HGF)/c-Met oncogenic pathway. Experimental studies have examined parity and obesity individually, but to date, the joint effects of parity and obesity have not been studied. We investigated the role of obesity in parous mice on BBC. Parity alone dramatically blunted tumor latency compared to nulliparous controls with no effects on tumor number or growth, while obesity had only a minor role in further reducing latency. Obesity-associated metabolic mediators and hormones such as insulin, estrogen, and progesterone were not significantly regulated by obesity. Plasma IL-6 was also significantly elevated by obesity in parous mice. We have previously reported a potential role for stromal-derived hepatocyte growth factor (HGF) via its cognate receptor c-Met in the etiology of obesity-induced BBC tumor onset and in both human and murine primary coculture models of BBC-aggressiveness. Obesity-associated c-Met concentrations were 2.5-fold greater in normal mammary glands of parous mice. Taken together, our studies demonstrate that, parity in C3(1)-TAg mice dramatically reduced BBC latency compared to nulliparous mice. In parous mice, c-Met is regulated by obesity in unaffected mammary gland and is associated with tumor onset. C3(1)-TAg mice recapitulate epidemiologic findings such that parity drives increased BBC risk and potential

  11. Expression of hepatocyte growth factor and the proto-oncogenic receptor c-Met in canine osteosarcoma

    NARCIS (Netherlands)

    Fieten, H|info:eu-repo/dai/nl/314112596; Spee, B|info:eu-repo/dai/nl/304830925; Ijzer, J|info:eu-repo/dai/nl/304839663; Kik, M J|info:eu-repo/dai/nl/080432565; Penning, L C|info:eu-repo/dai/nl/110369181; Kirpensteijn, J|info:eu-repo/dai/nl/189846992

    Hepatocyte growth factor (HGF) and the proto-oncogenic receptor c-Met are implicated in growth, invasion, and metastasis in human cancer. Little information is available on the expression and role of both gene products in canine osteosarcoma. We hypothesized that the expression of c-Met is

  12. c-MET receptor tyrosine kinase as a molecular target in advanced hepatocellular carcinoma

    Directory of Open Access Journals (Sweden)

    Granito A

    2015-04-01

    Full Text Available Alessandro Granito,1 Elena Guidetti,1 Laura Gramantieri2,3 1Dipartimento di Scienze Mediche e Chirurgiche Università di Bologna, Bologna, Italy; 2Dipartimento dell'Apparato Digerente, Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy; 3Centro di Ricerca Biomedica Applicata (CRBA, Azienda Ospedaliero-Universitaria Policlinico S Orsola-Malpighi e Università di Bologna, Bologna, Italy Abstract: c-MET is the membrane receptor for hepatocyte growth factor (HGF, also known as scatter factor or tumor cytotoxic factor, a mitogenic growth factor for hepatocytes. HGF is mainly produced by cells of mesenchymal origin and it mainly acts on neighboring epidermal and endothelial cells, regulating epithelial growth and morphogenesis. HGF/MET signaling has been identified among the drivers of tumorigenesis in human cancers. As such, c-MET is a recognized druggable target, and against it, targeted agents are currently under clinical investigation. c-MET overexpression is a common event in a wide range of human malignancies, including gastric, lung, breast, ovary, colon, kidney, thyroid, and liver carcinomas. Despite c-MET overexpression being reported by a large majority of studies, no evidence for a c-MET oncogenic addiction exists in hepatocellular carcinoma (HCC. In particular, c-MET amplification is a rare event, accounting for 4%–5% of cases while no mutation has been identified in c-MET oncogene in HCC. Thus, the selection of patient subgroups more likely to benefit from c-MET inhibition is challenging. Notwithstanding, c-MET overexpression was reported to be associated with increased metastatic potential and poor prognosis in patients with HCC, providing a rationale for its therapeutic inhibition. Here we summarize the role of activated HGF/MET signaling in HCC, its prognostic relevance, and the implications for therapeutic approaches in HCC. Keywords: hepatocellular carcinoma, c-MET, clinical trials

  13. HGF/C-Met在舌部鳞状细胞癌的表达及其临床意义%Expression of Hepatocyte Growth Factor (HGF) and c-Met in Squamous Cell Carcinoma of the Oral Tongue(SCCOT)

    Institute of Scientific and Technical Information of China (English)

    陈仲伟; 徐冬贵; 朱李军; 王启朋; 冯航; 江穗

    2013-01-01

    目的:探讨肝细胞生长因子及其受体C-Met蛋白在舌鳞癌中的表达与其临床病理特征之间的关系.方法:通过免疫组化法检测10例正常舌组织、14例舌癌前病变及63例舌鳞癌中肝细胞生长因子、C-Met的表达,数据通过SPSS13.0统计软件非参数秩和检验统计.结果:肝细胞生长因子和C-Met在舌癌、舌癌前病变及正常舌组织的阳性表达率分别为84.1%、57.1%、40.0%和76.2%、35.7%、20.0%,其表达差异均具有统计学意义(P<0.05).在中、低分化组(90.3%)及有淋巴结转移组(100%)舌鳞癌中肝细胞生长因子的阳性表达率显著高于高分化组(78.1%)及无转移淋巴结组(76.7%);在Ⅲ、Ⅳ期(82.1%)及有淋巴结转移组(85.0%)的舌鳞癌中C-Met阳性表达率显著高于Ⅰ、Ⅱ期(71.4%)及无转移淋巴结组(72.1%),表达差异均具有统计学意义(p<0.05);63例舌癌组织切片中46例HGF及C-Met都有阳性表达,其在舌鳞状细胞癌中的表达显著正相关(P<0.01).结论:过度表达的HGF/C-Met可作为判断舌鳞状细胞癌生物学行为、恶性潜能和预测淋巴结转移趋势的参考指标.%Objective: To evaluate the relationship of the expression of hepatocyte growth factor (HGF)/c-Met and clinical and pathologic characteristics of patients with squamous cell carcinoma of the oral tongue(SCCOT). Methods; Tumors from 63 patients with SCCOT, precancerous lesions of tongue from 14 patients and normal tissues of the tongue from 10 patients were evaluated for the expression of HGF and c -Met by immunohistochemis-try. Results: The positive rates of HGF and c-Met immunostaining in SCCOT were 84. 1% and 76. 2% respectively, which was significantly higher than that of the precancerous and normal groups (57. 1 % ,35. 7% and 40. 0% ,20. 0%). The HGF/c-Met staining was significantly correlated with lymph node metastasis(P<0. 05), tumor classification P<0. 05) and TNM pathologic stages. There was a

  14. Curcumin inhibited HGF-induced EMT and angiogenesis through regulating c-Met dependent PI3K/Akt/mTOR signaling pathways in lung cancer

    Directory of Open Access Journals (Sweden)

    Demin Jiao

    2016-01-01

    Full Text Available The epithelial-mesenchymal transition (EMT and angiogenesis have emerged as two pivotal events in cancer progression. Curcumin has been extensively studied in preclinical models and clinical trials of cancer prevention due to its favorable toxicity profile. However, the possible involvement of curcumin in the EMT and angiogenesis in lung cancer remains unclear. This study found that curcumin inhibited hepatocyte growth factor (HGF-induced migration and EMT-related morphological changes in A549 and PC-9 cells. Moreover, pretreatment with curcumin blocked HGF-induced c-Met phosphorylation and downstream activation of Akt, mTOR, and S6. These effects mimicked that of c-Met inhibitor SU11274 or PI3 kinase inhibitor LY294002 or mTOR inhibitor rapamycin treatment. c-Met gene overexpression analysis further demonstrated that curcumin suppressed lung cancer cell EMT by inhibiting c-Met/Akt/mTOR signaling pathways. In human umbilical vein endothelial cells (HUVECs, we found that curcumin also significantly inhibited PI3K/Akt/mTOR signaling and induced apoptosis and reduced migration and tube formation of HGF-treated HUVEC. Finally, in the experimental mouse model, we showed that curcumin inhibited HGF-stimulated tumor growth and induced an increase in E-cadherin expression and a decrease in vimentin, CD34, and vascular endothelial growth factor (VEGF expression. Collectively, these findings indicated that curcumin could inhibit HGF-promoted EMT and angiogenesis by targeting c-Met and blocking PI3K/Akt/mTOR pathways.

  15. HGF, MET, and matrix-related proteases in hepatocellular carcinoma, fibrolamellar variant, cirrhotic and normal liver.

    Science.gov (United States)

    Schoedel, Karen E; Tyner, Valerie Zajac; Kim, Tae-Hyoung; Michalopoulos, George K; Mars, Wendy M

    2003-01-01

    Fibrolamellar variant is an uncommon subcategory of hepatocellular carcinoma with a better prognostic outcome. Proteinases and growth factors that are involved in the remodeling of extracellular matrix may influence the behavior of cancers. To determine whether these factors contribute to the distinct etiologies of fibrolamellar hepatocellular carcinoma and traditional hepatocellular carcinoma, we assayed hepatocyte growth factor, the hepatocyte growth factor receptor, and two hepatocyte growth factor activators, hepatocyte growth factor activator and urokinase-type plasminogen activator, in hepatocellular carcinoma, fibrolamellar hepatocellular carcinoma, cirrhotic liver and normal liver. In addition, we examined the urokinase-type plasminogen activator receptor, the type 1 plasminogen activator inhibitor, plasmin, fibrinogen, and the type IV matrix metalloproteinases. Eighteen hepatocellular carcinomas and 11 fibrolamellar hepatocellular carcinomas were obtained as paraffin embedded sections from the University of Pittsburgh Department of Pathology. Frozen tissues from a subset of cases (9 hepatocellular carcinomas, 4 fibrolamellar hepatocellular carcinomas, 12 cirrhotic livers and 2 normal livers) were also available for analysis. Antibodies against urokinase-type plasminogen activator, urokinase-type plasminogen activator receptor, hepatocyte growth factor and hepatocyte growth factor receptor were used to analyze immunoperoxidase stained slides from the paraffin blocks. Western blot analyses using antibodies against hepatocyte growth factor, hepatocyte growth factor receptor, phosphotyrosine, hepatocyte growth factor activator, urokinase-type plasminogen activator receptor, urokinase-type plasminogen activator, plasminogen activator inhibitor-1, fibrinogen and plasmin were performed on membrane-enriched fractions from the frozen tissue, as was collagen zymography for matrix metalloproteinase-2 and matrix metalloproteinase-9. The most notable findings are as

  16. HGF Modulates Actin Cytoskeleton Remodeling and Contraction in Testicular Myoid Cells

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    Angela Catizone

    2015-01-01

    Full Text Available The presence of the HGF/Met system in the testicular myoid cells was first discovered by our group. However, the physiological role of this pathway remains poorly understood. We previously reported that HGF increases uPA secretion and TGF-β activation in cultured tubular fragments and that HGF is maximally expressed at Stages VII–VIII of the seminiferous epithelium cycle, when myoid cell contraction occurs. It is well known that the HGF/Met pathway is involved in cytoskeletal remodeling; moreover, the interaction of uPA with its receptor, uPAR, as well as the activation of TGF-β have been reported to be related to the actin cytoskeleton contractility of smooth muscle cells. Herein, we report that HGF induces actin cytoskeleton remodeling in vitro in isolated myoid cells and myoid cell contraction in cultured seminiferous tubules. To better understand these phenomena, we evaluated: (1 the regulation of the uPA machinery in isolated myoid cells after HGF administration; and (2 the effect of uPA or Met inhibition on HGF-treated tubular fragments. Because uPA activates latent TGF-β, the secretion of this factor was also evaluated. We found that both uPA and TGF-β activation increase after HGF administration. In testicular tubular fragments, HGF-induced TGF-β activation and myoid cell contraction are abrogated by uPA or Met inhibitor administration.

  17. Expression of hepatocyte growth factor and its receptor c-Met in lens-induced myopia in guinea pigs

    Institute of Scientific and Technical Information of China (English)

    LI Xiu-juan; YANG Xiao-peng; WAN Guang-ming; WANG Yu-ying; ZHANG Jin-song

    2013-01-01

    Background Myopia is a common disorder and the incidence has increased yearly,but its pathogenesis remains unclear.The aim of this study was to investigate the possible role of hepatocyte growth factor (HGF) and its receptor c-Met in the development of lens-induced myopia in guinea pigs.Methods Sixty one-week-old guinea pigs were chosen.The right eyes were treated with-10.0 diopters (D) lenses as the lens-induced myopia group; the left eyes remained untreated as the control group.Six weeks later,refractive status and axial length were determined by streak retinoscopy and A-scan ultrasonography,respectively.The guinea pigs were killed and both eyes collected.Morphological changes were observed by hematoxylin and eosin staining.The expression levels of HGF,c-Met,and matrix metalloproteinase 2 (MMP-2) mRNA and protein in the posterior sclera were analyzed by RT-PCR and Western blotting,respectively.Results The lens-induced myopia group became myopic with a significant increase in axial length and a significant decrease in refraction.Compared with the control group,the posterior retina and sclera were thinner in the lens-induced myopia group.The expression levels of HGF and MMP-2 mRNA and protein and of phosphorylated c-Met protein were significantly higher in the posterior sclera of the lens-induced myopia group than in the control group (all P <0.05).In the lens-induced myopia group,the expression level of MMP-2 in the posterior sclera positively correlated with the expression level of HGF (r=0.902,P <0.05) and phosphorylated c-Met (r=0.885,P <0.05).Conclusion HGF/c-Met might play a role in the development of lens-induced myopia in guinea pigs by upregulating the expression of MMP-2.

  18. A novel antagonist anti-cMet antibody with antitumor activities targeting both ligand-dependent and ligand-independent c-Met receptors.

    Science.gov (United States)

    Gonzalez, Alexandra; Broussas, Matthieu; Beau-Larvor, Charlotte; Haeuw, Jean-François; Boute, Nicolas; Robert, Alain; Champion, Thierry; Beck, Alain; Bailly, Christian; Corvaïa, Nathalie; Goetsch, Liliane

    2016-10-15

    c-Met is a prototypic member of a sub-family of RTKs. Inappropriate c-Met activation plays a crucial role in tumor formation, proliferation and metastasis. Using a key c-Met dimerization assay, a set of 12 murine whole IgG1 monoclonal antibodies was selected and a lead candidate, m224G11, was humanized by CDR-grafting and engineered to generate a divalent full antagonist humanized IgG1 antibody, hz224G11. Neither m224G11 nor hz224G11 bind to the murine c-Met receptor. Their antitumor activity was investigated in vitro in a set of experiments consistent with the reported pleiotropic effects mediated by c-Met and, in vivo, using several human tumor xenograft models. Both m224G11 and hz224G11 exhibited nanomolar affinities for the receptor and inhibited HGF binding, c-Met phosphorylation, and receptor dimerization in a similar fashion, resulting in a profound inhibition of all c-Met functions in vitro. These effects were presumably responsible for the inhibition of c-Met's major functions including cell proliferation, migration, invasion scattering, morphogenesis and angiogenesis. In addition to these in vitro properties, hz224G11 dramatically inhibits the growth of autocrine, partially autophosphorylated and c-Met amplified cell lines in vivo. Pharmacological studies performed on Hs746T gastric cancer xenografts demonstrate that hz224G11 strongly downregulates c-Met expression and phosphorylation. It also decreases the tumor mitotic index (Ki67) and induces apoptosis. Taken together, the in vitro and in vivo data suggest that hz224G11 is a promising candidate for the treatment of tumors. This antibody, now known as ABT-700 and currently in Phase I clinical trials, may provide a novel therapeutic approach to c-Met-expressing cancers.

  19. ExpressionofEzrin,HGF,C-metinpancreatic cancerandnon-cancerouspancreatic tissuesofrats

    Institute of Scientific and Technical Information of China (English)

    Xing-Guo Tan; Zhu-Lin Yang

    2010-01-01

    BACKGROUND: Recent studies have conifrmed that the expression of Ezrin, hepatocyte growth factor (HGF) and its receptor (C-met) is related to the genesis, progress, invasion and metastasis of some malignant tumors. Researches have also found that the biological function of Ezrin is closely related to HGF/C-met in malignant tumors. However, there is no report on the expression levels of Ezrin, HGF and C-met in rat pancreatic cancer induced by dimethylbenzanthracene (DMBA). This study aimed to detect the expression of Ezrin, HGF and C-met in rat pancreatic cancer and non-cancerous pancreatic tissues, and assess its effect in cancer induction by DMBA. METHODS: Ninety Sprague-Dawley rats were divided into 3 groups randomly: 40 in a pancreatic cancer model group (group A), 40 in a trichostatin A (TSA) intervention group (group B), and 10 in a control group (group C). DMBA was directly implanted into the parenchyma of rat pancreas in group A+group B. The rats of group B were treated with 1 ml of TSA saline solution (1μg/ml) via intraperitoneal injection weekly. The carcinogenesis of rats executed within 3-5 months in groups A and B was observed by macrograph and microscopy. Meanwhile, the rats in group C were executed within 5 months. The EnVisionTM immunohistochemistry for detecting the expression levels of Ezrin, HGF and C-met was used in parafifn-embedded sections of the pancreatic specimens. RESULTS: The incidence of pancreatic cancer in group A was 48.6%and in group B 33.3%. The maximal diameter of tumor mass was signiifcantly larger in group A than that in group B (P in the pancreas of group C and other main organs of groups A and B. The positive rates of Ezrin, HGF and C-met were signiifcantly higher in ductal adenocarcinoma than in non-cancerous pancreatic tissues of groups A and B (P0.05). The positive rates of Ezrin, HGF and C-met in non-cancerous pancreatic tissues proved mild to severe atypical hyperplasia of the ductal epithelia. The pancreas of group

  20. [Thirty years of Met receptor research: from the discovery of an oncogene to the development of targeted therapies].

    Science.gov (United States)

    Montagne, Rémi; Furlan, Alessandro; Kherrouche, Zoulika; Tulasne, David

    2014-10-01

    In 1984, the Met receptor and its ligand, the HGF/SF, were discovered thanks to their ability to induce cell transformation and proliferation. Thirty years of research highlighted their crucial role in the development and homeostasis of various structures, including many epithelial organs. This period also allowed unraveling the structural basis of their interaction and their complex signaling network. In parallel, Met was shown to be deregulated and associated with a poor prognosis in many cancers. Met involvement in resistance to current therapies is also being deciphered. Based on these data, pharmaceutical companies developed a variety of Met inhibitors, some of which are evaluated in phase III clinical trials. In this review, we trace the exemplary track record of research on Met receptor, which allowed moving from bench to bedside through the development of therapies targeting its activity. Many questions still remain unanswered such as the involvement of Met in several processes of development, the mechanisms involving Met in resistance to current therapies or the likely emergence of resistances to Met-targeted therapies.

  1. Targeting of the MET receptor tyrosine kinase by small molecule inhibitors leads to MET accumulation by impairing the receptor downregulation.

    Science.gov (United States)

    Leiser, Dominic; Pochon, Benoît; Blank-Liss, Wieslawa; Francica, Paola; Glück, Astrid A; Aebersold, Daniel M; Zimmer, Yitzhak; Medová, Michaela

    2014-03-03

    The MET receptor tyrosine kinase is deregulated primarily via overexpression or point mutations in various human cancers and different strategies for MET inhibition are currently evaluated in clinical trials. We observed by Western blot analysis and by Flow cytometry that MET inhibition by different MET small molecule inhibitors surprisingly increases in a dose-dependent manner total MET levels in treated cells. Mechanistically, this inhibition-related MET accumulation was associated with reduced Tyr1003 phosphorylation and MET physical association with the CBL ubiquitin ligase with concomitant decrease in MET ubiquitination. These data may suggest careful consideration for design of anti-MET clinical protocols. Copyright © 2014 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

  2. HGF induces EMT in non-small-cell lung cancer through the hBVR pathway.

    Science.gov (United States)

    Liu, Fang; Song, Shasha; Yi, Zhi; Zhang, Min; Li, Jiali; Yang, Fang; Yin, Hongtao; Yu, Xiufeng; Guan, Chao; Liu, Ying; Liu, Zizhen; Wang, Jing; Zhu, Daling

    2017-09-15

    The epithelial-to-mesenchymal transition (EMT) is a crucial event during non-small-cell lung cancer (NSCLC) invasion and metastasis. However, the mechanisms involved in NSCLC EMT have not been fully clarified. Hepatocyte growth factor (HGF) and human biliverdin reductase (hBVR) are reported to contribute to EMT in several diseases. Here, we show that compared with transforming growth factor beta (TGF-β), fibroblast growth factor (FGF), and epidermal growth factor (EGF), HGF is an important cell factor for EMT in NSCLC cell lines A549 and H460. Met protein, HGF receptors, and hBVR were found to be highly expressed and positively correlated with EMT in NSCLC tissue sections. In addition, HGF and hBVR induced a decrease in epithelial protein marker expression and an increase in mesenchymal protein marker expression as well as increased cellular migration and invasion, indicating that both HGF and hBVR mediate EMT in A549 and H460 cell lines. Furthermore, HGF-induced EMT and migration and invasion in both cell lines was inhibited by si-hBVR. Taken together, our data show that HGF induces EMT in NSCLC through the hBVR pathway. Copyright © 2017. Published by Elsevier B.V.

  3. Impact of MET inhibition on small-cell lung cancer cells showing aberrant activation of the hepatocyte growth factor/MET pathway.

    Science.gov (United States)

    Taniguchi, Hirokazu; Yamada, Tadaaki; Takeuchi, Shinji; Arai, Sachiko; Fukuda, Koji; Sakamoto, Shuichi; Kawada, Manabu; Yamaguchi, Hiroyuki; Mukae, Hiroshi; Yano, Seiji

    2017-07-01

    Small-cell lung cancer (SCLC) accounts for approximately 15% of all lung cancers, and is characterized as extremely aggressive, often displaying rapid tumor growth and multiple organ metastases. In addition, the clinical outcome of SCLC patients is poor due to early relapse and acquired resistance to standard chemotherapy treatments. Hence, novel therapeutic strategies for the treatment of SCLC are urgently required. Accordingly, several molecular targeted therapies were evaluated in SCLC; however, they failed to improve the clinical outcome. The receptor tyrosine kinase MET is a receptor for hepatocyte growth factor (HGF), and aberrant activation of HGF/MET signaling is known as one of the crucial mechanisms enabling cancer progression and invasion. Here, we found that the HGF/MET signaling was aberrantly activated in chemoresistant or chemorelapsed SCLC cell lines (SBC-5, DMS273, and DMS273-G3H) by the secretion of HGF and/or MET copy number gain. A cell-based in vitro assay revealed that HGF/MET inhibition, induced either by MET inhibitors (crizotinib and golvatinib), or by siRNA-mediated knockdown of HGF or MET, constrained growth of chemoresistant SCLC cells through the inhibition of ERK and AKT signals. Furthermore, treatment with either crizotinib or golvatinib suppressed the systemic metastasis of SBC-5 cell tumors in natural killer cell-depleted SCID mice, predominantly through cell cycle arrest. These findings reveal the therapeutic potential of targeting the HGF/MET pathway for inhibition, to constrain tumor progression of SCLC cells showing aberrant activation of HGF/MET signaling. We suggest that it would be clinically valuable to further investigate HGF/MET-mediated signaling in SCLC cells. © 2017 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

  4. 非肝硬变性胆道梗阻大鼠肝脏部分切除术后肝内促肝细胞生长因子及其受体mRNA 的表达变化%Expression of HGF/Met mRNA and TGF-α/EGFR mRNA in the liver/hepatocyte after partial hepatectomy in noncirrhotic obstructive rats

    Institute of Scientific and Technical Information of China (English)

    徐明清; 韩本立; 薛兰; 龚建平; 董家鸿; 王曙光

    2001-01-01

    Objective To investigate the expression of HGF and TGF-α and their receptor, Met (HGF receptor) and EGFR (TGF-αreceptor) mRNA, in the regenerative liver/hepatocytes after 70% partial hepatectomy (70% PH) in noncirrhotic biliary obstruction rats. Methods Wistar rats were divided randomly into N-PH group, BDO-RBF-PH group and BDO-RBF group. The expression of HGF/Met mRNA and TGF-α/EGFR mRNA was measured by RT-PCR in the liver/hepatocytes at the time point of 0, 6, 12, 24, 48 and 72 h after 70% PH or RBF. Results In N-PH group, the expression of HGF/Met mRNA increased sharply and peaked at 6 h, and maintained at a high level until 24 h after 70% PH. In BDO-RBF-PH group however, the expression of HGF/Met mRNA increased slowly and peaked at 12 h after 70% PH. The peak level was lower in BDO-RBF-PH group than in N-PH one. The expression of TGF-α/EGFR mRNA increased sharply and peaked at 24 h after 70% PH in N-PH group. However, the expression of TGF-α/EGFR mRNA elevated slowly and peaked at 48 h after 70% PH in BDO-RBF-PH group with a lower peak level than that in N-PH group. Conclusion The expression of HGF/Met mRNA and TGF-α/EGFR mRNA in the regenerative liver/hepatocytes after 70% PH decreases significantly in noncirrhotic biliary duct obstruction rats. There is a tendency that the expression of HGF mRNA and TGF-α mRNA is less than Met mRNA and EGFR mRNA.%目的 检测非肝硬变性胆道梗阻肝脏部分切除(PH)术后肝内促肝细胞生长的肝细胞生长因子(HGF)与转化生长因子-α(TGF-α)及其受体Met基因(HGF受体)、表皮生长因子受体EGFR(亦是TGF-α受体)mRNA的表达变化。方法 Wistar大鼠随机分为正常70%肝部分切除组(N-PH)、胆道梗阻(BDO)胆流再通(RBF)70%PH组(BDO-RBF-PH)、及胆道梗阻胆流再通组(BDO-RBF)。观察时相点为术后0、6、12、24、48及72 h。RT-PCR法检测肝内HGF mRNA、TGF-α mRNA及肝细胞Met mRNA与EGFR m

  5. MET receptor variant R970C favors calpain-dependent generation of a fragment promoting epithelial cell scattering.

    Science.gov (United States)

    Montagne, Rémi; Baranzelli, Anne; Muharram, Ghaffar; Catherine, Leroy; Lesaffre, Marie; Vinchent, Audrey; Kherrouche, Zoulika; Werkmeister, Elisabeth; Cortot, Alexis B; Tulasne, David

    2017-01-04

    The receptor tyrosine kinase MET and its ligand, the hepatocyte growth factor, are essential to embryonic development, whereas deregulation of MET signaling is associated with tumorigenesis leading to various cancers, including lung carcinoma. Mutations in the MET kinase domain lead to constitutive kinase activity and are associated with tumorigenesis. In lung cancer, however, some mutations are found in the juxtamembrane domain, and their functional consequences are unknown. Because the juxtamembrane domain of MET is targeted by several proteolytic cleavages, involved in its degradation during cell death or under steady-state conditions, we evaluated the influence of these mutations on the MET proteolytic cleavages. In stably transfected epithelial cells expressing MET, the juxtamembrane mutations R970C, P991S, and T992I were found not to modify the known caspase or presenilin-dependent regulated intramembrane proteolysis. Yet when overexpressed, the R970C variant caused generation of an as yet undescribed 45-kDa fragment (p45 MET). This fragment was found in the confluent lung cancer cell line NCI-H1437 carrying the R970C mutation and at a lesser extent in cell lines expressing WT MET, suggesting that R970C mutation favors this cleavage. Generation of p45 MET required the activity of the calpain proteases, confirming the involvement of proteolysis. Ectopic expression of reconstituted p45 MET in epithelial cell lines favored cell scattering and invasion indicating active role of this fragment in HGF/SF induced responses. Hence, although the juxtamembrane mutations of MET do not affect its known proteolytic cleavages, the R970C MET variant favors calpain dependent proteolytic cleavage in lung cancer cells.

  6. Decorin is down-regulated in multiple myeloma and MGUS bone marrow plasma and inhibits HGF-induced myeloma plasma cell viability and migration

    DEFF Research Database (Denmark)

    Kristensen, Ida Bruun; Pedersen, Lise Mariager; Rø, Torstein Baade;

    2013-01-01

    OBJECTIVES: Decorin is a stromal-produced small leucine-rich proteoglycan known to attenuate tumour pro-survival, migration, proliferation and angiogenic signalling pathways. Recent studies have shown that decorin interacts with the hepatocyte growth factor (HGF) receptor c-Met, a potential key p...... of decorin to inhibit HGF-induced effects on MM cell lines were analysed in vitro using cell viability and Transwell migration assays. RESULTS: We found that decorin concentrations were significantly higher (p...

  7. Met-Independent Hepatocyte Growth Factor-mediated regulation of cell adhesion in human prostate cancer cells

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    Davis Rodney

    2006-07-01

    Full Text Available Abstract Background Prostate cancer cells communicate reciprocally with the stromal cells surrounding them, inside the prostate, and after metastasis, within the bone. Each tissue secretes factors for interpretation by the other. One stromally-derived factor, Hepatocyte Growth Factor (HGF, was found twenty years ago to regulate invasion and growth of carcinoma cells. Working with the LNCaP prostate cancer progression model, we found that these cells could respond to HGF stimulation, even in the absence of Met, the only known HGF receptor. The new HGF binding partner we find on the cell surface may help to clarify conflicts in the past literature about Met expression and HGF response in cancer cells. Methods We searched for Met or any HGF binding partner on the cells of the PC3 and LNCaP prostate cancer cell models, using HGF immobilized on agarose beads. By using mass spectrometry analyses and sequencing we have identified nucleolin protein as a novel HGF binding partner. Antibodies against nucleolin (or HGF were able to ameliorate the stimulatory effects of HGF on met-negative prostate cancer cells. Western blots, RT-PCR, and immunohistochemistry were used to assess nucleolin levels during prostate cancer progression in both LNCaP and PC3 models. Results We have identified HGF as a major signaling component of prostate stromal-conditioned media (SCM and have implicated the protein nucleolin in HGF signal reception by the LNCaP model prostate cancer cells. Antibodies that silence either HGF (in SCM or nucleolin (on the cell surfaces eliminate the adhesion-stimulatory effects of the SCM. Likewise, addition of purified HGF to control media mimics the action of SCM. C4-2, an LNCaP lineage-derived, androgen-independent human prostate cancer cell line, responds to HGF in a concentration-dependent manner by increasing its adhesion and reducing its migration on laminin substratum. These HGF effects are not due to shifts in the expression levels of

  8. Role of HGF in obesity-associated tumorigenesis: C3(1)-TAg mice as a model for human basal-like breast cancer

    Science.gov (United States)

    Sundaram, Sneha; Freemerman, Alex J.; Johnson, Amy R.; Milner, J. Justin; McNaughton, Kirk K.; Galanko, Joseph A.; Bendt, Katharine M.; Darr, David B.; Perou, Charles M.; Troester, Melissa A.; Makowski, Liza

    2013-01-01

    Obesity is associated with basal-like breast cancer (BBC), an aggressive breast cancer subtype. The objective of this study was to determine whether obesity promotes BBC onset in adulthood and to evaluate the role of stromal-epithelial interactions in obesity-associated tumorigenesis. We hypothesized that hepatocyte growth factor (HGF) plays a promoting role in BBC, which express the HGF receptor, c-Met. In C3(1)-Tag mice, a murine model of BBC, we demonstrated that obesity leads to a significant increase in HGF secretion and an associated decrease in tumor latency. By immunohistochemical analysis, normal mammary gland exhibited obesity-induced HGF, c-Met and phospho-c-Met, indicating that activation of the cascade was obesity-driven. HGF secretion was also increased from primary mammary fibroblasts isolated from normal mammary glands and tumors of obese mice compared to lean. These results demonstrate that obesity-induced elevation of HGF expression is a stable phenotype, maintained after several passages, and after removal of dietary stimulation. Conditioned media from primary tumor fibroblasts from obese mice drove tumor cell proliferation. In co-culture, neutralization of secreted HGF blunted tumor cell migration, further linking obesity-mediated HGF-dependent effects to in vitro measures of tumor aggressiveness. In sum, these results demonstrate that HGF/c-Met plays an important role in obesity-associated carcinogenesis. Understanding the effects of obesity on risk and progression is important given that epidemiologic studies imply a portion of BBC could be eliminated by reducing obesity. PMID:24218051

  9. Role of HGF in obesity-associated tumorigenesis: C3(1)-TAg mice as a model for human basal-like breast cancer.

    Science.gov (United States)

    Sundaram, Sneha; Freemerman, Alex J; Johnson, Amy R; Milner, J Justin; McNaughton, Kirk K; Galanko, Joseph A; Bendt, Katharine M; Darr, David B; Perou, Charles M; Troester, Melissa A; Makowski, Liza

    2013-12-01

    Obesity is associated with basal-like breast cancer (BBC), an aggressive breast cancer subtype. The objective of this study was to determine whether obesity promotes BBC onset in adulthood and to evaluate the role of stromal-epithelial interactions in obesity-associated tumorigenesis. We hypothesized that hepatocyte growth factor (HGF) plays a promoting role in BBC, which express the HGF receptor, c-Met. In C3(1)-T(Ag) mice, a murine model of BBC, we demonstrated that obesity leads to a significant increase in HGF secretion and an associated decrease in tumor latency. By immunohistochemical analysis, normal mammary gland exhibited obesity-induced HGF, c-Met and phospho-c-Met, indicating that the activation of the cascade was obesity-driven. HGF secretion was also increased from primary mammary fibroblasts isolated from normal mammary glands and tumors of obese mice compared to lean. These results demonstrate that obesity-induced elevation of HGF expression is a stable phenotype, maintained after several passages, and after removal of dietary stimulation. Conditioned media from primary tumor fibroblasts from obese mice drove tumor cell proliferation. In co-culture, neutralization of secreted HGF blunted tumor cell migration, further linking obesity-mediated HGF-dependent effects to in vitro measures of tumor aggressiveness. In sum, these results demonstrate that HGF/c-Met plays an important role in obesity-associated carcinogenesis. Understanding the effects of obesity on risk and progression is important given that epidemiologic studies imply a portion of BBC could be eliminated by reducing obesity.

  10. Aptamers Binding to c-Met Inhibiting Tumor Cell Migration.

    Directory of Open Access Journals (Sweden)

    Birgit Piater

    Full Text Available The human receptor tyrosine kinase c-Met plays an important role in the control of critical cellular processes. Since c-Met is frequently over expressed or deregulated in human malignancies, blocking its activation is of special interest for therapy. In normal conditions, the c-Met receptor is activated by its bivalent ligand hepatocyte growth factor (HGF. Also bivalent antibodies can activate the receptor by cross linking, limiting therapeutic applications. We report the generation of the RNA aptamer CLN64 containing 2'-fluoro pyrimidine modifications by systematic evolution of ligands by exponential enrichment (SELEX. CLN64 and a previously described single-stranded DNA (ssDNA aptamer CLN3 exhibited high specificities and affinities to recombinant and cellular expressed c-Met. Both aptamers effectively inhibited HGF-dependent c-Met activation, signaling and cell migration. We showed that these aptamers did not induce c-Met activation, revealing an advantage over bivalent therapeutic molecules. Both aptamers were shown to bind overlapping epitopes but only CLN3 competed with HGF binding to cMet. In addition to their therapeutic and diagnostic potential, CLN3 and CLN64 aptamers exhibit valuable tools to further understand the structural and functional basis for c-Met activation or inhibition by synthetic ligands and their interplay with HGF binding.

  11. The motogenic and mitogenic responses to HGF are amplified by the Shc adaptor protein

    DEFF Research Database (Denmark)

    Pelicci, G; Giordano, S; Zhen, Z

    1995-01-01

    The receptor of Hepatocyte Growth Factor-Scatter Factor (HGF) is a tyrosine kinase which regulates cell motility and growth. After ligand-induced tyrosine phosphorylation, the HGF receptor associates with the Shc adaptor, via the SH2 domain. Site-directed mutagenesis of the HGF receptor indicates...

  12. The HGF/c-MET Axis as a Critical Driver of Resistance to Androgen Suppression in Metastatic Castrate-Resistant Prostate Cancer

    Science.gov (United States)

    2016-10-01

    resistant prostate cancer PRINCIPAL INVESTIGATOR: Todd M. Morgan CONTRACTING ORGANIZATION: University of Michigan Ann Arbor, MI REPORT DATE: October...NAME(S) AND ADDRESS(ES) University of Michigan Ann Arbor, MI 8. PERFORMING ORGANIZATION REPORT NUMBER University of Michigan Ann Arbor, Michigan...efficacious than either inhibitor alone . These data support the concept that the MET pathway may be an key mechanism of resistance in men with CRPC

  13. HGF–MET Cascade, a Key Target for Inhibiting Cancer Metastasis: The Impact of NK4 Discovery on Cancer Biology and Therapeutics

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    Shinya Mizuno

    2013-01-01

    Full Text Available Hepatocyte growth factor (HGF was discovered in 1984 as a mitogen of rat hepatocytes in a primary culture system. In the mid-1980s, MET was identified as an oncogenic mutant protein that induces malignant phenotypes in a human cell line. In the early 1990s, wild-type MET was shown to be a functional receptor of HGF. Indeed, HGF exerts multiple functions, such as proliferation, morphogenesis and anti-apoptosis, in various cells via MET tyrosine kinase phosphorylation. During the past 20 years, we have accumulated evidence that HGF is an essential conductor for embryogenesis and tissue regeneration in various types of organs. Furthermore, we found in the mid-1990s that stroma-derived HGF is a major contributor to cancer invasion at least in vitro. Based on this background, we prepared NK4 as an antagonist of HGF: NK4 inhibits HGF-mediated MET tyrosine phosphorylation by competing with HGF for binding to MET. In vivo, NK4 treatments produced the anti-tumor outcomes in mice bearing distinct types of malignant cancers, associated with the loss in MET activation. There are now numerous reports showing that HGF-antagonists and MET-inhibitors are logical for inhibiting tumor growth and metastasis. Additionally, NK4 exerts anti-angiogenic effects, partly through perlecan-dependent cascades. This paper focuses on the chronology and significance of HGF-antagonisms in anti-tumor researches, with an interest in NK4 discovery. Tumor HGF–MET axis is now critical for drug resistance and cancer stem cell maintenance. Thus, oncologists cannot ignore this cascade for the future success of anti-metastatic therapy.

  14. Met in Urological Cancers

    Energy Technology Data Exchange (ETDEWEB)

    Miyata, Yasuyoshi, E-mail: int.doc.miya@m3.dion.ne.jp; Asai, Akihiro; Mitsunari, Kensuke; Matsuo, Tomohiro; Ohba, Kojiro; Mochizuki, Yasushi; Sakai, Hideki [Department of Urology, Nagasaki University Hospital, 1-7-1 Sakamoto, Nagasaki 852-8501 (Japan)

    2014-12-16

    Met is a tyrosine kinase receptor that is considered to be a proto-oncogene. The hepatocyte growth factor (HGF)-Met signaling system plays an important role in tumor growth, invasion, and metastasis in many types of malignancies. Furthermore, Met expression has been reported to be a useful predictive biomarker for disease progression and patient survival in these malignancies. Many studies have focused on the clinical significance and prognostic role of Met in urological cancers, including prostate cancer (PCa), renal cell carcinoma (RCC), and urothelial cancer. Several preclinical studies and clinical trials are in progress. In this review, the current understanding of the pathological role of Met in cancer cell lines, its clinical significance in cancer tissues, and its predictive value in patients with urological cancers are summarized. In particular, Met-related malignant behavior in castration-resistant PCa and the different pathological roles Met plays in papillary RCC and other histological types of RCC are the subjects of focus. In addition, the pathological significance of phosphorylated Met in these cancers is shown. In recent years, Met has been recognized as a potential therapeutic target in various types of cancer; therapeutic strategies used by Met-targeted agents in urological cancers are summarized in this review.

  15. Oncogenic activation of the Met receptor tyrosine kinase fusion protein, Tpr-Met, involves exclusion from the endocytic degradative pathway.

    Science.gov (United States)

    Mak, H H L; Peschard, P; Lin, T; Naujokas, M A; Zuo, D; Park, M

    2007-11-01

    Multiple mechanisms of dysregulation of receptor tyrosine kinases (RTKs) are observed in human cancers. In addition to gain-of-function, loss of negative regulation also contributes to oncogenic activation of RTKs. Negative regulation of many RTKs involves their internalization and degradation in the lysosome, a process regulated through ubiquitination. RTK oncoproteins activated following chromosomal translocation, are no longer transmembrane proteins, and are predicted to escape lysosomal degradation. To test this, we used the Tpr-Met oncogene, generated following chromosomal translocation of the hepatocyte growth factor receptor (Met). Unlike Met, Tpr-Met is localized in the cytoplasm and also lacks the binding site for Cbl ubiquitin ligases. We determined whether subcellular localization of Tpr-Met, and/or loss of its Cbl-binding site, is important for oncogenic activity. Presence of a Cbl-binding site and ubiquitination of cytosolic Tpr-Met oncoproteins does not alter their transforming activity. In contrast, plasma membrane targeting allows Tpr-Met to enter the endocytic pathway, and Tpr-Met transforming activity as well as protein stability are decreased in a Cbl-dependent manner. We show that transformation by Tpr-Met is in part dependent on its ability to escape normal downregulatory mechanisms. This provides a paradigm for many RTK oncoproteins activated following chromosomal translocation.

  16. A novel activating role of SRC and STAT3 on HGF transcription in human breast cancer cells

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    Elliott Bruce E

    2007-10-01

    Full Text Available Abstract We have previously determined that the HGF promoter can be transactivated by a combination of activated Src and wild-type Stat3 in the mouse breast cell lines HC11 and SP1. To determine if this pathway is of relevance for the human disease, a series of human breast and other human cells lines were examined, and the status of key proteins in these cells determined. All of the human breast cell lines exhibited strong transactivation by a combination of activated Src and Stat3. This activation was dependent on a Stat3 recognition element present at nt-95. The exception was the ErbB2 over-expressing cell line SK-BR-3 where Stat3 alone could transactivate HGF though Src augmented this effect. Increased phosphorylation of Stat3 tyrosine 705 was also observed in this line. Analysis of three ovarian cell lines revealed that Src/Stat3 expression was not able to activate the HGF promoter in two of these lines (SKOV3 and IOSE-80PC. Src/Stat3 expression did activate HGF transcription in OVCAR3 cells, but this effect was not mediated by the Stat3 site at nt-95. Stat3 phosphorylation at tyrosine 705 was observed in IOSE-80PC cells, but was insufficient to allow for activation of the HGF promoter. Human kidney (HEK293 and cervical carcinoma (HeLa cells were also not Src/Stat3 permissive, despite high levels of Stat3 phospho-Y705. These results suggest that human breast cells are a uniquely permissive environment for HGF transactivation by Src/Stat3 which may allow for the inappropriate activation of HGF transcription during the early stages of breast transformation. This could lead to paracrine or autocrine activation of the Met receptor in breast carcinoma cells.

  17. mTOR inhibitors control the growth of EGFR mutant lung cancer even after acquiring resistance by HGF.

    Directory of Open Access Journals (Sweden)

    Daisuke Ishikawa

    Full Text Available Resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs, gefitinib and erlotinib, is a critical problem in the treatment of EGFR mutant lung cancer. Several mechanisms, including bypass signaling by hepatocyte growth factor (HGF-triggered Met activation, are implicated as mediators of resistance. The mammalian target of rapamycin (mTOR, is a downstream conduit of EGFR and MET signaling, and is thus considered a therapeutically attractive target in the treatment of various types of cancers. The purpose of this study was to examine whether 2 clinically approved mTOR inhibitors, temsirolimus and everolimus, overcome HGF-dependent resistance to EGFR-TKIs in EGFR mutant lung cancer cells. Both temsirolimus and everolimus inhibited the phosphorylation of p70S6K and 4E-BP1, which are downstream targets of the mTOR pathway, and reduced the viability of EGFR mutant lung cancer cells, PC-9, and HCC827, even in the presence of HGF in vitro. In a xenograft model, temsirolimus suppressed the growth of PC-9 cells overexpressing the HGF-gene; this was associated with suppression of the mTOR signaling pathway and tumor angiogenesis. In contrast, erlotinib did not suppress this signaling pathway or tumor growth. Multiple mechanisms, including the inhibition of vascular endothelial growth factor production by tumor cells and suppression of endothelial cell viability, contribute to the anti-angiogenic effect of temsirolimus. These findings indicate that mTOR inhibitors may be useful for controlling HGF-triggered EGFR-TKI resistance in EGFR mutant lung cancer, and they provide the rationale for clinical trials of mTOR inhibitors in patients stratified by EGFR mutation and HGF expression status.

  18. Targeting hepatocyte growth factor receptor (Met) positive tumor cells using internalizing nanobody-decorated albumin nanoparticles

    NARCIS (Netherlands)

    Heukers, Raimond|info:eu-repo/dai/nl/325788103; Altintas, Isil|info:eu-repo/dai/nl/341537160; Raghoenath, Smiriti; De Zan, Erica; Pepermans, Richard; Roovers, Rob C.|info:eu-repo/dai/nl/205435599; Haselberg, Rob|info:eu-repo/dai/nl/304822647; Hennink, Wim E.|info:eu-repo/dai/nl/070880409; Schiffelers, Raymond M.|info:eu-repo/dai/nl/212909509; Kok, Robbert J.|info:eu-repo/dai/nl/170678326; Van Bergen en Henegouwen, Paul M P|info:eu-repo/dai/nl/071919481

    2014-01-01

    The hepatocyte growth factor receptor (HGFR, c-Met or Met) is a receptor tyrosine kinase that is involved in embryogenesis, tissue regeneration and wound healing. Abnormal activation of this proto-oncogene product is implicated in the development, progression and metastasis of many cancers. Current

  19. The BDNF Val66Met polymorphism impairs NMDA receptor-dependent synaptic plasticity in the hippocampus.

    Science.gov (United States)

    Ninan, Ipe; Bath, Kevin G; Dagar, Karishma; Perez-Castro, Rosalia; Plummer, Mark R; Lee, Francis S; Chao, Moses V

    2010-06-30

    The Val66Met polymorphism in the brain-derived neurotrophic factor (BDNF) gene results in a defect in regulated release of BDNF and affects episodic memory and affective behaviors. However, the precise role of the BDNF Val66Met polymorphism in hippocampal synaptic transmission and plasticity has not yet been studied. Therefore, we examined synaptic properties in the hippocampal CA3-CA1 synapses of BDNF(Met/Met) mice and matched wild-type mice. Although basal glutamatergic neurotransmission was normal, both young and adult mice showed a significant reduction in NMDA receptor-dependent long-term potentiation. We also found that NMDA receptor-dependent long-term depression was decreased in BDNF(Met/Met) mice. However, mGluR-dependent long-term depression was not affected by the BDNF Val66Met polymorphism. Consistent with the NMDA receptor-dependent synaptic plasticity impairment, we observed a significant decrease in NMDA receptor neurotransmission in the CA1 pyramidal neurons of BDNF(Met/Met) mice. Thus, these results show that the BDNF Val66Met polymorphism has a direct effect on NMDA receptor transmission, which may account for changes in synaptic plasticity in the hippocampus.

  20. Hepatocyte growth factor/cMET pathway activation enhances cancer hallmarks in adrenocortical carcinoma

    Science.gov (United States)

    Phan, Liem M.; Fuentes-Mattei, Enrique; Wu, Weixin; Velazquez-Torres, Guermarie; Sircar, Kanishka; Wood, Christopher G.; Hai, Tao; Jimenez, Camilo; Cote, Gilbert J.; Ozsari, Levent; Hofmann, Marie-Claude; Zheng, Siyuan; Verhaak, Roeland; Pagliaro, Lance; Cortez, Maria Angelica; Lee, Mong-Hong; Yeung, Sai-Ching J.; Habra, Mouhammed Amir

    2015-01-01

    Adrenocortical carcinoma (ACC) is a rare malignancy with poor prognosis and limited response to chemotherapy. Hepatocyte growth factor (HGF) and its receptor cMET augment cancer growth and resistance to chemotherapy, but their role in ACC has not been examined. In this study, we investigated the association between HGF/cMET expression and cancer hallmarks of ACC. Transcriptomic and immunohistochemical analyses indicated that increased HGF/cMET expression in human ACC samples was positively associated with cancer-related biological processes including proliferation and angiogenesis, and negatively correlated with apoptosis. Accordingly, treatment of ACC cells with exogenous HCG resulted in increased cell proliferation in vitro and in vivo while short hairpin RNA-mediated knockdown or pharmacological inhibition of cMET suppressed cell proliferation and tumor growth. Moreover, exposure of cells to mitotane, cisplatin, or radiation rapidly induced pro-cMET expression and was associated with an enrichment of genes (e.g., CYP450 family) related to therapy resistance further implicating cMET in the anticancer drug response. Together, these data suggest an important role for HGF/cMET signaling in ACC growth and resistance to commonly used treatments. Targeting cMET, alone or in combination with other drugs, could provide a breakthrough in the management of this aggressive cancer. PMID:26282167

  1. Inhibition of c-Met as a Therapeutic Strategy for Esophageal Adenocarcinoma

    Directory of Open Access Journals (Sweden)

    Gregory A. Watson

    2006-11-01

    Full Text Available The hepatocyte growth factor (HGF receptor c-Met is a tyrosine kinase receptor with established oncogenic properties. We have previously shown that c-Met is usually overexpressed in esophageal adenocarcinoma (EA, yet the implications of c-Met inhibition in EA remain unknown. Three c-Met-overexpressiog EA cell lines (Seg-1, Bic-1, Flo-1 were used to examine the effects of a c-Met-specific small molecule inhibitor (PHA665752 on cell viability, apoptosis, motility, invasion, downstream signaling pathways. PHA665752 demonstrated dose-dependent inhibition of constitutive and/or HGF-induced phosphorylation of c-Met, which correlated with reduced cell viability and inhibition of extracellular regulated kinase 1/2 phosphorylation in all three EA cell lines. In contrast, PHA665752 induced apoptosis and reduced motility and invasion in only one EA cell line, Flo-1. Interestingly, Flo-1 was the only cell line in which phosphatidylinositol 3-kinase (PI3K/Akt was induced following HGF stimulation. The PI3K inhibitor LY294002 produced effects equivalent to those of PHA665752 in these cells. We conclude that inhibition of c-Met may be a useful therapeutic strategy for EA. Factors other than receptor overexpression, such as c-Met-dependent PI3K/Akt signaling, may be predictive of an individual tumor's response to c-Met inhibition.

  2. Promise and challenges on the horizon of MET-targeted cancer therapeutics

    Institute of Scientific and Technical Information of China (English)

    Yu-Wen; Zhang

    2015-01-01

    MET(MNNG HOS transforming gene) is one of the receptor tyrosine kinases whose activities are frequently altered in human cancers, and it is a promising therapeutic target. MET is normally activated by its lone ligand, hepatocyte growth factor(HGF), eliciting its diverse biological activities that are crucial for development and physiology. Alteration of the HGF-MET axis results in inappropriate activation of a cascade of intracellular signaling pathways that contributes to hallmark cancer events including deregulated cell proliferation and survival, angiogenesis, invasion, andmetastasis. Aberrant MET activation results from autocrine or paracrine mechanisms due to overexpression of HGF and/or MET or from a ligand-independent mechanism caused by activating mutations or amplification of MET. The literature provides compelling evidence for the role of MET signaling in cancer development and progression. The finding that cancer cells often use MET activation to escape therapies targeting other pathways strengthens the argument for MET-targeted therapeutics. Diverse strategies have been explored to deactivate MET signaling, and compounds and biologics targeting the MET pathway are in clinical development. Despite promising results from various clinical trials, we are still waiting for true MET-targeted therapeutics in the clinic. This review will explore recent progress and hurdles in the pursuit of METtargeted cancer drugs and discuss the challenges in such development.

  3. Necroptosis Induced by Ad-HGF Activates Endogenous C-Kit+ Cardiac Stem Cells and Promotes Cardiomyocyte Proliferation and Angiogenesis in the Infarcted Aged Heart

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    Jiabao Liu

    2016-12-01

    Full Text Available Background/Aims: The discovery of c-kit+ cardiac stem cells (CSCs provided us with new therapeutic targets to repair the damaged heart. However, the precise mechanisms regulating CSC proliferation and differentiation in the aged heart remained elusive. Necroptosis, a type of regulated cell death, has recently been shown to occur following myocardial infarction (MI; however, its effect on c-kit+ CSCs remains unknown. We investigated the effects of hepatocyte growth factor (HGF and necroptosis on the proliferation and differentiation of endogenous c-kit+ CSCs in aged rat hearts following MI. Methods: The c-kit+ CSCs and HGF/p-Met expression levels in neonatal, adult and aged rats were compared using immunofluorescence and Western blotting. Immediately after MI, adenovirus carrying the HGF gene (Ad-HGF was injected into the left ventricular wall surrounding the infarct areas of the aged rat heart. The proliferation and differentiation of the endogenous c-kit+ CSCs were studied using immunofluorescence. The signalling pathways were analysed via Western blotting and ELISA. Results: HGF/p-Met expression levels and c-kit+ CSC abundance gradually decreased with age. Ad-HGF promoted c-kit+ CSC differentiation into precursor cells of cardiomyocyte, endothelial and smooth muscle cell lineages and enhanced cardiomyocyte proliferation and angiogenesis in aged rats; these effects were reversed by the inhibition of necroptosis. Ad-HGF administration induced necroptosis by increasing the expression of receptor interacting protein kinase (RIP 1 and receptor interacting protein kinase (RIP 3 proteins in the infarcted heart. Moreover, Ad-HGF-induced necroptosis increased high-mobility group box 1 protein (HMGB1 levels and enhanced the abundance of c-kit+ cells in the bone marrow, which may partly account for the beneficial effect of necroptosis on the c-kit+ CSCs. Conclusion: Ad-HGF-induced necroptosis facilitated aged heart repair after MI by promoting c-kit+ CSC

  4. Science Signaling Podcast for 21 June 2016: MET and skin cancer.

    Science.gov (United States)

    Yuspa, Stuart H; VanHook, Annalisa M

    2016-06-21

    This Podcast features an interview with Stuart Yuspa, senior author of a Research Article that appears in the 21 June 2016 issue of Science Signaling, about how activation of the receptor tyrosine kinase MET stimulates the formation of squamous cell carcinoma in the skin. Hepatocyte growth factor (HGF) is produced by mesenchymal cells and stimulates MET, which is present on the surface of epithelial cells. HGF-MET signaling directs the proliferation and migration of epithelial cells during the development of various organs and is important during wound healing. Aberrant MET activation has been implicated in several types of cancer, including squamous cell carcinoma. Using a model in which mice overexpressing HGF develop spontaneous squamous cell carcinomas in the skin, Cataisson et al found that MET promoted the development of squamous tumors by stimulating the synthesis and release of ligands that activate the epidermal growth factor receptor (EGFR). This mechanism was similar to that through which oncogenic RAS promotes skin tumors. Blocking EGFR signaling caused HGF-induced squamous tumors to regress, suggesting that EGFR inhibitors might be useful for treating squamous cell carcinomas.Listen to Podcast. Copyright © 2016, American Association for the Advancement of Science.

  5. Microtubule dynamics control HGF-induced lung endothelial barrier enhancement.

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    Xinyong Tian

    Full Text Available Microtubules (MT play a vital role in many cellular functions, but their role in peripheral actin cytoskeletal dynamics which is essential for control of endothelial barrier and monolayer integrity is less understood. We have previously described the enhancement of lung endothelial cell (EC barrier by hepatocyte growth factor (HGF which was associated with Rac1-mediated remodeling of actin cytoskeleton. This study investigated involvement of MT-dependent mechanisms in the HGF-induced enhancement of EC barrier. HGF-induced Rac1 activation was accompanied by phosphorylation of stathmin, a regulator of MT dynamics. HGF also stimulated MT peripheral growth monitored by time lapse imaging and tracking analysis of EB-1-decorated MT growing tips, and increased the pool of acetylated tubulin. These effects were abolished by EC pretreatment with HGF receptor inhibitor, downregulation of Rac1 pathway, or by expression of a stathmin-S63A phosphorylation deficient mutant. Expression of stathmin-S63A abolished the HGF protective effects against thrombin-induced activation of RhoA cascade, permeability increase, and EC barrier dysfunction. These results demonstrate a novel MT-dependent mechanism of HGF-induced EC barrier regulation via Rac1/PAK1/stathmin-dependent control of MT dynamics.

  6. 6-Phosphogluconate dehydrogenase regulates tumor cell migration in vitro by regulating receptor tyrosine kinase c-Met

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    Chan, Barden, E-mail: cchan@bidmc.harvard.edu [Division of Interdisciplinary Medicine and Biotechnology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215 (United States); VanderLaan, Paul A. [Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215 (United States); Sukhatme, Vikas P. [Division of Interdisciplinary Medicine and Biotechnology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215 (United States)

    2013-09-20

    Highlights: •Expression of 6PGD positively correlates with advancing stage of lung carcinoma. •Knockdown of 6PGD by shRNA potently inhibits c-Met tyrosine phosphorylation. •Exogenous HGF fails to restore c-Met phosphorylation in cells with 6PGD knocked down. •6PGD knockdown results in inhibition of cell migration in vitro. •Constitutively active TPR-cMet significantly restores migration of cells without 6PGD. -- Abstract: 6-Phosphogluconate dehydrogenase (6PGD) is the third enzyme in the oxidative pentose phosphate pathway (PPP). Recently, we reported that knockdown of 6PGD inhibited lung tumor growth in vitro and in a xenograft model in mice. In this study, we continued to examine the functional role of 6PGD in cancer. We show that 6PGD expression positively correlates with advancing stage of lung carcinoma. In search of functional signals related to 6PGD, we discovered that knockdown of 6PGD significantly inhibited phosphorylation of c-Met at tyrosine residues known to be critical for activity. This downregulation of c-Met phosphorylation correlated with inhibition of cell migration in vitro. Overexpression of a constitutively active c-Met specifically rescued the migration but not proliferation phenotype of 6PGD knockdown. Therefore, 6PGD appears to be required for efficient c-Met signaling and migration of tumor cells in vitro.

  7. The Met receptor tyrosine kinase prevents zebrafish primary motoneurons from expressing an incorrect neurotransmitter

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    Eisen Judith S

    2008-07-01

    Full Text Available Abstract Background Expression of correct neurotransmitters is crucial for normal nervous system function. How neurotransmitter expression is regulated is not well-understood; however, previous studies provide evidence that both environmental signals and intrinsic differentiation programs are involved. One environmental signal known to regulate neurotransmitter expression in vertebrate motoneurons is Hepatocyte growth factor, which acts through the Met receptor tyrosine kinase and also affects other aspects of motoneuron differentiation, including axonal extension. Here we test the role of Met in development of motoneurons in embryonic zebrafish. Results We found that met is expressed in all early developing, individually identified primary motoneurons and in at least some later developing secondary motoneurons. We used morpholino antisense oligonucleotides to knock down Met function and found that Met has distinct roles in primary and secondary motoneurons. Most secondary motoneurons were absent from met morpholino-injected embryos, suggesting that Met is required for their formation. We used chemical inhibitors to test several downstream pathways activated by Met and found that secondary motoneuron development may depend on the p38 and/or Akt pathways. In contrast, primary motoneurons were present in met morpholino-injected embryos. However, a significant fraction of them had truncated axons. Surprisingly, some CaPs in met morpholino antisense oligonucleotide (MO-injected embryos developed a hybrid morphology in which they had both a peripheral axon innervating muscle and an interneuron-like axon within the spinal cord. In addition, in met MO-injected embryos primary motoneurons co-expressed mRNA encoding Choline acetyltransferase, the synthetic enzyme for their normal neurotransmitter, acetylcholine, and mRNA encoding Glutamate decarboxylase 1, the synthetic enzyme for GABA, a neurotransmitter never normally found in these motoneurons, but

  8. Magic-factor 1, a partial agonist of Met, induces muscle hypertrophy by protecting myogenic progenitors from apoptosis.

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    Marco Cassano

    Full Text Available BACKGROUND: Hepatocyte Growth Factor (HGF is a pleiotropic cytokine of mesenchymal origin that mediates a characteristic array of biological activities including cell proliferation, survival, motility and morphogenesis. Its high affinity receptor, the tyrosine kinase Met, is expressed by a wide range of tissues and can be activated by either paracrine or autocrine stimulation. Adult myogenic precursor cells, the so called satellite cells, express both HGF and Met. Following muscle injury, autocrine HGF-Met stimulation plays a key role in promoting activation and early division of satellite cells, but is shut off in a second phase to allow myogenic differentiation. In culture, HGF stimulation promotes proliferation of muscle precursors thereby inhibiting their differentiation. METHODOLOGY/PRINCIPAL FINDINGS: Magic-Factor 1 (Met-Activating Genetically Improved Chimeric Factor-1 or Magic-F1 is an HGF-derived, engineered protein that contains two Met-binding domains repeated in tandem. It has a reduced affinity for Met and, in contrast to HGF it elicits activation of the AKT but not the ERK signaling pathway. As a result, Magic-F1 is not mitogenic but conserves the ability to promote cell survival. Here we show that Magic-F1 protects myogenic precursors against apoptosis, thus increasing their fusion ability and enhancing muscular differentiation. Electrotransfer of Magic-F1 gene into adult mice promoted muscular hypertrophy and decreased myocyte apoptosis. Magic-F1 transgenic mice displayed constitutive muscular hypertrophy, improved running performance and accelerated muscle regeneration following injury. Crossing of Magic-F1 transgenic mice with alpha-sarcoglycan knock-out mice -a mouse model of muscular dystrophy- or adenovirus-mediated Magic-F1 gene delivery resulted in amelioration of the dystrophic phenotype as measured by both anatomical/histological analysis and functional tests. CONCLUSIONS/SIGNIFICANCE: Because of these features Magic-F1

  9. Anti-Differentiation Effect of Oncogenic Met Receptor in Terminally-Differentiated Myotubes

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    Valentina Sala

    2015-02-01

    Full Text Available Activation of the hepatocyte growth factor/Met receptor is involved in muscle regeneration, through promotion of proliferation and inhibition of differentiation in myogenic stem cells (MSCs. We previously described that the specific expression of an oncogenic version of the Met receptor (Tpr–Met in terminally-differentiated skeletal muscle causes muscle wasting in vivo. Here, we induced Tpr–Met in differentiated myotube cultures derived from the transgenic mouse. These cultures showed a reduced protein level of myosin heavy chain (MyHC, increased phosphorylation of Erk1,2 MAPK, the formation of giant sacs of myonuclei and the collapse of elongated myotubes. Treatment of the cultures with an inhibitor of the MAPK kinase pathway or with an inhibitor of the proteasome increased the expression levels of MyHC. In addition, the inhibition of the MAPK kinase pathway prevented the formation of myosacs and myotube collapse. Finally, we showed that induction of Tpr–Met in primary myotubes was unable to produce endoreplication in their nuclei. In conclusion, our data indicate that multinucleated, fused myotubes may be forced to disassemble their contractile apparatus by the Tpr–Met oncogenic factor, but they resist the stimulus toward the reactivation of the cell cycle.

  10. Inhibition of c-Met activation sensitizes osteosarcoma cells to cisplatin via suppression of the PI3K-Akt signaling.

    Science.gov (United States)

    Wang, Kelai; Zhuang, Yan; Liu, Chunlan; Li, Yang

    2012-10-01

    Osteosarcoma is a common malignant bone tumor. Cisplatin (CDDP) achieves a high response rate in osteosarcoma. However, osteosarcoma usually exhibits cisplatin resistance. Many members of receptor tyrosine kinases (RTKs)(1) have been demonstrated to be overexpressed and constitutively activated in various tumors including osteosarcoma, resulting in malignant progression and insensitivity to chemotherapy. Hepatocyte growth factor receptor (HGFR/c-Met) also appears overexpressed and activated in osteosarcoma cells. Nevertheless, which role of c-Met activation in cisplatin efficacy against osteosarcoma cells remains still elusive. This study found that inhibition of c-Met activity by PHA-665752 or blockade of the interaction of autocrined HGF with c-Met with neutralizing anti-HGF antibody promoted cisplatin efficacy in osteosarcoma cells, while addition of recombinant human HGF (rh-HGF) counteracts cisplatin cytotoxicity. Specifically, we demonstrated that inhibition of c-Met activity led to suppression of the PI3K-Akt pathway, thus enhancing cisplatin chemosensitivity. Our study clearly suggests that inhibition of c-Met activity can effectively sensitize osteosarcoma cells to cisplatin via suppression of the PI3K-Akt signaling.

  11. The c-Met Inhibitor MSC2156119J Effectively Inhibits Tumor Growth in Liver Cancer Models

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    Bladt, Friedhelm, E-mail: Friedhelm.Bladt@merckgroup.com; Friese-Hamim, Manja; Ihling, Christian; Wilm, Claudia; Blaukat, Andree [EMD Serono, and Merck Serono Research and Development, Merck KGaA, Darmstadt 64293 (Germany)

    2014-08-19

    The mesenchymal-epithelial transition factor (c-Met) is a receptor tyrosine kinase with hepatocyte growth factor (HGF) as its only high-affinity ligand. Aberrant activation of c-Met is associated with many human malignancies, including hepatocellular carcinoma (HCC). We investigated the in vivo antitumor and antimetastatic efficacy of the c-Met inhibitor MSC2156119J (EMD 1214063) in patient-derived tumor explants. BALB/c nude mice were inoculated with MHCC97H cells or with tumor fragments of 10 patient-derived primary liver cancer explants selected according to c-Met/HGF expression levels. MSC2156119J (10, 30, and 100 mg/kg) and sorafenib (50 mg/kg) were administered orally as single-agent treatment or in combination, with vehicle as control. Tumor response, metastases formation, and alpha fetoprotein (AFP) levels were measured. MSC2156119J inhibited tumor growth and induced complete regression in mice bearing subcutaneous and orthotopic MHCC97H tumors. AFP levels were undetectable after 5 weeks of MSC2156119J treatment, and the number of metastatic lung foci was reduced. Primary liver explant models with strong c-Met/HGF activation showed increased responsiveness to MSC2156119J, with MSC2156119J showing similar or superior activity to sorafenib. Tumors characterized by low c-Met expression were less sensitive to MSC2156119J. MSC2156119J was better tolerated than sorafenib, and combination therapy did not improve efficacy. These findings indicate that selective c-Met/HGF inhibition with MSC2156119J is associated with marked regression of c-Met high-expressing tumors, supporting its clinical development as an antitumor treatment for HCC patients with active c-Met signaling.

  12. Co-cultivation of pancreatic cancer cells with orthotopic tumor-derived fibroblasts: fibroblasts stimulate tumor cell invasion via HGF secretion whereas cancer cells exert a minor regulative effect on fibroblasts HGF production.

    Science.gov (United States)

    Qian, Li-Wu; Mizumoto, Kazuhiro; Maehara, Naoki; Ohuchida, Kenoki; Inadome, Naoki; Saimura, Michiyo; Nagai, Eishi; Matsumoto, Kunio; Nakamura, Toshikazu; Tanaka, Masao

    2003-02-10

    The intensive stromal reaction is one of characteristics of pancreatic exocrine carcinoma. The mutual interaction between pancreatic cancer cells and orthotopic tumor-derived fibroblasts have not been clarified yet. In this study, we sought to elucidate the mechanism underlying the tumor-stromal interaction with an in vitro coculture experimental system. Considerable strong c-Met expression was detected in seven out ten lines of human pancreatic carcinoma cells, as determined by Western blotting. For hepatocyte growth factor (HGF)-production, however, none or only trace amounts of HGF could be detected in those ten cell lines. Of the two lots of tumor-derived fibroblasts obtained from two pancreatic cancer patients, the fibroblasts capable to produce HGF could initiate an apparent invasion-stimulating response in strong c-Met-expressed Suit-2 and Panc-1 cells but not in faint expressed Mia PaCa-2 and BxPC-3 cells. A specialized HGF antagonist, NK4 would effectively inhibit the fibroblast-mediated invasive growth, thus proving the key role of the paracrine-fashioned HGF/c-Met pathway in the tumor-stromal interaction. On the other hand, the regulative action of cancer cells on HGF expression of fibroblasts was also investigated using direct or indirect coculture systems. For the fibroblasts that originally did not produce HGF, cancer cells failed to show any HGF-inductive effect. For the HGF-producing fibroblasts, despite of somewhat upregulation or downregulation in fibroblast HGF expression, the feedback regulation by studied pancreatic cancer cells in both coculture modes were relatively limited. This in vitro study sketched out the interaction between cancerous and stromal compartments with an emphasis on HGF/c-Met signal pathway, thus possibly helping to unveil the more complicated mutual modulation in vivo between pancreatic cancer and host mesenchymal tissues.

  13. The novel ATP-competitive inhibitor of the MET hepatocyte growth factor receptor EMD1214063 displays inhibitory activity against selected MET-mutated variants.

    Science.gov (United States)

    Medová, Michaela; Pochon, Benoît; Streit, Bruno; Blank-Liss, Wieslawa; Francica, Paola; Stroka, Deborah; Keogh, Adrian; Aebersold, Daniel M; Blaukat, Andree; Bladt, Friedhelm; Zimmer, Yitzhak

    2013-11-01

    The receptor tyrosine kinase MET is a prime target in clinical oncology due to its aberrant activation and involvement in the pathogenesis of a broad spectrum of malignancies. Similar to other targeted kinases, primary and secondary mutations seem to represent an important resistance mechanism to MET inhibitors. Here, we report the biologic activity of a novel MET inhibitor, EMD1214063, on cells that ectopically express the mutated MET variants M1268T, Y1248H, H1112Y, L1213V, H1112L, V1110I, V1206L, and V1238I. Our results show a dose-dependent decrease in MET autophosphorylation in response to EMD1214063 in five of the eight cell lines (IC50 2-43 nmol/L). Blockade of MET by EMD1214063 was accompanied by a reduced activation of downstream effectors in cells expressing EMD1214063-sensitive mutants. In all sensitive mutant-expressing lines, EMD1214063 altered cell-cycle distribution, primarily with an increase in G1 phase. EMD1214063 strongly influenced MET-driven biologic functions, such as cellular morphology, MET-dependent cell motility, and anchorage-independent growth. To assess the in vivo efficacy of EMD1214063, we used a xenograft tumor model in immunocompromised mice bearing NIH3T3 cells expressing sensitive and resistant MET-mutated variants. Animals were randomized for the treatment with EMD1214063 (50 mg/kg/d) or vehicle only. Remarkably, five days of EMD1214063 treatment resulted in a complete regression of the sensitive H1112L-derived tumors, whereas tumor growth remained unaffected in mice with L1213V tumors and in vehicle-treated animals. Collectively, the current data identifies EMD1214063 as a potent MET small-molecule inhibitor with selective activity towards mutated MET variants. ©2013 AACR.

  14. Establishment of Multiple Myeloma Cell lines with Hepatocyte growth factor (HGF) overexpression and knockdown

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    Qadir, Fouzia

    2013-01-01

    Multiple myeloma is the malignancy of plasma cells which causes 0.9 % of all cancer related deaths. These malignant plasma cells acquire chromosomal abnormalities and complex genetic instability. Hepatocyte growth factor (HGF) is a multifunctional cytokine promoting cell proliferation, survival, motility, scattering, differentiation and morphogenesis. HGF/c-MET pathway plays an important role in multiple myeloma pathogenesis and in extravasation and homing of myeloma cells to bone marrow micr...

  15. The clinical and functional significance of c-Met in breast cancer: a review.

    Science.gov (United States)

    Ho-Yen, Colan M; Jones, J Louise; Kermorgant, Stephanie

    2015-04-08

    c-Met is a receptor tyrosine kinase that upon binding of its ligand, hepatocyte growth factor (HGF), activates downstream pathways with diverse cellular functions that are important in organ development and cancer progression. Anomalous c-Met signalling has been described in a variety of cancer types, and the receptor is regarded as a novel therapeutic target. In breast cancer there is a need to develop new treatments, particularly for the aggressive subtypes such as triple-negative and basal-like cancer, which currently lack targeted therapy. Over the last two decades, much has been learnt about the functional role of c-Met signalling in different models of breast development and cancer. This work has been complemented by clinical studies, establishing the prognostic significance of c-Met in tissue samples of breast cancer. While the clinical trials of anti-c-Met therapy in advanced breast cancer progress, there is a need to review the existing evidence so that the potential of these treatments can be better appreciated. The aim of this article is to examine the role of HGF/c-Met signalling in in vitro and in vivo models of breast cancer, to describe the mechanisms of aberrant c-Met signalling in human tissues, and to give a brief overview of the anti-c-Met therapies currently being evaluated in breast cancer patients. We will show that the HGF/c-Met pathway is associated with breast cancer progression and suggest that there is a firm basis for continued development of anti-c-Met treatment, particularly for patients with basal-like and triple-negative breast cancer.

  16. In Vivo Direct Molecular Imaging of Early Tumorigenesis and Malignant Progression Induced by Transgenic Expression of GFP-Met

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    Sharon Moshitch-Moshkovitz

    2006-05-01

    Full Text Available The tyrosine kinase receptor Met and its ligand, hepatocyte growth factor/scatter factor (HGF/SF, play an important role in normal developmental processes, as well as in tumorigenicity and metastasis. We constructed a green fluorescent protein (GFP Met chimeric molecule that functions similarly to the wild-type Met receptor and generated GFP-Met transgenic mice. These mice ubiquitously expressed GFP-Met in specific epithelial and endothelial cells and displayed enhanced GFP-Met fluorescence in sebaceous glands. Thirty-two percent of males spontaneously developed adenomas, adenocarcinomas, and angiosarcomas in their lower abdominal sebaceous glands. Approximately 70% of adenocarcinoma tumors metastasized to the kidneys, lungs, or liver. Quantitative subcellularresolution intravital imaging revealed very high levels of GFP-Met in tumor lesions and in single isolated cells surrounding them, relative to normal sebaceous glands. These single cells preceded the formation of local and distal metastases. Higher GFP-Met levels correlated with earlier tumor onset and aggressiveness, further demonstrating the role of Met-HGF/SF signaling in cellular transformation and acquisition of invasive and metastatic phenotypes. Our novel mouse model and high-resolution intravital molecular imaging create a powerful tool that enables direct realtime molecular imaging of receptor expression and localization during primary events of tumorigenicity and metastasis at single-cell resolution.

  17. The c-Met receptor tyrosine kinase inhibitor MP470 radiosensitizes glioblastoma cells

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    Bearss David

    2009-12-01

    Full Text Available Abstract Purpose Glioblastoma multiforme (GBM is resistant to current cytotoxic therapies, in part because of enhanced DNA repair. Activation of the receptor tyrosine kinase c-Met has been shown to protect cancer cells from DNA damage. We hypothesized that inhibiting c-Met would decrease this protection and thus sensitize resistant tumor cells to the effects of radiation therapy. Materials and methods Eight human GBM cell lines were screened for radiosensitivity to the small-molecule c-Met inhibitor MP470 with colony-count assays. Double-strand (ds DNA breaks was quantified by using antibodies to gamma H2AX. Western blotting demonstrate expression of RAD51, glycogen synthase kinase (GSK-3β, and other proteins. A murine xenograft tumor flank model was used for in vivo radiosensitization studies. Results MP470 reduced c-Met phosphorylation and enhanced radiation-induced cell kill by 0.4 logs in SF767 cells. Cells pretreated with MP470 had more ds DNA damage than cells treated with radiation alone. Mechanistically, MP470 was shown to inhibit dsDNA break repair and increase apoptosis. MP470 influences various survival and DNA repair related proteins such as pAKT, RAD51 and GSK3β. In vivo, the addition of MP470 to radiation resulted in a tumor-growth-delay enhancement ratio of 2.9 over radiation alone and extended survival time. Conclusions GBM is a disease site where radiation is often used to address both macroscopic and microscopic disease. Despite attempts at dose escalation outcomes remain poor. MP470, a potent small-molecule tyrosine kinase inhibitor of c-Met, radiosensitized several GBM cell lines both in vitro and in vivo, and may help to improve outcomes for patients with GBM.

  18. Activation of c-MET induces a stem-like phenotype in human prostate cancer.

    Directory of Open Access Journals (Sweden)

    Geert J L H van Leenders

    Full Text Available Prostate cancer consists of secretory cells and a population of immature cells. The function of immature cells and their mutual relation with secretory cells are still poorly understood. Immature cells either have a hierarchical relation to secretory cells (stem cell model or represent an inducible population emerging upon appropriate stimulation of differentiated cells. Hepatocyte Growth Factor (HGF receptor c-MET is specifically expressed in immature prostate cells. Our objective is to determine the role of immature cells in prostate cancer by analysis of the HGF/c-MET pathway.Gene-expression profiling of DU145 prostate cancer cells stimulated with HGF revealed induction of a molecular signature associated with stem cells, characterized by up-regulation of CD49b, CD49f, CD44 and SOX9, and down-regulation of CD24 ('stem-like signature'. We confirmed the acquisition of a stem-like phenotype by quantitative PCR, FACS analysis and Western blotting. Further, HGF led to activation of the stem cell related Notch pathway by up-regulation of its ligands Jagged-1 and Delta-like 4. Small molecules SU11274 and PHA665752 targeting c-MET activity were both able to block the molecular and biologic effects of HGF. Knock-down of c-MET by shRNA infection resulted in significant reduction and delay of orthotopic tumour-formation in male NMRI mice. Immunohistochemical analysis in prostatectomies revealed significant enrichment of c-MET positive cells at the invasive front, and demonstrated co-expression of c-MET with stem-like markers CD49b and CD49f.In conclusion, activation of c-MET in prostate cancer cells induced a stem-like phenotype, indicating a dynamic relation between differentiated and stem-like cells in this malignancy. Its mediation of efficient tumour-formation in vivo and predominant receptor expression at the invasive front implicate that c-MET regulates tumour infiltration in surrounding tissues putatively by acquisition of a stem-like phenotype.

  19. The EGFR/ErbB3 Pathway Acts as a Compensatory Survival Mechanism upon c-Met Inhibition in Human c-Met+ Hepatocellular Carcinoma.

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    Steven N Steinway

    Full Text Available c-Met, a high-affinity receptor for Hepatocyte Growth Factor (HGF, plays a critical role in tumor growth, invasion, and metastasis. Hepatocellular carcinoma (HCC patients with activated HGF/c-Met signaling have a significantly worse prognosis. Targeted therapies using c-Met tyrosine kinase inhibitors are currently in clinical trials for HCC, although receptor tyrosine kinase inhibition in other cancers has demonstrated early success. Unfortunately, therapeutic effect is frequently not durable due to acquired resistance.We utilized the human MHCC97-H c-Met positive (c-Met+ HCC cell line to explore the compensatory survival mechanisms that are acquired after c-Met inhibition. MHCC97-H cells with stable c-Met knockdown (MHCC97-H c-Met KD cells were generated using a c-Met shRNA vector with puromycin selection and stably transfected scrambled shRNA as a control. Gene expression profiling was conducted, and protein expression was analyzed to characterize MHCC97-H cells after blockade of the c-Met oncogene. A high-throughput siRNA screen was performed to find putative compensatory survival proteins, which could drive HCC growth in the absence of c-Met. Findings from this screen were validated through subsequent analyses.We have previously demonstrated that treatment of MHCC97-H cells with a c-Met inhibitor, PHA665752, results in stasis of tumor growth in vivo. MHCC97-H c-Met KD cells demonstrate slower growth kinetics, similar to c-Met inhibitor treated tumors. Using gene expression profiling and siRNA screening against 873 kinases and phosphatases, we identified ErbB3 and TGF-α as compensatory survival factors that are upregulated after c-Met inhibition. Suppressing these factors in c-Met KD MHCC97-H cells suppresses tumor growth in vitro. In addition, we found that the PI3K/Akt signaling pathway serves as a negative feedback signal responsible for the ErbB3 upregulation after c-Met inhibition. Furthermore, in vitro studies demonstrate that

  20. Efficacy of c-Met inhibitor for advanced prostate cancer

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    Christensen James G

    2010-10-01

    Full Text Available Abstract Background Aberrant expression of HGF/SF and its receptor, c-Met, often correlates with advanced prostate cancer. Our previous study showed that expression of c-Met in prostate cancer cells was increased after attenuation of androgen receptor (AR signalling. This suggested that current androgen ablation therapy for prostate cancer activates c-Met expression and may contribute to development of more aggressive, castration resistant prostate cancer (CRPC. Therefore, we directly assessed the efficacy of c-Met inhibition during androgen ablation on the growth and progression of prostate cancer. Methods We tested two c-Met small molecule inhibitors, PHA-665752 and PF-2341066, for anti-proliferative activity by MTS assay and cell proliferation assay on human prostate cancer cell lines with different levels of androgen sensitivity. We also used renal subcapsular and castrated orthotopic xenograft mouse models to assess the effect of the inhibitors on prostate tumor formation and progression. Results We demonstrated a dose-dependent inhibitory effect of PHA-665752 and PF-2341066 on the proliferation of human prostate cancer cells and the phosphorylation of c-Met. The effect on cell proliferation was stronger in androgen insensitive cells. The c-Met inhibitor, PF-2341066, significantly reduced growth of prostate tumor cells in the renal subcapsular mouse model and the castrated orthotopic mouse model. The effect on cell proliferation was greater following castration. Conclusions The c-Met inhibitors demonstrated anti-proliferative efficacy when combined with androgen ablation therapy for advanced prostate cancer.

  1. Met receptor tyrosine kinase signaling induces secretion of the angiogenic chemokine interleukin-8/CXCL8 in pancreatic cancer.

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    Kristen S Hill

    Full Text Available At diagnosis, the majority of pancreatic cancer patients present with advanced disease when curative resection is no longer feasible and current therapeutic treatments are largely ineffective. An improved understanding of molecular targets for effective intervention of pancreatic cancer is thus urgent. The Met receptor tyrosine kinase is one candidate implicated in pancreatic cancer. Notably, Met is over expressed in up to 80% of invasive pancreatic cancers but not in normal ductal cells correlating with poor overall patient survival and increased recurrence rates following surgical resection. However the functional role of Met signaling in pancreatic cancer remains poorly understood. Here we used RNA interference to directly examine the pathobiological importance of increased Met signaling for pancreatic cancer. We show that Met knockdown in pancreatic tumor cells results in decreased cell survival, cell invasion, and migration on collagen I in vitro. Using an orthotopic model for pancreatic cancer, we provide in vivo evidence that Met knockdown reduced tumor burden correlating with decreased cell survival and tumor angiogenesis, with minimal effect on cell growth. Notably, we report that Met signaling regulates the secretion of the pro-angiogenic chemokine interleukin-8/CXCL8. Our data showing that the interleukin-8 receptors CXCR1 and CXCR2 are not expressed on pancreatic tumor cells, suggests a paracrine mechanism by which Met signaling regulates interleukin-8 secretion to remodel the tumor microenvironment, a novel finding that could have important clinical implications for improving the effectiveness of treatments for pancreatic cancer.

  2. HGF/c-MET Pathway in AIDS-Related Lymphoma

    Science.gov (United States)

    2016-09-01

    Morrow RA, Corey L, Kiviat N, Wald A. HIV infection and human herpesvirus-8 oral shedding among men who have sex with men. J Acquir Immune Defic...progression, membrane trafficking , and stage differentiation in Giardia lamblia. J Lipid Res 2010; 519:2527-2545. 28. Abe A, Wu D, Shayman JA and Radin NS

  3. Human adult chondrocytes express hepatocyte growth factor (HGF) isoforms but not HgF: potential implication of osteoblasts on the presence of HGF in cartilage.

    Science.gov (United States)

    Guévremont, Melanie; Martel-Pelletier, Johanne; Massicotte, Frédéric; Tardif, Ginette; Pelletier, Jean-Pierre; Ranger, Pierre; Lajeunesse, Daniel; Reboul, Pascal

    2003-06-01

    HGF is increased in human OA cartilage, possibly from Ob's. RT-PCR shows HGF isoforms are differently regulated between chondrocytes and Ob. A paracrine cross-talk between subchondral bone and cartilage may occur during OA. Recently, hepatocyte growth factor (HGF) has been identified by immunohistochemistry in cartilage and more particularly in the deep zone of human osteoarthritic (OA) cartilage. By investigating HGF expression in cartilage, we found that chondrocytes did not express HGF; however, they expressed the two truncated isoforms, namely HGF/NK1 and HGF/NK2. Because the only other cells localized near the deep zone are osteoblasts from the subchondral bone plate, we hypothesized that they were expressing HGF. Indeed, we found that HGF was synthesized by osteoblasts from the subchondral bone plate. Moreover, OA osteoblasts produced five times more HGF than normal osteoblasts and almost no HGF/NK1, unlike normal osteoblasts. Because prostaglandin E2 (PGE2) and pro-inflammatory cytokines such as interleukin (IL)-1 and IL-6 are involved in OA progression, we investigated whether these factors impact HGF produced by normal osteoblasts. PGE2 was the only factor tested that was able to stimulate HGF synthesis. However, the addition of NS398, a selective inhibitor of cyclo-oxygenase-2 (COX-2) had no effect on HGF produced by OA osteoblasts. HGF/NK2 had a moderate stimulating effect on HGF production by normal osteoblasts, whereas osteocalcin was not modulated by either HGF or HGF/NK2. When investigating signaling routes that might be implicated in OA osteoblast-produced HGF, we found that protein kinase A was at least partially involved. In summary, this study raises the hypothesis that the HGF found in articular cartilage is produced by osteoblasts, diffuses into the cartilage, and may be implicated in the OA process.

  4. Expressions of estrogen receptor subtypes and c-met proto-oncogene in endometrial carcinoma and their correlation

    Institute of Scientific and Technical Information of China (English)

    2010-01-01

    Objective To investigate the expressions of estrogen receptor(ER)subtypes and c-met proto-oncogene in human endometrial carcinomas and to assess the clinical significance of ER and c-met in this carcinoma.Methods Reverse transcription PCR(RT-PCR)was used to detect the expressions of ERα,ERβ and c-met proto-oncogene mRNA in 30 samples of endometrial carcinoma and 11 samples of normal endometrium.Results The expression of ERα in endometrial carcinoma(0.70±0.40)was significantly reduced in comparison to that i...

  5. Receptor-type Protein Tyrosine Phosphatase β Regulates Met Phosphorylation and Function in Head and Neck Squamous Cell Carcinoma

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    Yiru Xu

    2012-11-01

    Full Text Available Head and neck squamous cell carcinoma (HNSCC is the sixth most common cancer and has a high rate of mortality. Emerging evidence indicates that hepatocyte growth factor receptor (or Met pathway plays a pivotal role in HNSCC metastasis and resistance to chemotherapy. Met function is dependent on tyrosine phosphorylation that is under direct control by receptor-type protein tyrosine phosphatase β (RPTP-β. We report here that RPTP-β expression is significantly downregulated in HNSCC cells derived from metastatic tumors compared to subject-matched cells from primary tumors. Knockdown of endogenous RPTP-β in HNSCC cells from primary tumor potentiated Met tyrosine phosphorylation, downstream mitogen-activated protein (MAP kinase pathway activation, cell migration, and invasion. Conversely, restoration of RPTP-β expression in cells from matched metastatic tumor decreased Met tyrosine phosphorylation and downstream functions. Furthermore, we observed that six of eight HNSCC tumors had reduced levels of RPTP-β protein in comparison with normal oral tissues. Collectively, the results demonstrate the importance of RPTP-β in tumor biology of HNSCC through direct dephosphorylation of Met and regulation of downstream signal transduction pathways. Reduced RPTP-β levels, with or without Met overexpression, could promote Met activation in HNSCC tumors.

  6. The MET Receptor Tyrosine Kinase Confers Repair of Murine Pancreatic Acinar Cells following Acute and Chronic Injury

    Science.gov (United States)

    Gaziova, Ivana; Jackson, Daniel; Boor, Paul J.; Carter, Dwayne; Cruz-Monserrate, Zobeida; Elferink, Cornelis J.; Joshi, Aditya D.; Kaphalia, Bhupendra; Logsdon, Craig D.; Pereira de Castro, Karen; Soong, Lynn; Tao, Xinrong; Qiu, Suimin; Elferink, Lisa A.

    2016-01-01

    Acinar cells represent the primary target in necroinflammatory diseases of the pancreas, including pancreatitis. The signaling pathways guiding acinar cell repair and regeneration following injury remain poorly understood. The purpose of this study was to determine the importance of Hepatocyte Growth Factor Receptor/MET signaling as an intrinsic repair mechanism for acinar cells following acute damage and chronic alcohol-associated injury. Here, we generated mice with targeted deletion of MET in adult acinar cells (MET-/-). Acute and repetitive pancreatic injury was induced in MET-/- and control mice with cerulein, and chronic injury by feeding mice Lieber-DeCarli diets containing alcohol with or without enhancement of repetitive pancreatic injury. We examined the exocrine pancreas of these mice histologically for acinar death, edema, inflammation and collagen deposition and changes in the transcriptional program. We show that MET expression is relatively low in normal adult pancreas. However, MET levels were elevated in ductal and acinar cells in human pancreatitis specimens, consistent with a role for MET in an adaptive repair mechanism. We report that genetic deletion of MET in adult murine acinar cells was linked to increased acinar cell death, chronic inflammation and delayed recovery (regeneration) of pancreatic exocrine tissue. Notably, increased pancreatic collagen deposition was detected in MET knockout mice following repetitive injury as well alcohol-associated injury. Finally, we identified specific alterations of the pancreatic transcriptome associated with MET signaling during injury, involved in tissue repair, inflammation and endoplasmic reticulum stress. Together, these data demonstrate the importance of MET signaling for acinar repair and regeneration, a novel finding that could attenuate the symptomology of pancreatic injury. PMID:27798657

  7. Biochemical and pharmacological characterization of human c-Met neutralizing monoclonal antibody CE-355621

    Science.gov (United States)

    Michaud, Neil R.; Jani, Jitesh P.; Hillerman, Stephen; Tsaparikos, Konstantinos E.; Barbacci-Tobin, Elsa G.; Knauth, Elisabeth; Putz Jr., Henry; Campbell, Mary; Karam, George A.; Chrunyk, Boris; Gebhard, David F.; Green, Larry L.; Xu, Jinghai J.; Dunn, Margaret C.; Coskran, Tim M.; Lapointe, Jean-Martin; Cohen, Bruce D.; Coleman, Kevin G.; Bedian, Vahe; Vincent, Patrick; Kajiji, Shama; Steyn, Stefan J.; Borzillo, Gary V.; Los, Gerrit

    2012-01-01

    The c-Met proto-oncogene is a multifunctional receptor tyrosine kinase that is stimulated by its ligand, hepatocyte growth factor (HGF), to induce cell growth, motility and morphogenesis. Dysregulation of c-Met function, through mutational activation or overexpression, has been observed in many types of cancer and is thought to contribute to tumor growth and metastasis by affecting mitogenesis, invasion, and angiogenesis. We identified human monoclonal antibodies that bind to the extracellular domain of c-Met and inhibit tumor growth by interfering with ligand-dependent c-Met activation. We identified antibodies representing four independent epitope classes that inhibited both ligand binding and ligand-dependent activation of c-Met in A549 cells. In cells, the antibodies antagonized c-Met function by blocking receptor activation and by subsequently inducing downregulation of the receptor, translating to phenotypic effects in soft agar growth and tubular morphogenesis assays. Further characterization of the antibodies in vivo revealed significant inhibition of c-Met activity (≥ 80% lasting for 72–96 h) in excised tumors corresponded to tumor growth inhibition in multiple xenograft tumor models. Several of the antibodies identified inhibited the growth of tumors engineered to overexpress human HGF and human c-Met (S114 NIH 3T3) when grown subcutaneously in athymic mice. Furthermore, lead candidate antibody CE-355621 inhibited the growth of U87MG human glioblastoma and GTL-16 gastric xenografts by up to 98%. The findings support published pre-clinical and clinical data indicating that targeting c-Met with human monoclonal antibodies is a promising therapeutic approach for the treatment of cancer. PMID:23007574

  8. Delivery of an engineered HGF fragment in an extracellular matrix-derived hydrogel prevents negative LV remodeling post-myocardial infarction.

    Science.gov (United States)

    Sonnenberg, Sonya B; Rane, Aboli A; Liu, Cassie J; Rao, Nikhil; Agmon, Gillie; Suarez, Sophia; Wang, Raymond; Munoz, Adam; Bajaj, Vaibhav; Zhang, Shirley; Braden, Rebecca; Schup-Magoffin, Pamela J; Kwan, Oi Ling; DeMaria, Anthony N; Cochran, Jennifer R; Christman, Karen L

    2015-03-01

    Hepatocyte growth factor (HGF) has been shown to have anti-fibrotic, pro-angiogenic, and cardioprotective effects; however, it is highly unstable and expensive to manufacture, hindering its clinical translation. Recently, a HGF fragment (HGF-f), an alternative c-MET agonist, was engineered to possess increased stability and recombinant expression yields. In this study, we assessed the potential of HGF-f, delivered in an extracellular matrix (ECM)-derived hydrogel, as a potential treatment for myocardial infarction (MI). HGF-f protected cardiomyocytes from serum-starvation and induced down-regulation of fibrotic markers in whole cardiac cell isolate compared to the untreated control. The ECM hydrogel prolonged release of HGF-f compared to collagen gels, and in vivo delivery of HGF-f from ECM hydrogels mitigated negative left ventricular (LV) remodeling, improved fractional area change (FAC), and increased arteriole density in a rat myocardial infarction model. These results indicate that HGF-f may be a viable alternative to using recombinant HGF, and that an ECM hydrogel can be employed to increase growth factor retention and efficacy.

  9. Genetic Evidence for Function of the bHLH-PAS Protein Gce/Met As a Juvenile Hormone Receptor.

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    Marek Jindra

    2015-07-01

    Full Text Available Juvenile hormones (JHs play a major role in controlling development and reproduction in insects and other arthropods. Synthetic JH-mimicking compounds such as methoprene are employed as potent insecticides against significant agricultural, household and disease vector pests. However, a receptor mediating effects of JH and its insecticidal mimics has long been the subject of controversy. The bHLH-PAS protein Methoprene-tolerant (Met, along with its Drosophila melanogaster paralog germ cell-expressed (Gce, has emerged as a prime JH receptor candidate, but critical evidence that this protein must bind JH to fulfill its role in normal insect development has been missing. Here, we show that Gce binds a native D. melanogaster JH, its precursor methyl farnesoate, and some synthetic JH mimics. Conditional on this ligand binding, Gce mediates JH-dependent gene expression and the hormone's vital role during development of the fly. Any one of three different single amino acid mutations in the ligand-binding pocket that prevent binding of JH to the protein block these functions. Only transgenic Gce capable of binding JH can restore sensitivity to JH mimics in D. melanogaster Met-null mutants and rescue viability in flies lacking both Gce and Met that would otherwise die at pupation. Similarly, the absence of Gce and Met can be compensated by expression of wild-type but not mutated transgenic D. melanogaster Met protein. This genetic evidence definitively establishes Gce/Met in a JH receptor role, thus resolving a long-standing question in arthropod biology.

  10. NK3 and NK4 of HGF enhance filamin production via STAT pathway, but not NK1 and NK2 in human breast cancer cells

    Institute of Scientific and Technical Information of China (English)

    Ya-ling LIN; Hsiu-ling CHEN; Hsiu-maan KUO; Shi-ping HE

    2008-01-01

    Aim: The purpose of this study was to reveal the effects of hepatocyte growth factor (HGF) variants on human breast cancer cells and the differential signaling pathways of the variants in controlling cell proliferation and invasion. Methods: Four HGF variants (NK1, NK2, NK3, and NK4) were created by gene engineering, and the variant DNA fragments were cloned into pGEM-T for DNA sequencing and then transferred to a pTrcHis-A plasmid for expression. Recombinant pro-teins were purified from Escherichia coll, and a series of assays, including cell proliferation and invasion were carried out. Phosphorylated components in the HGF-c-Met and STAT (signal transducers and activators of transcription) path-ways were detected by immunoprecipitation-Western blots. Results: All the HGF variants inhibited the vigorous growth of the cancer cells differently and dose-dependently, but the effect of NK3 or NK4 was 7.5-fold higher than NK 1 or NK2. In addition, the assays for the phosphorylation of the components in the HGF-c-Met pathway showed that NK3 and NK4 inhibited invasion via the STAT pathway, whereas NK1 and NK2 were via the HGF--c-Met pathway. Conclusion: The engineered HGF variants inhibited the proliferation of human breast cancer cells via different signaling pathways, NK1 and NK2 via the HGF-c-Met pathways, and NK3 and NK4 via the STAT pathway, the latter being a possible key route for the inhibition of cell invasion. All of the HGF variants have the potential to become pharmaceutical drugs in the treatment of human cancer.

  11. cMET in NSCLC: Can We Cut off the Head of the Hydra? From the Pathway to the Resistance

    Directory of Open Access Journals (Sweden)

    Nele Van Der Steen

    2015-03-01

    Full Text Available In the last decade, the tyrosine kinase receptor cMET, together with its ligand hepatocyte growth factor (HGF, has become a target in non-small cell lung cancer (NSCLC. Signalization via cMET stimulates several oncological processes amongst which are cell motility, invasion and metastasis. It also confers resistance against several currently used targeted therapies, e.g., epidermal growth factor receptor (EGFR inhibitors. In this review, we will discuss the basic structure of cMET and the most important signaling pathways. We will also look into aberrations in the signaling and the effects thereof in cancer growth, with the focus on NSCLC. Finally, we will discuss the role of cMET as resistance mechanism.

  12. cMET in NSCLC: Can We Cut off the Head of the Hydra? From the Pathway to the Resistance

    Energy Technology Data Exchange (ETDEWEB)

    Van Der Steen, Nele [Center for Oncological Research Antwerp, University of Antwerp, Universiteitsplein 1, Wilrijk 2610 (Belgium); Pauwels, Patrick [Center for Oncological Research Antwerp, University of Antwerp, Universiteitsplein 1, Wilrijk 2610 (Belgium); Molecular Pathology Unit, Pathology Department, Antwerp University Hospital, Wilrijkstraat 10, Edegem 2650 (Belgium); Gil-Bazo, Ignacio [Department of Oncology, Clínica Universidad de Navarra, Pamplona 31008 (Spain); Castañon, Eduardo [Department of Oncology, Clínica Universidad de Navarra, Pamplona 31008 (Spain); Phase I-Early Clinical Trials Unit, Oncology Department, Antwerp University Hospital, Wilrijkstraat 10, Edegem 2650 (Belgium); Raez, Luis [Thoracic Oncology Program, Memorial Cancer Institute, Memorial Health Care System, Pembroke Pines, FL 33024 (United States); Cappuzzo, Federico [4Thoracic Oncology Program, Memorial Cancer Institute, Memorial Health Care System, Pembroke Pines, FL 33024 (United States); Rolfo, Christian, E-mail: Christian.Rolfo@uza.be [Center for Oncological Research Antwerp, University of Antwerp, Universiteitsplein 1, Wilrijk 2610 (Belgium); Phase I-Early Clinical Trials Unit, Oncology Department, Antwerp University Hospital, Wilrijkstraat 10, Edegem 2650 (Belgium)

    2015-03-25

    In the last decade, the tyrosine kinase receptor cMET, together with its ligand hepatocyte growth factor (HGF), has become a target in non-small cell lung cancer (NSCLC). Signalization via cMET stimulates several oncological processes amongst which are cell motility, invasion and metastasis. It also confers resistance against several currently used targeted therapies, e.g., epidermal growth factor receptor (EGFR) inhibitors. In this review, we will discuss the basic structure of cMET and the most important signaling pathways. We will also look into aberrations in the signaling and the effects thereof in cancer growth, with the focus on NSCLC. Finally, we will discuss the role of cMET as resistance mechanism.

  13. EGFR is dispensable for c-Met-mediated proliferation and survival activities in mouse adult liver oval cells.

    Science.gov (United States)

    Martínez-Palacián, A; del Castillo, G; Herrera, B; Fernández, M; Roncero, C; Fabregat, I; Sánchez, A

    2012-02-01

    Liver progenitor cells rise as potential critical players in hepatic regeneration but also carcinogenesis. It is therefore mandatory to define the signals controlling their activation and expansion. Recently, by using a novel in vitro model of oval cell lines expressing a mutant tyrosine kinase-inactive form of c-Met we demonstrated that autocrine c-Met signalling plays an essential role in promoting oval cell survival. Here, we investigated the significance of the epidermal growth factor receptor (EGFR) signalling in oval cell proliferation and survival, as well as a potential functional crosstalk between the c-Met and the EGFR pathways. We found an autocrine activation of the EGFR-triggered pathway in Met(flx/flx) and Met(-/-) oval cells as judged by constitutive expression of the EGFR ligands, transforming growth factor-alpha (TGF-α) and heparin-binding EGF like growth factor (HB-EGF), and activation of EGFR. On the other hand, treatment with AG1478, a specific inhibitor of EGFR, effectively blocked endogenous and EGF-induced proliferation, while increased serum withdrawal and transforming growth factor-beta (TGF-β)-induced apoptosis. These results suggest that constitutively activated EGFR might promote oval cell proliferation and survival. We found that hepatocyte growth factor (HGF) does not transactivate EGFR nor EGF transactivates c-Met. Furthermore, treatment with AG1478 or EGFR gene silencing did not interfere with HGF-mediated activation of target signals, such as protein kinase B (AKT/PKB), and extracellular signal-regulated kinases 1/2 (ERK 1/2), nor did it have any effect on HGF-induced proliferative and antiapoptotic activities in Met(flx/flx) cells, showing that HGF does not require EGFR activation to mediate such responses. EGF induced proliferation and survival equally in Met(flx/flx) and Met(-/-) oval cells, proving that EGFR signalling does not depend on c-Met tyrosine kinase activity. Together, our results provide strong evidence that in

  14. MET Suppresses Epithelial VEGFR2 via Intracrine VEGF-induced Endoplasmic Reticulum-associated Degradation

    Directory of Open Access Journals (Sweden)

    Tom T. Chen

    2015-05-01

    Full Text Available Hepatocyte growth factor (HGF and vascular endothelial growth factor (VEGF drive cancer through their respective receptors, MET and VEGF receptor 2 (VEGFR2. VEGFR2 inhibits MET by promoting MET dephosphorylation. However, whether MET conversely regulates VEGFR2 remains unknown. Here we show that MET suppresses VEGFR2 protein by inducing its endoplasmic-reticulum-associated degradation (ERAD, via intracrine VEGF action. HGF–MET signaling in epithelial cancer cells promoted VEGF biosynthesis through PI3-kinase. In turn, VEGF and VEGFR2 associated within the ER, activating inositol-requiring enzyme 1α, and thereby facilitating ERAD-mediated depletion of VEGFR2. MET disruption upregulated VEGFR2, inducing compensatory tumor growth via VEGFR2 and MEK. However, concurrent disruption of MET and either VEGF or MEK circumvented this, enabling more profound tumor inhibition. Our findings uncover unique cross-regulation between MET and VEGFR2—two RTKs that play significant roles in tumor malignancy. Furthermore, these results suggest rational combinatorial strategies for targeting RTK signaling pathways more effectively, which has potentially important implications for cancer therapy.

  15. Antagonism of the Met5-enkephalin-opioid growth factor receptor-signaling axis promotes MSC to differentiate into osteoblasts.

    Science.gov (United States)

    Thakur, Nikhil A; DeBoyace, Sean D; Margulies, Bryan S

    2016-07-01

    Chronic opioid therapy is associated with bone loss. This led us to hypothesize that the opioid antagonists, that include naloxone, would stimulate bone formation by regulating MSC differentiation. The opioid growth factor receptor (OGFR) is a non-canonical opioid receptor that binds naloxone with high affinity whereas the native opioid growth factor, met5-enkephalin (met5), binds both the OGFR and the canonical delta opioid receptor (OPRD). Naloxone and an shRNA OGFR lentivirus were employed to disrupt the OGFR-signaling axis in cultured MSC. In parallel, naloxone was administered to bone marrow using a mouse unicortical defect model. OPRD, OGFR, and the met5-ligand were highly expressed in MSC and osteoblasts. A pulse-dose of naloxone increased mineral formation in MSC cultures in contrast to MSC treated with continuous naloxone or OGFR deficient MSC. Importantly, SMAD1 and SMAD8/9 expression increased after a pulse dose of naloxone whereas SMAD1, SMAD7, and ID1 were increased in the OGFR deficient MSC. Inhibited OGFR signaling decreased proliferation and increased p21 expression. The addition of naloxone to the unicortical defect resulted in increased bone formation within the defect. Our data suggest that novel mechanism through which signaling through the OGFR regulates osteogenesis via negative regulation of SMAD1 and p21. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:1195-1205, 2016.

  16. The Molecular Crosstalk between the MET Receptor Tyrosine Kinase and the DNA Damage Response — Biological and Clinical Aspects

    Energy Technology Data Exchange (ETDEWEB)

    Medová, Michaela, E-mail: michaela.medova@dkf.unibe.ch; Aebersold, Daniel M.; Zimmer, Yitzhak, E-mail: michaela.medova@dkf.unibe.ch [Department of Radiation Oncology, Inselspital, Bern University Hospital, and University of Bern, 3010 Bern (Switzerland); Department of Clinical Research, University of Bern, DKF, MEM-E807, Murtenstrasse 35, 3010 Bern (Switzerland)

    2013-12-19

    Radiation therapy remains an imperative treatment modality for numerous malignancies. Enduring significant technical achievements both on the levels of treatment planning and radiation delivery have led to improvements in local control of tumor growth and reduction in healthy tissue toxicity. Nevertheless, resistance mechanisms, which presumably also involve activation of DNA damage response signaling pathways that eventually may account for loco-regional relapse and consequent tumor progression, still remain a critical problem. Accumulating data suggest that signaling via growth factor receptor tyrosine kinases, which are aberrantly expressed in many tumors, may interfere with the cytotoxic impact of ionizing radiation via the direct activation of the DNA damage response, leading eventually to so-called tumor radioresistance. The aim of this review is to overview the current known data that support a molecular crosstalk between the hepatocyte growth factor receptor tyrosine kinase MET and the DNA damage response. Apart of extending well established concepts over MET biology beyond its function as a growth factor receptor, these observations directly relate to the role of its aberrant activity in resistance to DNA damaging agents, such as ionizing radiation, which are routinely used in cancer therapy and advocate tumor sensitization towards DNA damaging agents in combination with MET targeting.

  17. Interaction of apoptotic cells with macrophages upregulates COX-2/PGE2 and HGF expression via a positive feedback loop.

    Science.gov (United States)

    Byun, Ji Yeon; Youn, Young-So; Lee, Ye-Ji; Choi, Youn-Hee; Woo, So-Yeon; Kang, Jihee Lee

    2014-01-01

    Recognition of apoptotic cells by macrophages is crucial for resolution of inflammation, immune tolerance, and tissue repair. Cyclooxygenase-2 (COX-2)/prostaglandin E2 (PGE2) and hepatocyte growth factor (HGF) play important roles in the tissue repair process. We investigated the characteristics of macrophage COX-2 and PGE2 expression mediated by apoptotic cells and then determined how macrophages exposed to apoptotic cells in vitro and in vivo orchestrate the interaction between COX-2/PGE2 and HGF signaling pathways. Exposure of RAW 264.7 cells and primary peritoneal macrophages to apoptotic cells resulted in induction of COX-2 and PGE2. The COX-2 inhibitor NS-398 suppressed apoptotic cell-induced PGE2 production. Both NS-398 and COX-2-siRNA, as well as the PGE2 receptor EP2 antagonist, blocked HGF expression in response to apoptotic cells. In addition, the HGF receptor antagonist suppressed increases in COX-2 and PGE2 induction. The in vivo relevance of the interaction between the COX-2/PGE2 and HGF pathways through a positive feedback loop was shown in cultured alveolar macrophages following in vivo exposure of bleomycin-stimulated lungs to apoptotic cells. Our results demonstrate that upregulation of the COX-2/PGE2 and HGF in macrophages following exposure to apoptotic cells represents a mechanism for mediating the anti-inflammatory and antifibrotic consequences of apoptotic cell recognition.

  18. Interaction of Apoptotic Cells with Macrophages Upregulates COX-2/PGE2 and HGF Expression via a Positive Feedback Loop

    Directory of Open Access Journals (Sweden)

    Ji Yeon Byun

    2014-01-01

    Full Text Available Recognition of apoptotic cells by macrophages is crucial for resolution of inflammation, immune tolerance, and tissue repair. Cyclooxygenase-2 (COX-2/prostaglandin E2 (PGE2 and hepatocyte growth factor (HGF play important roles in the tissue repair process. We investigated the characteristics of macrophage COX-2 and PGE2 expression mediated by apoptotic cells and then determined how macrophages exposed to apoptotic cells in vitro and in vivo orchestrate the interaction between COX-2/PGE2 and HGF signaling pathways. Exposure of RAW 264.7 cells and primary peritoneal macrophages to apoptotic cells resulted in induction of COX-2 and PGE2. The COX-2 inhibitor NS-398 suppressed apoptotic cell-induced PGE2 production. Both NS-398 and COX-2-siRNA, as well as the PGE2 receptor EP2 antagonist, blocked HGF expression in response to apoptotic cells. In addition, the HGF receptor antagonist suppressed increases in COX-2 and PGE2 induction. The in vivo relevance of the interaction between the COX-2/PGE2 and HGF pathways through a positive feedback loop was shown in cultured alveolar macrophages following in vivo exposure of bleomycin-stimulated lungs to apoptotic cells. Our results demonstrate that upregulation of the COX-2/PGE2 and HGF in macrophages following exposure to apoptotic cells represents a mechanism for mediating the anti-inflammatory and antifibrotic consequences of apoptotic cell recognition.

  19. Impact of Cell-surface Antigen Expression on Target Engagement and Function of an Epidermal Growth Factor Receptor × c-MET Bispecific Antibody*

    Science.gov (United States)

    Jarantow, Stephen W.; Bushey, Barbara S.; Pardinas, Jose R.; Boakye, Ken; Lacy, Eilyn R.; Sanders, Renouard; Sepulveda, Manuel A.; Moores, Sheri L.; Chiu, Mark L.

    2015-01-01

    The efficacy of engaging multiple drug targets using bispecific antibodies (BsAbs) is affected by the relative cell-surface protein levels of the respective targets. In this work, the receptor density values were correlated to the in vitro activity of a BsAb (JNJ-61186372) targeting epidermal growth factor receptor (EGFR) and hepatocyte growth factor receptor (c-MET). Simultaneous binding of the BsAb to both receptors was confirmed in vitro. By using controlled Fab-arm exchange, a set of BsAbs targeting EGFR and c-MET was generated to establish an accurate receptor quantitation of a panel of lung and gastric cancer cell lines expressing heterogeneous levels of EGFR and c-MET. EGFR and c-MET receptor density levels were correlated to the respective gene expression levels as well as to the respective receptor phosphorylation inhibition values. We observed a bias in BsAb binding toward the more highly expressed of the two receptors, EGFR or c-MET, which resulted in the enhanced in vitro potency of JNJ-61186372 against the less highly expressed target. On the basis of these observations, we propose an avidity model of how JNJ-61186372 engages EGFR and c-MET with potentially broad implications for bispecific drug efficacy and design. PMID:26260789

  20. Impact of Cell-surface Antigen Expression on Target Engagement and Function of an Epidermal Growth Factor Receptor × c-MET Bispecific Antibody.

    Science.gov (United States)

    Jarantow, Stephen W; Bushey, Barbara S; Pardinas, Jose R; Boakye, Ken; Lacy, Eilyn R; Sanders, Renouard; Sepulveda, Manuel A; Moores, Sheri L; Chiu, Mark L

    2015-10-09

    The efficacy of engaging multiple drug targets using bispecific antibodies (BsAbs) is affected by the relative cell-surface protein levels of the respective targets. In this work, the receptor density values were correlated to the in vitro activity of a BsAb (JNJ-61186372) targeting epidermal growth factor receptor (EGFR) and hepatocyte growth factor receptor (c-MET). Simultaneous binding of the BsAb to both receptors was confirmed in vitro. By using controlled Fab-arm exchange, a set of BsAbs targeting EGFR and c-MET was generated to establish an accurate receptor quantitation of a panel of lung and gastric cancer cell lines expressing heterogeneous levels of EGFR and c-MET. EGFR and c-MET receptor density levels were correlated to the respective gene expression levels as well as to the respective receptor phosphorylation inhibition values. We observed a bias in BsAb binding toward the more highly expressed of the two receptors, EGFR or c-MET, which resulted in the enhanced in vitro potency of JNJ-61186372 against the less highly expressed target. On the basis of these observations, we propose an avidity model of how JNJ-61186372 engages EGFR and c-MET with potentially broad implications for bispecific drug efficacy and design.

  1. Targeting FGFR Pathway in Human Hepatocellular Carcinoma: Expressing pFGFR and pMET for Antitumor Activity.

    Science.gov (United States)

    Jo, Jae-Cheol; Choi, Eun Kyoung; Shin, Jae-Sik; Moon, Jai-Hee; Hong, Seung-Woo; Lee, Ha-Reum; Kim, Seung-Mi; Jung, Soo-A; Lee, Dae-Hee; Jung, Seang Hwan; Lee, Sun-Hye; Kim, Jeong Eun; Kim, Kyu-pyo; Hong, Yong Sang; Suh, Young-Ah; Jang, Se Jin; Choi, Eun Kyung; Lee, Jung Shin; Jin, Dong-Hoon; Kim, Tae Won

    2015-11-01

    The MET receptor tyrosine kinase, the receptor for hepatocyte growth factor (HGF), has been implicated in cancer growth, invasion, migration, angiogenesis, and metastasis in a broad variety of human cancers, including human hepatocellular carcinoma (HCC). Recently, MET was suggested to be a potential target for the personalized treatment of HCC with an active HGF-MET signaling pathway. However, the mechanisms of resistance to MET inhibitors need to be elucidated to provide effective treatment. Here, we show that HCC cells exhibit different sensitivities to the MET inhibitor PHA665752, depending on the phosphorylation status of FGFR. Treatment of cells expressing both phospho-FGFR and phospho-MET with the inhibitor PHA665752 did not cause growth inhibition and cell death, whereas treatment with AZD4547, a pan-FGFR inhibitor, resulted in decreased colony formation and cleavage of caspase-3. Moreover, silencing of endogenous FGFR1 and FGFR2 by RNAi of HCC cells expressing phospho-FGFR, phospho-FGFR2, and phospho-MET overcame the resistance to PHA665752 treatment. Treatment of primary cancer cells from patients with HCC expressing both phospho-FGFR and phospho-MET with PHA665752 did not induce cell death, whereas AZD4547 treatment induced cell death through the cleavage of caspase-3. In addition, treatment of cells resistant to PHA665752 with AZD4547 abrogated the activation of downstream effectors of cell growth, proliferation, and survival. On the basis of these results, we conclude that the FGFR pathway is critical for HCC survival, and that targeting this pathway with AZD4547 may be beneficial for the treatment of patients with HCC-expressing phospho-FGFR and phospho-MET. ©2015 American Association for Cancer Research.

  2. Thyroid hormone receptor-beta agonist GC-1 inhibits Met-β-catenin driven hepatocellular cancer.

    Science.gov (United States)

    Puliga, Elisabetta; Min, Qian; Tao, Junyan; Zhang, Rong; Pradhan-Sundd, Tirthadipa; Poddar, Minakshi; Singh, Sucha; Columbano, Amedeo; Yu, Jinming; Monga, Satdarshan P

    2017-08-11

    The thyromimetic agent GC-1 induces hepatocyte proliferation via Wnt/β-catenin signaling and may promoting regeneration in both acute and chronic liver insufficiencies. However, β-catenin activation particularly due to mutations in CTNNB1 is seen in a subset of hepatocellular carcinomas (HCC). Thus, it will be critical to address any effect of GC-1 on HCC growth and development, before its use can be advocated to stimulate regeneration in chronic liver diseases. In the current study, we first examine the effect of GC-1 on β-catenin-TCF4 activity in HCC cell lines harboring wild-type or mutated-CTNNB1. Next, we assess the effect of GC-1 on HCC in FVB mice generated by hydrodynamic tail vein injection of hMet-S45Y-β-catenin, using the sleeping beauty transposon-transposase. Four weeks following injection, mice were fed GC-1- (5mg/kg) or basal-diet for 10 or 21 days. GC-1 treatment showed no effect on β-catenin-TCF4 activity in HCC cells, irrespective of CTNNB1 mutations. Treatment with GC-1 for 10 or 21 days led to a significant reduction in tumor burden, associated with decreased tumor cell proliferation, and dramatic decreases in p-Met (Y1234/1235) p-ERK and p-STAT3 without affecting β-catenin and its downstream targets. GC-1 exerts a notable antitumoral effect on hMet-S45Y-β-catenin HCC, by inactivating Met signaling. GC-1 does not promote β-catenin activation in HCC. Thus GC-1 may be safe for use in inducing regeneration during chronic hepatic insufficiency. Copyright © 2017. Published by Elsevier Inc.

  3. Ability of the Met kinase inhibitor crizotinib and new generation EGFR inhibitors to overcome resistance to EGFR inhibitors.

    Directory of Open Access Journals (Sweden)

    Shigeki Nanjo

    Full Text Available PURPOSE: Although EGF receptor tyrosine kinase inhibitors (EGFR-TKI have shown dramatic effects against EGFR mutant lung cancer, patients ultimately develop resistance by multiple mechanisms. We therefore assessed the ability of combined treatment with the Met inhibitor crizotinib and new generation EGFR-TKIs to overcome resistance to first-generation EGFR-TKIs. EXPERIMENTAL DESIGN: Lung cancer cell lines made resistant to EGFR-TKIs by the gatekeeper EGFR-T790M mutation, Met amplification, and HGF overexpression and mice with tumors induced by these cells were treated with crizotinib and a new generation EGFR-TKI. RESULTS: The new generation EGFR-TKI inhibited the growth of lung cancer cells containing the gatekeeper EGFR-T790M mutation, but did not inhibit the growth of cells with Met amplification or HGF overexpression. In contrast, combined therapy with crizotinib plus afatinib or WZ4002 was effective against all three types of cells, inhibiting EGFR and Met phosphorylation and their downstream molecules. Crizotinib combined with afatinib or WZ4002 potently inhibited the growth of mouse tumors induced by these lung cancer cell lines. However, the combination of high dose crizotinib and afatinib, but not WZ4002, triggered severe adverse events. CONCLUSIONS: Our results suggest that the dual blockade of mutant EGFR and Met by crizotinib and a new generation EGFR-TKI may be promising for overcoming resistance to reversible EGFR-TKIs but careful assessment is warranted clinically.

  4. TEC protein tyrosine kinase is involved in the Erk signaling pathway induced by HGF

    Energy Technology Data Exchange (ETDEWEB)

    Li, Feifei; Jiang, Yinan [Department of Pathophysiology, Anhui Medical University, Hefei 230032 (China); Zheng, Qiping [Department of Anatomy and Cell Biology, Rush University Medical Center, Chicago, IL 60612 (United States); Yang, Xiaoming [Institute of Radiation Medicine, Academy of Military Medical Sciences, Beijing 100850 (China); Wang, Siying, E-mail: sywang@ahmu.edu.cn [Department of Pathophysiology, Anhui Medical University, Hefei 230032 (China)

    2011-01-07

    Research highlights: {yields} TEC is rapidly tyrosine-phosphorylated and activated by HGF-stimulation in vivo or after partial hepatectomy in mice. {yields} TEC enhances the activity of Elk and serum response element (SRE) in HGF signaling pathway in hepatocyte. {yields} TEC promotes hepatocyte proliferation through the Erk-MAPK pathway. -- Abstract: Background/aims: TEC, a member of the TEC family of non-receptor type protein tyrosine kinases, has recently been suggested to play a role in hepatocyte proliferation and liver regeneration. This study aims to investigate the putative mechanisms of TEC kinase regulation of hepatocyte differentiation, i.e. to explore which signaling pathway TEC is involved in, and how TEC is activated in hepatocyte after hepatectomy and hepatocyte growth factor (HGF) stimulation. Methods: We performed immunoprecipitation (IP) and immunoblotting (IB) to examine TEC tyrosine phosphorylation after partial hepatectomy in mice and HGF stimulation in WB F-344 hepatic cells. The TEC kinase activity was determined by in vitro kinase assay. Reporter gene assay, antisense oligonucleotide and TEC dominant negative mutant (TEC{sup KM}) were used to examine the possible signaling pathways in which TEC is involved. The cell proliferation rate was evaluated by {sup 3}H-TdR incorporation. Results: TEC phosphorylation and kinase activity were increased in 1 h after hepatectomy or HGF treatment. TEC enhanced the activity of Elk and serum response element (SRE). Inhibition of MEK1 suppressed TEC phosphorylation. Blocking TEC activity dramatically decreased the activation of Erk. Reduced TEC kinase activity also suppressed the proliferation of WB F-344 cells. These results suggest TEC is involved in the Ras-MAPK pathway and acts between MEK1 and Erk. Conclusions: TEC promotes hepatocyte proliferation and regeneration and is involved in HGF-induced Erk signaling pathway.

  5. Isolation and characterization of anti c-met single chain fragment variable (scFv) antibodies.

    Science.gov (United States)

    Qamsari, Elmira Safaie; Sharifzadeh, Zahra; Bagheri, Salman; Riazi-Rad, Farhad; Younesi, Vahid; Abolhassani, Mohsen; Ghaderi, Sepideh Safaei; Baradaran, Behzad; Somi, Mohammad Hossein; Yousefi, Mehdi

    2017-12-01

    The receptor tyrosine kinase (RTK) Met is the cell surface receptor for hepatocyte growth factor (HGF) involved in invasive growth programs during embryogenesis and tumorgenesis. There is compelling evidence suggesting important roles for c-Met in colorectal cancer proliferation, migration, invasion, angiogenesis, and survival. Hence, a molecular inhibitor of an extracellular domain of c-Met receptor that blocks c-Met-cell surface interactions could be of great thera-peutic importance. In an attempt to develop molecular inhibitors of c-Met, single chain variable fragment (scFv) phage display libraries Tomlinson I + J against a specific synthetic oligopeptide from the extracellular domain of c-Met receptor were screened; selected scFv were then characterized using various immune techniques. Three c-Met specific scFv (ES1, ES2, and ES3) were selected following five rounds of panning procedures. The scFv showed specific binding to c-Met receptor, and significantly inhibited proliferation responses of a human colorectal carcinoma cell line (HCT-116). Moreover, anti- apoptotic effects of selected scFv antibodies on the HCT-116 cell line were also evaluated using Annexin V/PI assays. The results demonstrated rates of apoptotic cell death of 46.0, 25.5, and 37.8% among these cells were induced by use of ES1, ES2, and ES3, respectively. The results demonstrated ability to successfully isolate/char-acterize specific c-Met scFv that could ultimately have a great therapeutic potential in immuno-therapies against (colorectal) cancers.

  6. Cerebral 5-HT2A receptor and serotonin transporter binding in humans are not affected by the val66met BDNF polymorphism status or blood BDNF levels

    DEFF Research Database (Denmark)

    Klein, Anders Bue; Trajkovska, Viktorija; Erritzoe, David;

    2010-01-01

    Recent studies have proposed an interrelation between the brain-derived neurotrophic factor (BDNF) val66met polymorphism and the serotonin system. In this study, we investigated whether the BDNF val66met polymorphism or blood BDNF levels are associated with cerebral 5-hydroxytryptamine 2A (5-HT(2A......)) receptor or serotonin transporter (SERT) binding in healthy subjects. No statistically significant differences in 5-HT(2A) receptor or SERT binding were found between the val/val and met carriers, nor were blood BDNF values associated with SERT binding or 5-HT(2A) receptor binding. In conclusion, val66met...... BDNF polymorphism status is not associated with changes in the serotonergic system. Moreover, BDNF levels in blood do not correlate with either 5-HT(2A) or SERT binding....

  7. Host-pathogen systems biology: logical modelling of hepatocyte growth factor and Helicobacter pylori induced c-Met signal transduction

    Directory of Open Access Journals (Sweden)

    Kähne Thilo

    2008-01-01

    Full Text Available Abstract Background The hepatocyte growth factor (HGF stimulates mitogenesis, motogenesis, and morphogenesis in a wide range of tissues, including epithelial cells, on binding to the receptor tyrosine kinase c-Met. Abnormal c-Met signalling contributes to tumour genesis, in particular to the development of invasive and metastatic phenotypes. The human microbial pathogen Helicobacter pylori can induce chronic gastritis, peptic ulceration and more rarely, gastric adenocarcinoma. The H. pylori effector protein cytotoxin associated gene A (CagA, which is translocated via a type IV secretion system (T4SS into epithelial cells, intracellularly modulates the c-Met receptor and promotes cellular processes leading to cell scattering, which could contribute to the invasiveness of tumour cells. Using a logical modelling framework, the presented work aims at analysing the c-Met signal transduction network and how it is interfered by H. pylori infection, which might be of importance for tumour development. Results A logical model of HGF and H. pylori induced c-Met signal transduction is presented in this work. The formalism of logical interaction hypergraphs (LIH was used to construct the network model. The molecular interactions included in the model were all assembled manually based on a careful meta-analysis of published experimental results. Our model reveals the differences and commonalities of the response of the network upon HGF and H. pylori induced c-Met signalling. As another important result, using the formalism of minimal intervention sets, phospholipase Cγ1 (PLCγ1 was identified as knockout target for repressing the activation of the extracellular signal regulated kinase 1/2 (ERK1/2, a signalling molecule directly linked to cell scattering in H. pylori infected cells. The model predicted only an effect on ERK1/2 for the H. pylori stimulus, but not for HGF treatment. This result could be confirmed experimentally in MDCK cells using a specific

  8. Negative Suppressors of Oncogenic Activation of the Met Receptor Tyrosine Kinase

    Science.gov (United States)

    2008-09-01

    We thank members of the Park lab, Dr. Sergio Grinstein and Dr. Stephane Laporte for their helpful comments on the manuscript. We would like to...of Hrs couples receptor sorting to vesicle formation. Journal of cell science 116: 4169-4179 Veracini L, Franco M, Boureux A, Simon V, Roche S

  9. Synthesis of Z-CCK-27-32-NH2, Z-Tyr(SO-3)-Met-Gly-Trp-Met-Asp-NH2, a cholecystokinin receptor antagonist and an inhibitor of gastrin-induced acid secretion.

    Science.gov (United States)

    Briet, C; Aumelas, A; Martinez, J

    1985-09-01

    The synthesis of the hexapeptide Z-Tyr(SO-3)-Met-Gly-Trp-Met-Asp-NH2, representing the C-terminal sequence of cholecystokinin minus the C-terminal phenylalanyl residue is described. This peptide was shown to be the most potent cholecystokinin receptor antagonist in vitro described to date. It is also able to inhibit gastrin-induced acid secretion in vivo, in the rat and was proved to antagonize the action of the C-terminal octapeptide of cholecystokinin in the central nervous system.

  10. The Plasticity of Oncogene Addiction: Implications for Targeted Therapies Directed to Receptor Tyrosine Kinases

    Directory of Open Access Journals (Sweden)

    Vinochani Pillay

    2009-05-01

    Full Text Available A common mutation of the epidermal growth factor receptor (EGFR in glioblastoma multiforme (GBM is an extracellular truncation known as the de2-7 EGFR (or EGFRvIII. Hepatocyte growth factor (HGF is the ligand for the receptor tyrosine kinase (RTK c-Met, and this signaling axis is often active in GBM. The expression of the HGF/c-Met axis or de2-7 EGFR independently enhances GBMgrowth and invasiveness, particularly through the phosphatidylinositol-3 kinase/pAkt pathway. Using RTK arrays, we show that expression of de2-7 EGFR in U87MG GBM cells leads to the coactivation of several RTKs, including platelet-derived growth factor receptor β and c-Met. A neutralizing antibody to HGF (AMG102 did not inhibit de2-7 EGFR-mediated activation of c-Met, demonstrating that it is ligand-independent. Therapy for parental U87MG xenografts with AMG 102 resulted in significant inhibition of tumor growth, whereas U87MG.Δ2-7 xenografts were profoundly resistant. Treatment of U87MG.Δ2-7 xenografts with panitumumab, an anti-EGFR antibody, only partially inhibited tumor growth as xenografts rapidly reverted to the HGF/c-Met signaling pathway. Cotreatment with panitumumab and AMG 102 prevented this escape leading to significant tumor inhibition through an apoptotic mechanism, consistent with the induction of oncogenic shock. This observation provides a rationale for using panitumumab and AMG 102 in combination for the treatment of GBM patients. These results illustrate that GBM cells can rapidly change the RTK driving their oncogene addiction if the alternate RTK signals through the same downstream pathway. Consequently, inhibition of a dominant oncogene by targeted therapy can alter the hierarchy of RTKs resulting in rapid therapeutic resistance.

  11. Ezrin ubiquitylation by the E3 ubiquitin ligase, WWP1, and consequent regulation of hepatocyte growth factor receptor activity.

    Directory of Open Access Journals (Sweden)

    Rania F Zaarour

    Full Text Available The membrane cytoskeleton linker ezrin participates in several functions downstream of the receptor Met in response to Hepatocyte Growth Factor (HGF stimulation. Here we report a novel interaction of ezrin with a HECT E3 ubiquitin ligase, WWP1/Aip5/Tiul1, a potential oncogene that undergoes genomic amplification and overexpression in human breast and prostate cancers. We show that ezrin binds to the WW domains of WWP1 via the consensus motif PPVY(477 present in ezrin's C-terminus. This association results in the ubiquitylation of ezrin, a process that requires an intact PPVY(477 motif. Interestingly ezrin ubiquitylation does not target the protein for degradation by the proteasome. We find that ezrin ubiquitylation by WWP1 in epithelial cells leads to the upregulation of Met level in absence of HGF stimulation and increases the response of Met to HGF stimulation as measured by the ability of the cells to heal a wound. Interestingly this effect requires ubiquitylated ezrin since it can be rescued, after depletion of endogenous ezrin, by wild type ezrin but not by a mutant of ezrin that cannot be ubiquitylated. Taken together our data reveal a new role for ezrin in Met receptor stability and activity through its association with the E3 ubiquitin ligase WWP1. Given the role of Met in cell proliferation and tumorigenesis, our results may provide a mechanistic basis for understanding the role of ezrin in tumor progression.

  12. SGX523 is an exquisitely selective, ATP-competitive inhibitor of the MET receptor tyrosine kinase with antitumor activity in vivo

    Energy Technology Data Exchange (ETDEWEB)

    Buchanan, Sean G.; Hendle, Jorg; Lee, Patrick S.; Smith, Christopher R.; Bounaud, Pierre-Yves; Jessen, Katti A.; Tang, Crystal M.; Huser, Nanni H.; Felce, Jeremy D.; Froning, Karen J.; Peterman, Marshall C.; Aubol, Brandon E.; Gessert, Steve F.; Sauder, J. Michael; Schwinn, Kenneth D.; Russell, Marijane; Rooney, Isabelle A.; Adams, Jason; Leon, Barbara C.; Do, Tuan H.; Blaney, Jeff M.; Sprengeler, Paul A.; Thompson, Devon A.; Smyth, Lydia; Pelletier, Laura A.; Atwell, Shane; Holme, Kevin; Wasserman, Stephen R.; Emtage, Spencer; Burley, Stephen K.; Reich, Siegfried H.; (Ventana); (SGX); (Genentech); (Amira)

    2010-01-12

    The MET receptor tyrosine kinase has emerged as an important target for the development of novel cancer therapeutics. Activation of MET by mutation or gene amplification has been linked to kidney, gastric, and lung cancers. In other cancers, such as glioblastoma, autocrine activation of MET has been demonstrated. Several classes of ATP-competitive inhibitor have been described, which inhibit MET but also other kinases. Here, we describe SGX523, a novel, ATP-competitive kinase inhibitor remarkable for its exquisite selectivity for MET. SGX523 potently inhibited MET with an IC{sub 50} of 4 nmol/L and is >1,000-fold selective versus the >200-fold selectivity of other protein kinases tested in biochemical assays. Crystallographic study revealed that SGX523 stabilizes MET in a unique inactive conformation that is inaccessible to other protein kinases, suggesting an explanation for the selectivity. SGX523 inhibited MET-mediated signaling, cell proliferation, and cell migration at nanomolar concentrations but had no effect on signaling dependent on other protein kinases, including the closely related RON, even at micromolar concentrations. SGX523 inhibition of MET in vivo was associated with the dose-dependent inhibition of growth of tumor xenografts derived from human glioblastoma and lung and gastric cancers, confirming the dependence of these tumors on MET catalytic activity. Our results show that SGX523 is the most selective inhibitor of MET catalytic activity described to date and is thus a useful tool to investigate the role of MET kinase in cancer without the confounding effects of promiscuous protein kinase inhibition.

  13. The MET/AXL/FGFR Inhibitor S49076 Impairs Aurora B Activity and Improves the Antitumor Efficacy of Radiotherapy.

    Science.gov (United States)

    Clémenson, Céline; Chargari, Cyrus; Liu, Winchygn; Mondini, Michele; Ferté, Charles; Burbridge, Mike F; Cattan, Valérie; Jacquet-Bescond, Anne; Deutsch, Eric

    2017-06-15

    Several therapeutic agents targeting HGF/MET signaling are under clinical development as single agents or in combination, notably with anti-EGFR therapies in non-small cell lung cancer (NSCLC). However, despite increasing data supporting a link between MET, irradiation, and cancer progression, no data regarding the combination of MET-targeting agents and radiotherapy are available from the clinic. S49076 is an oral ATP-competitive inhibitor of MET, AXL, and FGFR1-3 receptors that is currently in phase I/II clinical trials in combination with gefitinib in NSCLC patients whose tumors show resistance to EGFR inhibitors. Here, we studied the impact of S49076 on MET signaling, cell proliferation, and clonogenic survival in MET-dependent (GTL16 and U87-MG) and MET-independent (H441, H460, and A549) cells. Our data show that S49076 exerts its cytotoxic activity at low doses on MET-dependent cells through MET inhibition, whereas it inhibits growth of MET-independent cells at higher but clinically relevant doses by targeting Aurora B. Furthermore, we found that S49076 improves the antitumor efficacy of radiotherapy in both MET-dependent and MET-independent cell lines in vitro and in subcutaneous and orthotopic tumor models in vivo In conclusion, our study demonstrates that S49076 has dual antitumor activity and can be used in combination with radiotherapy for the treatment of both MET-dependent and MET-independent tumors. These results support the evaluation of combined treatment of S49076 with radiation in clinical trials without patient selection based on the tumor MET dependency status. Mol Cancer Ther; 16(10); 1-13. ©2017 AACR. ©2017 American Association for Cancer Research.

  14. Exogenous HGF Bypasses the Effects of ErbB Inhibition on Tumor Cell Viability in Medulloblastoma Cell Lines

    NARCIS (Netherlands)

    Zomerman, Waldrik W; Plasschaert, Sabine L. A.; Diks, Sander H.; Lourens, Harm-Jan; Meeuwsen-de Boer, Tiny; Hoving, Eelco W.; den Dunnen, Wilfred F. A.; de Bont, Eveline S. J. M.

    2015-01-01

    Recent clinical trials investigating receptor tyrosine kinase (RTK) inhibitors showed a limited clinical response in medulloblastoma. The present study investigated the role of micro-environmental growth factors expressed in the brain, such as HGF and EGF, in relation to the effects of hepatocyte gr

  15. Glomerular ultrafiltration and apical tubular action of IGF-I, TGF-beta, and HGF in nephrotic syndrome.

    Science.gov (United States)

    Wang, S N; Lapage, J; Hirschberg, R

    1999-10-01

    In nephrotic glomerulopathies, there is ultrafiltration of high molecular weight forms of insulin-like growth factor-I (IGF-I), hepatocyte growth factor (HGF), and transforming growth factor-beta (TGF-beta), which are bioactive in tubular fluid and act through apical tubular receptors. Experimental evidence indicates that ultrafiltered IGF-I, HGF, and TGF-beta may contribute to increased tubular phosphate and sodium absorption, synthesis of extracellular matrix proteins, and secretion of chemokines such as monocyte chemoattractant protein-1 (MCP-1). Through these mechanisms, glomerular proteinuria may contribute to tubulointerstitial pathobiology in nephrotic syndrome.

  16. MicroRNA-181b-5p, ETS1, and the c-Met pathway exacerbate the prognosis of pancreatic ductal adenocarcinoma after radiation therapy.

    Science.gov (United States)

    Tomihara, Hideo; Yamada, Daisaku; Eguchi, Hidetoshi; Iwagami, Yoshifumi; Noda, Takehiro; Asaoka, Tadafumi; Wada, Hiroshi; Kawamoto, Koichi; Gotoh, Kunihito; Takeda, Yutaka; Tanemura, Masahiro; Mori, Masaki; Doki, Yuichiro

    2017-03-01

    Preoperative chemoradiation therapy (CRT) for pancreatic ductal adenocarcinoma (PDAC) has emerged as a reasonable strategy that shows good prognostic impact. However, after preoperative CRT, resected specimens show remnant tumor cells, which indicate that some tumor cells had acquired or were selected for resistance to CRT. Recently, two oncological mechanisms, the EMT and the presence of CSCs, were reported to be associated with resistance in various cancers. Previous reports showed that HGF could induce EMT in PDAC cells; moreover, the HGF receptor, c-Met, was identified as a dominant pancreatic CSC marker. However, the clinical significance of c-Met expression remains unclear. So, we hypothesized that remnant PDAC tissue after CRT might harbor cells with high c-Met expression, and these cells may exacerbate patients' prognosis. In the immunohistochemical analysis, we showed that preoperative CRT was significantly associated with high c-Met expression; moreover, high c-Met expression was a significant marker of a dismal prognosis. Next, we investigated mechanisms of c-Met upregulation in PDAC cells. We established GEM-resistant and radioresistant PDAC cells to analyze the transcriptome involved in c-Met expression. The microarray data for the established radiation-resistant PDAC cells indicated miR-181b-5p downregulation, which targets ETS1, one of the transcription factors for c-Met, and it was shown that radiation exposure induced c-Met expression through ETS1 increase by the suppression of miR-181b-5p. These results suggested that targeting these mechanisms may promote the development of a novel multidisciplinary treatment strategy for improving preoperative CRT efficiency.

  17. Novel germline mutation (Leu512Met) in the thyrotropin receptor gene (TSHR) leading to sporadic non-autoimmune hyperthyroidism.

    Science.gov (United States)

    Roberts, Stephanie A; Moon, Jennifer E; Dauber, Andrew; Smith, Jessica R

    2017-03-01

    Primary nonautoimmune hyperthyroidism is a rare cause of neonatal hyperthyroidism. This results from an activating mutation in the thyrotropin-receptor (TSHR). It can be inherited in an autosomal dominant manner or occur sporadically as a de novo mutation. Affected individuals display a wide phenotype from severe neonatal to mild subclinical hyperthyroidism. We describe a 6-month-old boy with a de novo mutation in the TSHR gene who presented with accelerated growth, enlarging head circumference, tremor and thyrotoxicosis. Genomic DNA from the patient's and parents' peripheral blood leukocytes was extracted. Exons 9 and 10 of the TSHR gene were amplified by PCR and sequenced. Sequencing exon 10 of the TSHR gene revealed a novel heterozygous missense mutation substituting cytosine to adenine at nucleotide position 1534 in the patient's peripheral blood leukocytes. This leads to a substitution of leucine to methionine at amino acid position 512. The mutation was absent in the parents. In silico modeling by PolyPhen-2 and SIFT predicted the mutation to be deleterious. The p.Leu512Met mutation (c.1534C>A) of the TSHR gene has not been previously described in germline or somatic mutations. This case presentation highlights the possibility of mild thyrotoxicosis in affected individuals and contributes to the understanding of sporadic non-autoimmune primary hyperthyroidism.

  18. The role of cMet in non-small cell lung cancer resistant to EGFR-inhibitors: did we really find the target?

    Science.gov (United States)

    Passiglia, Francesco; Van Der Steen, Nele; Raez, Luis; Pauwels, Patrick; Gil-Bazo, Ignacio; Santos, Edgardo; Santini, Daniele; Tesoriere, Giovanni; Russo, Antonio; Bronte, Giuseppe; Zwaenepoel, Karen; Cappuzzo, Federico; Rolfo, Christian

    2014-01-01

    The advent of the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) represented the most important innovation in NSCLC treatment over the last years. However, despite a great initial activity, secondary mutations in the same target, or different alterations in other molecular pathways, inevitably occur, leading to the emergence of acquired resistance, in median within the first year of treatment. In this scenario, the mesenchymal-epidermal transition (cMET) tyrosine kinase receptor and its natural ligand, the hepatocyte growth factor (HGF), seem to play an important role. Indeed either the overexpression or the amplification of cMET, as well as the overexpression of the HGF, have been reported in a substantial subgroup of NSCLC patients resistant to EGFR-TKIs. Several cMET-inhibitors have been developed as potential therapeutic candidates, and are currently under investigation in clinical trials. These compounds include both monoclonal antibodies and TKIs, and most of them have been investigated as dual combinations including an anti-EGFR TKI, to improve the efficacy of the available treatments, and ultimately overcome acquired resistance to EGFR-inhibitors.

  19. Association between Hepatocyte Growth Factor (HGF) Gene Polymorphisms and Serum HGF Levels in Patients with Rheumatoid Arthritis.

    Science.gov (United States)

    Kara, Fatih; Yildirim, Abdulkadir; Gumusdere, Musa; Karatay, Saliha; Yildirim, Kadir; Bakan, Ebubekir

    2014-10-01

    Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by proliferation and insufficient apoptosis of synovial cell, inflammatory cell infiltration, angiogenesis, and destruction of joints. Hepatocyte growth factor (HGF) has many functions, such as regulation of inflammation, angiogenesis, and inhibition of apoptosis. The purpose of this study was to investigate the association between intron 13 C/A and intron 14 T/C HGF gene polymorphisms and serum HGF levels in patients with RA. 100 patients with RA and 123 healthy controls were included in this study. Serum HGF concentrations were measured using ELISA kit. Gene polymorphisms were determined by allelic discrimination analysis using the real-time PCR method. HGF levels, frequency of AA genotype and A allele for intron 13 C/A polymorphism and frequency of CC genotype and C allele for intron 14 T/C polymorphism were increased in patients with RA compared to healthy controls. There was no overall associations between genotypes and serum HGF concentrations in both patient and control groups. Our results indicate that HGF protein and gene may play an important role in the etiopathogenesis of RA. However, further studies are required for a better understanding of mechanisms related to the disease process.

  20. Matriptase is required for the active form of hepatocyte growth factor induced Met, focal adhesion kinase and protein kinase B activation on neural stem/progenitor cell motility.

    Science.gov (United States)

    Fang, Jung-Da; Lee, Sheau-Ling

    2014-07-01

    Hepatocyte growth factor (HGF) is a chemoattractant and inducer for neural stem/progenitor (NS/P) cell migration. Although the type II transmembrane serine protease, matriptase (MTP) is an activator of the latent HGF, MTP is indispensable on NS/P cell motility induced by the active form of HGF. This suggests that MTP's action on NS/P cell motility involves mechanisms other than proteolytic activation of HGF. In the present study, we investigate the role of MTP in HGF-stimulated signaling events. Using specific inhibitors of phosphatidylinositol-3-kinase (PI3K), protein kinase B (Akt) or focal adhesion kinase (FAK), we demonstrated that in NS/P cells HGF-activated c-Met induces PI3k-Akt signaling which then leads to FAK activation. This signaling pathway ultimately induces MMP2 expression and NS/P cell motility. Knocking down of MTP in NS/P cells with specific siRNA impaired HGF-stimulation of c-Met, Akt and FAK activation, blocked HGF-induced production of MMP2 and inhibited HGF-stimulated NS/P cell motility. MTP-knockdown NS/P cells cultured in the presence of recombinant protein of MTP protease domain or transfected with the full-length wild-type but not the protease-defected MTP restored HGF-responsive events in NS/P cells. In addition to functioning as HGF activator, our data revealed novel function of MTP on HGF-stimulated c-Met signaling activation.

  1. Ginsenoside-Rg{sub 1} induces angiogenesis by the inverse regulation of MET tyrosine kinase receptor expression through miR-23a

    Energy Technology Data Exchange (ETDEWEB)

    Kwok, Hoi-Hin [Dr. Gilbert Hung Ginseng Laboratory, Faculty of Science, Hong Kong Baptist University, Hong Kong SAR (China); Chan, Lai-Sheung [Department of Biology, Faculty of Science, Hong Kong Baptist University, Hong Kong SAR (China); Poon, Po-Ying [Dr. Gilbert Hung Ginseng Laboratory, Faculty of Science, Hong Kong Baptist University, Hong Kong SAR (China); Yue, Patrick Ying-Kit [Dr. Gilbert Hung Ginseng Laboratory, Faculty of Science, Hong Kong Baptist University, Hong Kong SAR (China); Department of Biology, Faculty of Science, Hong Kong Baptist University, Hong Kong SAR (China); Wong, Ricky Ngok-Shun, E-mail: rnswong@hkbu.edu.hk [Dr. Gilbert Hung Ginseng Laboratory, Faculty of Science, Hong Kong Baptist University, Hong Kong SAR (China); Department of Biology, Faculty of Science, Hong Kong Baptist University, Hong Kong SAR (China)

    2015-09-15

    Therapeutic angiogenesis has been implicated in ischemic diseases and wound healing. Ginsenoside-Rg{sub 1} (Rg{sub 1}), one of the most abundant active components of ginseng, has been demonstrated as an angiogenesis-stimulating compound in different models. There is increasing evidence implicating microRNAs (miRNAs), a group of non-coding RNAs, as important regulators of angiogenesis, but the role of microRNAs in Rg{sub 1}-induced angiogenesis has not been fully explored. In this report, we found that stimulating endothelial cells with Rg{sub 1} could reduce miR-23a expression. In silico experiments predicted hepatocyte growth factor receptor (MET), a well-established mediator of angiogenesis, as the target of miR-23a. Transfection of the miR-23a precursor or inhibitor oligonucleotides validated the inverse relationship of miR-23a and MET expression. Luciferase reporter assays further confirmed the interaction between miR-23a and the MET mRNA 3′-UTR. Intriguingly, ginsenoside-Rg{sub 1} was found to increase MET protein expression in a time-dependent manner. We further demonstrated that ginsenoside-Rg{sub 1}-induced angiogenic activities were indeed mediated through the down-regulation of miR-23a and subsequent up-regulation of MET protein expression, as confirmed by gain- and loss-of-function angiogenic experiments. In summary, our results demonstrated that ginsenoside-Rg{sub 1} could induce angiogenesis by the inverse regulation of MET tyrosine kinase receptor expression through miR-23a. This study has broadened our understanding of the non-genomic effects of ginsenoside-Rg{sub 1,} and provided molecular evidence that warrant further development of natural compound as novel angiogenesis-promoting therapy. - Highlights: • Therapeutic angiogenesis has been implicated in ischemic diseases and wound healing. • Ginsenoside-Rg{sub 1} (Rg{sub 1}) has been demonstrated as an angiogenesis-stimulating compound. • We found that Rg{sub 1} induces angiogenesis by

  2. Cardiac concentric hypertrophy promoted by activated Met receptor is mitigated in vivo by inhibition of Erk1,2 signalling with Pimasertib.

    Science.gov (United States)

    Sala, Valentina; Gallo, Simona; Gatti, Stefano; Medico, Enzo; Vigna, Elisa; Cantarella, Daniela; Fontani, Lara; Natale, Massimo; Cimino, James; Morello, Mara; Comoglio, Paolo Maria; Ponzetto, Antonio; Crepaldi, Tiziana

    2016-04-01

    Cardiac hypertrophy is a major risk factor for heart failure. Hence, its attenuation represents an important clinical goal. Erk1,2 signalling is pivotal in the cardiac response to stress, suggesting that its inhibition may be a good strategy to revert heart hypertrophy. In this work, we unveiled the events associated with cardiac hypertrophy by means of a transgenic model expressing activated Met receptor. c-Met proto-oncogene encodes for the tyrosine kinase receptor of Hepatocyte growth factor and is a strong inducer of Ras-Raf-Mek-Erk1,2 pathway. We showed that three weeks after the induction of activated Met, the heart presents a remarkable concentric hypertrophy, with no signs of congestive failure and preserved contractility. Cardiac enlargement is accompanied by upregulation of growth-regulating transcription factors, natriuretic peptides, cytoskeletal proteins, and Extracellular Matrix remodelling factors (Timp1 and Pai1). At a later stage, cardiac hypertrophic remodelling results into heart failure with preserved systolic function. Prevention trial by suppressing activated Met showed that cardiac hypertrophy is reversible, and progression to heart failure is prevented. Notably, treatment with Pimasertib, Mek1 inhibitor, attenuates cardiac hypertrophy and remodelling. Our results suggest that modulation of Erk1.2 signalling may constitute a new therapeutic approach for treating cardiac hypertrophies. Copyright © 2016 Elsevier Ltd. All rights reserved.

  3. Association of the insulin-receptor variant Met-985 with hyperglycemia and non-insulin-dependent diabetes mellitus in the Netherlands: A population-based study

    Energy Technology Data Exchange (ETDEWEB)

    `t Hart, L.M.; Maassen, J.A. [Leiden Univ. (Netherlands); Does, F.E.E. van der [Free Univ., Amsterdam (Netherlands)] [and others

    1996-11-01

    One of the characteristics of non-insulin-dependent diabetes mellitus (NIDDM) is the presence of insulin. Most NIDDM patients have a normal sequence of the insulin receptor, indicating that, if insulin-receptor mutations contribute to the development of NIDDM, they will be present only in a minor fraction of the NIDDM population. The goal of the present study was to examine whether insulin-receptor mutations contribute to the development of NIDDM. We examined 161 individuals with NIDDM and 538 healthy controls from the population-based Rotterdam study for the presence of mutations in the insulin-receptor gene by SSCP. A heterozygous mutation changing valine-985 into methionine was detected in 5.6% of diabetic subjects and in 1.3% of individuals with normal oral glucose tolerance test. Adjusted for age, gender, and body-mass index, this revealed a relative risk for diabetes of 4.49 (95% confidence interval 1.59-12.25) for Met-985 carriers. When the total study group was analyzed, the prevalence of the mutation increased with increasing serum glucose levels (test for trend P < .005). We conclude that the Met-985 insulin-receptor variant associates with hyperglycemia and represents a risk factor for NIDDM. 30 refs., 3 figs., 1 tab.

  4. MET is required for the recruitment of anti-tumoural neutrophils.

    Science.gov (United States)

    Finisguerra, Veronica; Di Conza, Giusy; Di Matteo, Mario; Serneels, Jens; Costa, Sandra; Thompson, A A Roger; Wauters, Els; Walmsley, Sarah; Prenen, Hans; Granot, Zvi; Casazza, Andrea; Mazzone, Massimiliano

    2015-06-18

    Mutations or amplification of the MET proto-oncogene are involved in the pathogenesis of several tumours, which rely on the constitutive engagement of this pathway for their growth and survival. However, MET is expressed not only by cancer cells but also by tumour-associated stromal cells, although its precise role in this compartment is not well characterized. Here we show that MET is required for neutrophil chemoattraction and cytotoxicity in response to its ligand hepatocyte growth factor (HGF). Met deletion in mouse neutrophils enhances tumour growth and metastasis. This phenotype correlates with reduced neutrophil infiltration to both the primary tumour and metastatic sites. Similarly, Met is necessary for neutrophil transudation during colitis, skin rash or peritonitis. Mechanistically, Met is induced by tumour-derived tumour necrosis factor (TNF)-α or other inflammatory stimuli in both mouse and human neutrophils. This induction is instrumental for neutrophil transmigration across an activated endothelium and for inducible nitric oxide synthase production upon HGF stimulation. Consequently, HGF/MET-dependent nitric oxide release by neutrophils promotes cancer cell killing, which abates tumour growth and metastasis. After systemic administration of a MET kinase inhibitor, we prove that the therapeutic benefit of MET targeting in cancer cells is partly countered by the pro-tumoural effect arising from MET blockade in neutrophils. Our work identifies an unprecedented role of MET in neutrophils, suggests a potential 'Achilles' heel' of MET-targeted therapies in cancer, and supports the rationale for evaluating anti-MET drugs in certain inflammatory diseases.

  5. Detection of MET mRNA in gastric cancer in situ. Comparison with immunohistochemistry and sandwich immunoassays.

    Science.gov (United States)

    Schmid, E; Klotz, M; Steiner-Hahn, K; Konen, T; Frisk, A L; Schatz, C; Krahn, T; von Ahsen, O

    2017-08-24

    Determination of predictive biomarkers by immunohistochemistry (IHC) relies on antibodies with high selectivity. RNA in situ hybridization (RNA ISH) may be used to confirm IHC and may potentially replace it if suitable antibodies are not available or are insufficiently selective to discriminate closely related protein isoforms. We validated RNA ISH as specificity control for IHC and as a potential alternative method for selecting patients for treatment with MET inhibitors. MET, the HGF receptor, is encoded by the MET proto-oncogene that may be activated by mutation or amplification. MET expression and activity were tested in a panel of control cell lines. MET could be detected in formalin fixed paraffin, embedded (FFPE) samples by IHC and RNA ISH, and this was confirmed by sandwich immunoassays of fresh frozen samples. Gastric cancer cell lines with high MET expression and phosphorylation of tyrosine-1349 respond to the MET inhibitor, BAY-853474. High expression and phosphorylation of MET is a predictive biomarker for response to MET inhibitors. We then analyzed MET expression and activity in a matched set of FFPE vs. fresh frozen tumor samples consisting of 20 cases of gastric cancer. Two of 20 clinical samples investigated exhibited high MET expression with RNA ISH and IHC. Both cases were shown by sandwich immunoassays to exhibits strong functional activity. Expression levels and functional activity in these two cases were in a range that predicted response to treatment. Our findings indicate that owing to its high selectivity, RNA ISH can be used to confirm findings obtained by IHC and potentially may replace IHC for certain targets if no suitable antibodies are available. RNA ISH is a valid platform for testing predictive biomarkers for patient selection.

  6. Combined Wnt/β-Catenin, Met, and CXCL12/CXCR4 Signals Characterize Basal Breast Cancer and Predict Disease Outcome

    Directory of Open Access Journals (Sweden)

    Jane D. Holland

    2013-12-01

    Full Text Available Prognosis for patients with estrogen-receptor (ER-negative basal breast cancer is poor, and chemotherapy is currently the best therapeutic option. We have generated a compound-mutant mouse model combining the activation of β-catenin and HGF (Wnt-Met signaling, which produced rapidly growing basal mammary gland tumors. We identified the chemokine system CXCL12/CXCR4 as a crucial driver of Wnt-Met tumors, given that compound-mutant mice also deficient in the CXCR4 gene were tumor resistant. Wnt-Met activation rapidly expanded a population of cancer-propagating cells, in which the two signaling systems control different functions, self-renewal and differentiation. Molecular therapy targeting Wnt, Met, and CXCR4 in mice significantly delayed tumor development. The expression of a Wnt-Met 322 gene signature was found to be predictive of poor survival of human patients with ER-negative breast cancers. Thus, targeting CXCR4 and its upstream activators, Wnt and Met, might provide an efficient strategy for breast cancer treatment.

  7. Combined Wnt/β-catenin, Met, and CXCL12/CXCR4 signals characterize basal breast cancer and predict disease outcome.

    Science.gov (United States)

    Holland, Jane D; Györffy, Balázs; Vogel, Regina; Eckert, Klaus; Valenti, Giovanni; Fang, Liang; Lohneis, Philipp; Elezkurtaj, Sefer; Ziebold, Ulrike; Birchmeier, Walter

    2013-12-12

    Prognosis for patients with estrogen-receptor (ER)-negative basal breast cancer is poor, and chemotherapy is currently the best therapeutic option. We have generated a compound-mutant mouse model combining the activation of β-catenin and HGF (Wnt-Met signaling), which produced rapidly growing basal mammary gland tumors. We identified the chemokine system CXCL12/CXCR4 as a crucial driver of Wnt-Met tumors, given that compound-mutant mice also deficient in the CXCR4 gene were tumor resistant. Wnt-Met activation rapidly expanded a population of cancer-propagating cells, in which the two signaling systems control different functions, self-renewal and differentiation. Molecular therapy targeting Wnt, Met, and CXCR4 in mice significantly delayed tumor development. The expression of a Wnt-Met 322 gene signature was found to be predictive of poor survival of human patients with ER-negative breast cancers. Thus, targeting CXCR4 and its upstream activators, Wnt and Met, might provide an efficient strategy for breast cancer treatment.

  8. Dopamine D3 Receptor Ser9Gly and Catechol-O-methyltransferase Val158Met Polymorphisms and Acute Pain in Sickle Cell Disease

    Science.gov (United States)

    Jhun, Ellie; He, Ying; Yao, Yingwei; Molokie, Robert E.; Wilkie, Diana J.; Wang, Zaijie Jim

    2014-01-01

    Background Pain in sickle cell disease (SCD) is characterized by episodes of acute pain, primarily responsible for acute health care utilization, and persistent chronic pain. Pain severity and frequency vary significantly among SCD patients. In this study, we investigated the possible contribution of monoamine gene polymorphisms to pain variation. Methods Adult subjects with SCD completed PAINReportIt®, a computerized McGill Pain Questionnaire, from which we calculated the Composite Pain Index. Utilization data were obtained from the medical record and biweekly telephone calls for 12 months. Utilization is defined as admissions to the emergency department and/or the acute care center resulting from a sickle cell pain crisis. We performed genotyping for catechol-O-methyltransferase (COMT) Val158Met (rs4680) and dopamine D3 receptor(DRD3) Ser9Gly (rs6280) polymorphisms, which were analyzed for associations with pain phenotypes. Results Binary logistic models revealed that DRD3 Ser9Gly heterozygote patients were more likely not to have an acute pain crisis (odds ratio [OR] [95% confidence interval (CI)], 4.37 [1.39, 22.89]; p=0.020), which remained so when demographic variables were considered (OR [95% CI], 4.53 [1.41, 28.58]; p=0.016). COMT Val158Met Met allele showed lower probability for zero utilization (OR [95% CI], 0.32 [0.12, 0.83]; p=0.020) than the Val allele. In the negative binomial regression analysis, subjects with COMT Met/Met genotype had utilization incident rate ratio [95% CI] of 2.20 [1.21, 3.99] over those with Val/Val (p=0.010). Conclusions These exploratory findings suggest that DRD3 Ser9Gly and COMT Val158Met may contribute to pain heterogeneity in SCD, as suggested by the different rates of acute pain crisis. Specifically, SCD patients with the DRD3 homozygote genotypes, COMT 158 Met allele or Met/Met genotype are more likely to have acute care utilization, an indicator of acute pain. These results, however, will need to be further examined in

  9. A Val85Met mutation in melanocortin-1 receptor is associated with reductions in eumelanic pigmentation and cell surface expression in domestic rock pigeons (Columba livia.

    Directory of Open Access Journals (Sweden)

    Michael W Guernsey

    Full Text Available Variation in the melanocortin-1 receptor (Mc1r is associated with pigmentation diversity in wild and domesticated populations of vertebrates, including several species of birds. Among domestic bird species, pigmentation variation in the rock pigeon (Columbalivia is particularly diverse. To determine the potential contribution of Mc1r variants to pigment diversity in pigeons, we sequenced Mc1r in a wide range of pigeon breeds and identified several single nucleotide polymorphisms, including a variant that codes for an amino acid substitution (Val85Met. In contrast to the association between Val85Met and eumelanism in other avian species, this change was associated with pheomelanism in pigeons. In vitro cAMP accumulation and protein expression assays revealed that Val85Met leads to decreased receptor function and reduced cell surface expression of the mutant protein. The reduced in vitro function is consistent with the observed association with reduced eumelanic pigmentation. Comparative genetic and cellular studies provide important insights about the range of mechanisms underlying diversity among vertebrates, including different phenotypic associations with similar mutations in different species.

  10. Lysophosphatidic acid transactivates both c-Met and epidermal growth factor receptor, and induces cyclooxygenase-2 expression in human colon cancer LoVo cells

    Institute of Scientific and Technical Information of China (English)

    Dai Shida; Joji Kitayama; Hironori Yamaguchi; Hiroharu Yamashita; Ken Mori; Toshiaki Watanabe; Hirokazu Nagawa

    2005-01-01

    AIM: To examine whether lysophosphatidic acid (LPA)induces phosphorylation of c-Met and epidermal growth factor receptor (EGFR), both of which have been proposed as prognostic markers of colorectal cancer, and whether LPA induces cyclooxygenase-2 (COX-2) expression in human colon cancer cells.METHODS: Using a human colon cancer cell line, LoVo cells, we performed immunoprecipitation analysis,followed by Western blot analysis. We also examined whether LPA induced COX-2 expression, by Western blot analysis.RESULTS: Immunoprecipitation analysis revealed that 10 μmol/L LPA induced tyrosine phosphorylation of c-Met and EGFR in LoVo cells within a few minutes. We found that c-Met tyrosine phosphorylation induced by LPA was not attenuated by pertussis toxin or a matrix metalloproteinase inhibitor, in marked contrast to the results for EGFR. In addition, 0.2-40 μmol/L LPA induced COX-2 expression in a dose-dependent manner.CONCLUSION: Our results suggest that LPA acts upstream of various receptor tyrosine kinases (RTKs) and COX-2,and thus may act as a potent stimulator of colorectal cancer.

  11. Inhibition of tubular cell proliferation by neutralizing endogenous HGF leads to renal hypoxia and bone marrow-derived cell engraftment in acute renal failure.

    Science.gov (United States)

    Ohnishi, Hiroyuki; Mizuno, Shinya; Nakamura, Toshikazu

    2008-02-01

    During the progression of acute renal failure (ARF), the renal tubular S3 segment is sensitive to ischemic stresses. For reversing tubular damage, resident tubular cells proliferate, and bone marrow-derived cells (BMDC) can be engrafted into injured tubules. However, how resident epithelium or BMDC are involved in tubular repair remains unknown. Using a mouse model of ARF, we examined whether hepatocyte growth factor (HGF) regulates a balance of resident cell proliferation and BMDC recruitment. Within 48 h post-renal ischemia, tubular destruction became evident, followed by two-waved regenerative events: 1) tubular cell proliferation between 2 and 4 days, along with an increase in blood HGF; and 2) appearance of BMDC in the tubules from 6 days postischemia. When anti-HGF IgG was injected in the earlier stage, tubular cell proliferation was inhibited, leading to an increase in BMDC in renal tubules. Under the HGF-neutralized state, stromal cell-derived factor-1 (SDF1) levels increased in renal tubules, associated with the enhanced hypoxia. Administrations of anti-SDF1 receptor IgG into ARF mice reduced the number of BMDC in interstitium and tubules. Thus possible cascades include 1) inhibition of tubular cell proliferation by neutralizing HGF leads to renal hypoxia and SDF1 upregulation; and 2) BMDC are eventually engrafted in tubules through SDF1-mediated chemotaxis. Inversely, administration of recombinant HGF suppressed the renal hypoxia, SDF1 upregulation, and BMDC engraftment in ARF mice by enhancing resident tubular cell proliferation. Thus we conclude that HGF is a positive regulator for eliciting resident tubular cell proliferation, and SDF1 for BMDC engraftment during the repair process of ARF.

  12. HGF is released from buccal fibroblasts after smokeless tobacco stimulation

    DEFF Research Database (Denmark)

    Dabelsteen, S; Christensen, S; Gron, B

    2005-01-01

    To investigate the effect of smokeless tobacco (ST) on (1) HGF, KGF and GM-CSF expression by buccal fibroblasts and (2) on keratinocyte and fibroblast proliferation. Buccal fibroblasts were stimulated with different concentrations of ST extracts in a double dilution from 0.50% w/v to 0.03% w...... on exposure time and on concentration of the tobacco extract. High concentration increased production of HGF 4-fold. KGF production was doubled when high concentration of tobacco was used, low concentration did not stimulate cells. GM-CSF production was low in both stimulated and non-stimulated cells...

  13. UniProt search blastx result: AK287970 [KOME

    Lifescience Database Archive (English)

    Full Text Available C 2.7.10.1) (HGF receptor) (Scatter factor receptor) (SF receptor) (HGF/SF receptor) (Met proto-oncogene tyrosine kinase) (c-Met) - Eulemur macaco macaco (Black lemur) 3.00E-20 ...

  14. UniProt search blastx result: AK287484 [KOME

    Lifescience Database Archive (English)

    Full Text Available C 2.7.10.1) (HGF receptor) (Scatter factor receptor) (SF receptor) (HGF/SF receptor) (Met proto-oncogene tyrosine kinase) (c-Met) - Eulemur macaco macaco (Black lemur) 3.00E-16 ...

  15. UniProt search blastx result: AK288291 [KOME

    Lifescience Database Archive (English)

    Full Text Available C 2.7.10.1) (HGF receptor) (Scatter factor receptor) (SF receptor) (HGF/SF receptor) (Met proto-oncogene tyrosine kinase) (c-Met) - Eulemur macaco macaco (Black lemur) 1.00E-13 ...

  16. UniProt search blastx result: AK287692 [KOME

    Lifescience Database Archive (English)

    Full Text Available C 2.7.10.1) (HGF receptor) (Scatter factor receptor) (SF receptor) (HGF/SF receptor) (Met proto-oncogene tyrosine kinase) (c-Met) - Eulemur macaco macaco (Black lemur) 1.00E-15 ...

  17. UniProt search blastx result: AK288206 [KOME

    Lifescience Database Archive (English)

    Full Text Available C 2.7.10.1) (HGF receptor) (Scatter factor receptor) (SF receptor) (HGF/SF receptor) (Met proto-oncogene tyrosine kinase) (c-Met) - Eulemur macaco macaco (Black lemur) 3.00E-21 ...

  18. UniProt search blastx result: AK288287 [KOME

    Lifescience Database Archive (English)

    Full Text Available C 2.7.10.1) (HGF receptor) (Scatter factor receptor) (SF receptor) (HGF/SF receptor) (Met proto-oncogene tyrosine kinase) (c-Met) - Eulemur macaco macaco (Black lemur) 7.00E-18 ...

  19. UniProt search blastx result: AK289170 [KOME

    Lifescience Database Archive (English)

    Full Text Available C 2.7.10.1) (HGF receptor) (Scatter factor receptor) (SF receptor) (HGF/SF receptor) (Met proto-oncogene tyrosine kinase) (c-Met) - Eulemur macaco macaco (Black lemur) 8.00E-19 ...

  20. UniProt search blastx result: AK287970 [KOME

    Lifescience Database Archive (English)

    Full Text Available C 2.7.10.1) (HGF receptor) (Scatter factor receptor) (SF receptor) (HGF/SF receptor) (Met proto-oncogene tyrosine kinase) (c-Met) - Neofelis nebulosa (Clouded leopard) 3.00E-20 ...

  1. UniProt search blastx result: AK287484 [KOME

    Lifescience Database Archive (English)

    Full Text Available C 2.7.10.1) (HGF receptor) (Scatter factor receptor) (SF receptor) (HGF/SF receptor) (Met proto-oncogene tyrosine kinase) (c-Met) - Neofelis nebulosa (Clouded leopard) 3.00E-16 ...

  2. UniProt search blastx result: AK288291 [KOME

    Lifescience Database Archive (English)

    Full Text Available C 2.7.10.1) (HGF receptor) (Scatter factor receptor) (SF receptor) (HGF/SF receptor) (Met proto-oncogene tyrosine kinase) (c-Met) - Neofelis nebulosa (Clouded leopard) 6.00E-14 ...

  3. UniProt search blastx result: AK289170 [KOME

    Lifescience Database Archive (English)

    Full Text Available C 2.7.10.1) (HGF receptor) (Scatter factor receptor) (SF receptor) (HGF/SF receptor) (Met proto-oncogene tyrosine kinase) (c-Met) - Neofelis nebulosa (Clouded leopard) 1.00E-18 ...

  4. UniProt search blastx result: AK288287 [KOME

    Lifescience Database Archive (English)

    Full Text Available C 2.7.10.1) (HGF receptor) (Scatter factor receptor) (SF receptor) (HGF/SF receptor) (Met proto-oncogene tyrosine kinase) (c-Met) - Neofelis nebulosa (Clouded leopard) 3.00E-18 ...

  5. UniProt search blastx result: AK288206 [KOME

    Lifescience Database Archive (English)

    Full Text Available C 2.7.10.1) (HGF receptor) (Scatter factor receptor) (SF receptor) (HGF/SF receptor) (Met proto-oncogene tyrosine kinase) (c-Met) - Neofelis nebulosa (Clouded leopard) 4.00E-21 ...

  6. UniProt search blastx result: AK288291 [KOME

    Lifescience Database Archive (English)

    Full Text Available C 2.7.10.1) (HGF receptor) (Scatter factor receptor) (SF receptor) (HGF/SF receptor) (Met proto-oncogene tyrosine kinase) (c-Met) - Callithrix jacchus (Common marmoset) 1.00E-13 ...

  7. UniProt search blastx result: AK288287 [KOME

    Lifescience Database Archive (English)

    Full Text Available C 2.7.10.1) (HGF receptor) (Scatter factor receptor) (SF receptor) (HGF/SF receptor) (Met proto-oncogene tyrosine kinase) (c-Met) - Callithrix jacchus (Common marmoset) 7.00E-18 ...

  8. UniProt search blastx result: AK287970 [KOME

    Lifescience Database Archive (English)

    Full Text Available C 2.7.10.1) (HGF receptor) (Scatter factor receptor) (SF receptor) (HGF/SF receptor) (Met proto-oncogene tyrosine kinase) (c-Met) - Callithrix jacchus (Common marmoset) 3.00E-20 ...

  9. UniProt search blastx result: AK288206 [KOME

    Lifescience Database Archive (English)

    Full Text Available C 2.7.10.1) (HGF receptor) (Scatter factor receptor) (SF receptor) (HGF/SF receptor) (Met proto-oncogene tyrosine kinase) (c-Met) - Callithrix jacchus (Common marmoset) 3.00E-21 ...

  10. UniProt search blastx result: AK287692 [KOME

    Lifescience Database Archive (English)

    Full Text Available C 2.7.10.1) (HGF receptor) (Scatter factor receptor) (SF receptor) (HGF/SF receptor) (Met proto-oncogene tyrosine kinase) (c-Met) - Callithrix jacchus (Common marmoset) 1.00E-15 ...

  11. UniProt search blastx result: AK287484 [KOME

    Lifescience Database Archive (English)

    Full Text Available C 2.7.10.1) (HGF receptor) (Scatter factor receptor) (SF receptor) (HGF/SF receptor) (Met proto-oncogene tyrosine kinase) (c-Met) - Callithrix jacchus (Common marmoset) 3.00E-16 ...

  12. UniProt search blastx result: AK289170 [KOME

    Lifescience Database Archive (English)

    Full Text Available C 2.7.10.1) (HGF receptor) (Scatter factor receptor) (SF receptor) (HGF/SF receptor) (Met proto-oncogene tyrosine kinase) (c-Met) - Callithrix jacchus (Common marmoset) 8.00E-19 ...

  13. UniProt search blastx result: AK287970 [KOME

    Lifescience Database Archive (English)

    Full Text Available C 2.7.10.1) (HGF receptor) (Scatter factor receptor) (SF receptor) (HGF/SF receptor) (Met proto-oncogene tyrosine kinase) (c-Met) - Gorilla gorilla gorilla (Lowland gorilla) 3.00E-20 ...

  14. UniProt search blastx result: AK287692 [KOME

    Lifescience Database Archive (English)

    Full Text Available C 2.7.10.1) (HGF receptor) (Scatter factor receptor) (SF receptor) (HGF/SF receptor) (Met proto-oncogene tyrosine kinase) (c-Met) - Gorilla gorilla gorilla (Lowland gorilla) 1.00E-15 ...

  15. UniProt search blastx result: AK288206 [KOME

    Lifescience Database Archive (English)

    Full Text Available C 2.7.10.1) (HGF receptor) (Scatter factor receptor) (SF receptor) (HGF/SF receptor) (Met proto-oncogene tyrosine kinase) (c-Met) - Gorilla gorilla gorilla (Lowland gorilla) 3.00E-21 ...

  16. UniProt search blastx result: AK288291 [KOME

    Lifescience Database Archive (English)

    Full Text Available C 2.7.10.1) (HGF receptor) (Scatter factor receptor) (SF receptor) (HGF/SF receptor) (Met proto-oncogene tyrosine kinase) (c-Met) - Gorilla gorilla gorilla (Lowland gorilla) 1.00E-13 ...

  17. UniProt search blastx result: AK287484 [KOME

    Lifescience Database Archive (English)

    Full Text Available C 2.7.10.1) (HGF receptor) (Scatter factor receptor) (SF receptor) (HGF/SF receptor) (Met proto-oncogene tyrosine kinase) (c-Met) - Gorilla gorilla gorilla (Lowland gorilla) 3.00E-16 ...

  18. UniProt search blastx result: AK288287 [KOME

    Lifescience Database Archive (English)

    Full Text Available C 2.7.10.1) (HGF receptor) (Scatter factor receptor) (SF receptor) (HGF/SF receptor) (Met proto-oncogene tyrosine kinase) (c-Met) - Loxodonta africana (African elephant) 3.00E-18 ...

  19. UniProt search blastx result: AK287970 [KOME

    Lifescience Database Archive (English)

    Full Text Available C 2.7.10.1) (HGF receptor) (Scatter factor receptor) (SF receptor) (HGF/SF receptor) (Met proto-oncogene tyrosine kinase) (c-Met) - Loxodonta africana (African elephant) 3.00E-20 ...

  20. UniProt search blastx result: AK287484 [KOME

    Lifescience Database Archive (English)

    Full Text Available C 2.7.10.1) (HGF receptor) (Scatter factor receptor) (SF receptor) (HGF/SF receptor) (Met proto-oncogene tyrosine kinase) (c-Met) - Loxodonta africana (African elephant) 3.00E-16 ...

  1. UniProt search blastx result: AK289170 [KOME

    Lifescience Database Archive (English)

    Full Text Available C 2.7.10.1) (HGF receptor) (Scatter factor receptor) (SF receptor) (HGF/SF receptor) (Met proto-oncogene tyrosine kinase) (c-Met) - Loxodonta africana (African elephant) 3.00E-18 ...

  2. UniProt search blastx result: AK288291 [KOME

    Lifescience Database Archive (English)

    Full Text Available C 2.7.10.1) (HGF receptor) (Scatter factor receptor) (SF receptor) (HGF/SF receptor) (Met proto-oncogene tyrosine kinase) (c-Met) - Loxodonta africana (African elephant) 5.00E-14 ...

  3. UniProt search blastx result: AK288206 [KOME

    Lifescience Database Archive (English)

    Full Text Available C 2.7.10.1) (HGF receptor) (Scatter factor receptor) (SF receptor) (HGF/SF receptor) (Met proto-oncogene tyrosine kinase) (c-Met) - Loxodonta africana (African elephant) 3.00E-21 ...

  4. Expression and migratory analysis of 5 human uveal melanoma cell lines for CXCL12, CXCL8, CXCL1, and HGF

    Directory of Open Access Journals (Sweden)

    Di Cesare Sebastian

    2007-01-01

    Full Text Available Abstract Background The aim of this study was to characterize the presence and roles of CXCL12, CXCL8, CXCL1, and HGF in five human uveal melanoma cell lines, using different methods, in order to ascertain their significance in this disease. Methods Five human uveal melanoma cell lines (92.1, SP6.5, MKT-BR, OCM-1, and UW-1 of known proliferative, invasive, and metastatic potential were used in this experiment. A migration assay was used in order to assess the responsiveness of each cell line towards the four chosen chemotactic factors. Immunohistochemistry was then performed for all five cell lines (cytospins using antibodies directed toward CXCL1, CXCL8 and their receptors CXCR2 and CXCR1 respectively. Quantitative real-time PCR was then performed on all five cell lines in order to establish the presence of these four chemotactic factors. Results All five human uveal melanoma cell lines migrated towards the four chosen chemotactic factors at a level greater than that of the negative control. Chemokines CXCL1 and CXCL8 resulted in the greatest number of migrating cells in all five of our cell lines. Immunohistochemistry confirmed the expression of CXCL1, CXCL8, and their receptors CXCR2 and CXCR1 in all five of the cell lines. Quantitative real-time PCR results established expression of CXCL8, CXCL1, and HGF in all 5 cell lines tested. CXCL1 and CXCL8 are highly expressed in SP6.5 and UW-1. None of the five cell lines expressed any detectable levels of CXCL12. Conclusion The migratory ability of the 5 human uveal melanoma cell lines was positively influenced by the four chemotactic factors tested, namely CXCL12, CXCL8, CXCL1, and HGF. Self-expression of chemotactic factors CXCL8, CXCL1, and HGF may indicate an autocrine system, which perhaps contributes to the cells' metastatic ability in vivo.

  5. A phase-I study of lapatinib in combination with foretinib, a c-MET, AXL and vascular endothelial growth factor receptor inhibitor, in human epidermal growth factor receptor 2 (HER-2)-positive metastatic breast cancer.

    Science.gov (United States)

    Chia, Stephen K; Ellard, Susan L; Mates, Mihaela; Welch, Stephen; Mihalcioiu, Catalin; Miller, Wilson H; Gelmon, Karen; Lohrisch, Caroline; Kumar, Vikaash; Taylor, Sara; Hagerman, Linda; Goodwin, Rachel; Wang, Tao; Sakashita, Shingo; Tsao, Ming S; Eisenhauer, Elizabeth; Bradbury, Penelope

    2017-05-02

    The mechanisms of resistance to anti-human epidermal growth factor receptor 2 (HER 2) therapies are unclear but may include the tyrosine-protein kinase Met (c-Met), vascular endothelial growth factor (VEGF) and AXL pathways. Foretinib is an inhibitor of c-Met, VEGF receptor 2 (VEGFR-2), platelet-derived growth factor receptor beta (PDGFRB), AXL, Fms-like tyrosine kinase 3 (FLT3), angiopoiten receptor (TIE-2), RET and RON kinases. This phase Ib study sought to establish the associated toxicities, pharmacokinetics (PK) and recommended phase II doses (RP2D) of foretinib and lapatinib in a cohort of HER-2-positive patients with metastatic breast cancer (MBC). Women with HER-2 positive MBC, Performance status (PS 0-2), and no limit on number of prior chemotherapies or lines of anti-HER-2 therapies were enrolled. A 3 + 3 dose escalation design was utilized. Four dose levels were intended with starting doses of foretinib 30 mg and lapatinib 750 mg orally once a day (OD) on a 4-weekly cycle. Assessment of c-MET status from the primary archival tissue was performed. We enrolled 19 patients, all evaluable for toxicity assessment and for response evaluation. Median age was 60 years (34-86 years), 95% were PS 0-1, 53% were estrogen receptor-positive and 95% had at least one prior anti-HER-2-based regimen. The fourth dose level was reached (foretinib 45 mg/lapatinib 1250 mg) with dose-limiting toxicities of grade-3 diarrhea and fatigue. There was only one grade-4 non-hematological toxicity across all dose levels. There were no PK interactions between the agents. A median of two cycles was delivered across the dose levels (range 1-20) with associated progression-free survival of 3.2 months (95% CI 1.61-4.34 months). By immunohistochemical assessment with a specified cutoff, none of the 17 samples tested were classified as positive for c-Met. The RP2D of the combined foretinib and lapatinib is 45 mg and 1000 mg PO OD, respectively. Limited activity was seen with this

  6. C-Met as a potential target for the treatment of gastrointestinal cancer: Current status and future perspectives.

    Science.gov (United States)

    Bahrami, Afsane; Shahidsales, Soodabeh; Khazaei, Majid; Ghayour-Mobarhan, Majid; Maftouh, Mina; Hassanian, Seyed Mahdi; Avan, Amir

    2017-10-01

    Aberrant activation of the HGF/c-Met signalling pathways is shown to be related with cell proliferation, progression, metastasis, and worse prognosis in several tumor types, including gastrointestinal cancers, suggesting its value as a stimulating-target for cancer-therapy. Several approaches have been developed for targeting HGF and/or c-Met, and one of them, crizotinib (dual c-Met/ALK inhibitor), is recently been approved by FDA for lung-cancers with ALK-rearrangement. The main aim of current review is to give an overview on the role of c-Met/HGF pathway in gastrointestinal cancer, in preclinical and clinical trials. Although several important matters is still remained to be elucidated on the molecular pathways underlying the antitumor effects of this therapy in gastrointestinal-cancers. Further investigations are warranted to recognize the main determinants of the activity of c-Met inhibitors, for parallel targeting signalling pathway associated/activated via MET/HGF pathway or in response to the cell resistance to anti-c-Met agents. Additionally, identification of patients that might benefit from therapy could help to increase the selectivity and efficacy of the therapy. © 2017 Wiley Periodicals, Inc.

  7. MET and Small-Cell Lung Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Gelsomino, Francesco, E-mail: francesco.gelsomino@istitutotumori.mi.it [Medical Oncology Unit 1, Medical Oncology Department, Fondazione IRCCS Istituto Nazionale Tumori, Via G. Venezian 1, 20133 Milano (Italy); Rossi, Giulio [Operative Unit of Pathology, Azienda Ospedaliero-Universitaria Policlinico, Via del Pozzo 71, 41124 Modena (Italy); Tiseo, Marcello [Medical Oncology Unit, Azienda Ospedaliero-Universitaria, Viale A. Gramsci 14, 43126 Parma (Italy)

    2014-10-13

    Small-cell lung cancer (SCLC) is one of the most aggressive lung tumors. The majority of patients with SCLC are diagnosed at an advanced stage. This tumor type is highly sensitive to chemo-radiation treatment, with very high response rates, but invariably relapses. At this time, treatment options are still limited and the prognosis of these patients is poor. A better knowledge of the molecular biology of SCLC allowed us to identify potential druggable targets. Among these, the MET/HGF axis seems to be one of the most aberrant signaling pathways involved in SCLC invasiveness and progression. In this review, we describe briefly all recent literature on the different molecular profiling in SCLC; in particular, we discuss the specific alterations involving c-MET gene and their implications as a potential target in SCLC.

  8. MET and Small-Cell Lung Cancer

    Directory of Open Access Journals (Sweden)

    Francesco Gelsomino

    2014-10-01

    Full Text Available Small-cell lung cancer (SCLC is one of the most aggressive lung tumors. The majority of patients with SCLC are diagnosed at an advanced stage. This tumor type is highly sensitive to chemo-radiation treatment, with very high response rates, but invariably relapses. At this time, treatment options are still limited and the prognosis of these patients is poor. A better knowledge of the molecular biology of SCLC allowed us to identify potential druggable targets. Among these, the MET/HGF axis seems to be one of the most aberrant signaling pathways involved in SCLC invasiveness and progression. In this review, we describe briefly all recent literature on the different molecular profiling in SCLC; in particular, we discuss the specific alterations involving c-MET gene and their implications as a potential target in SCLC.

  9. Association of the Met-196-Arg variation of human tumor necrosis factor receptor 2 (TNFR2) with paranoid schizophrenia.

    Science.gov (United States)

    Thabet, Sihem; Ben Nejma, Mouna; Zaafrane, Ferid; Gaha, Lotfi; Ben Salem, Kamel; Romdhane, Abdelaziz; Nour, Mohamed; Jrad, Besma Bel Hadj

    2011-03-01

    Research has provided strong evidence for oligodendrocyte and myelin-related genes dysfunction in schizophrenia. Several studies have suggested abnormalities in the expression of myelin-related genes including tumor necrosis factor receptor 2 (TNFR2) involved in the neurodegeneration and remyelination. In order to further assess the role of TNFR2 in schizophrenia, we examined a functional bi-allelic polymorphism associated with an impaired NF-KB signaling and cell survival. In the present case/control study, 220 patients with schizophrenia and 176 healthy controls were genotyped by RFLP-PCR for the T/G polymorphism at the position 676 in exon 6 of the TNFR2 gene. We found a trend towards over-representation of TNFR2 676G in the patients compared to the controls (p=0.19 and 0.09 respectively). Interestingly, when we evaluated the association between this genetic polymorphism and the clinical variables of schizophrenia, our findings indicated that the frequencies of the G/G genotype and the G allele were significantly higher in paranoid (p=0.014 and p=0.012 respectively) and adult-onset paranoid (p=0.004 and p=0.004 respectively) schizophrenia patient group compared to the controls. The potential association was confirmed by a logistic regression model only for development of the paranoid form of schizophrenia (p=0.022) indicating a substantially increased risk for paranoid schizophrenia with inheritance of the TNFR2(G) allele. In conclusion, this polymorphism in TNFR2 or a gene in proximity seems to be associated specifically with paranoid schizophrenia, at least in the Tunisian population. A replication of our findings in other and larger populations could be of particular importance to establish TNFR2 as one of the susceptibility genes of paranoid schizophrenia.

  10. Therapeutic angiogenesis induced by human hepatocyte growth factor (HGF) gene in rat myocardial ischemia models

    Institute of Scientific and Technical Information of China (English)

    2003-01-01

    In order to investigate the feasibility of myocardial ischemia gene therapy, we cloned human hepatocyte growth factor gene from human placenta cDNA library by the RT-PCR method. Recombination adenovirus Ad-HGF was constructed by the method of co-transfection and homologous recombination of plasmids in 293 cells. Ad-HGF was amplified in 293 cells and purified through CsCl density gradient centrifugation. Ad-HGF could be expressed in rat primary myocardial cells and HGF secreted into the culture media, which was tested by ELISA. The distribution and persistence of adenovirus in rat were investigated by green fluorescence protein as a report gene. In vivo we found that intramyocardial administration of Ad-HGF could induce angiogenesis in rat myocardium after ligation of coronary artery. The results suggested that Ad-HGF was effective in vitro and in vivo, and the data for designing human trial of gene therapy-- mediated cardiac angiogenesis were provided.

  11. Exogenous HGF Prevents Cardiomyocytes from Apoptosis after Hypoxia via Up-Regulating Cell Autophagy

    Directory of Open Access Journals (Sweden)

    Yunle Wang

    2016-06-01

    Full Text Available Background: Hepatocyte growth factor (HGF is widely known as a protective factor in ischemic myocardium, however HGF sensitive cellular mechanism remained ill-defined. Autophagy at early stage of hypoxia has been demonstrated to play a role in protecting myocardium both in vivo and vitro. We performed this study to investigate the association between the protective effect of HGF and autophagy. Methods: Ventricular myocytes were isolated from neonatal rat heart (NRVMs. We evaluated cardiomyocytes apoptosis by Hoechst staining and flow cytometry. Autophagy was assessed by transmission electron microscope and mRFP-GFP-LC3 adenovirus infection. Mitochondrial membrane potential was estimated by JC-1 staining. Western blotting and ELISA assay were used to quantify protein concentrations. Results: We found that autophagy in NRVMs increased at early stage after hypoxia and HGF release was consistent with the change of autophagy. Exogenous HGF enhanced autophagy and decreased apoptosis, while neutralizing HGF yielded opposite effects. Besides, inhibition of autophagy increased apoptosis of myocytes. Furthermore, exogenous HGF induced Parkin, the marker of mitochondrial autophagy, indicating increased clearance of injured mitochondria. Conclusions: Our results revealed a potential mechanism in which exogenous HGF prevented NRVMs from apoptosis after hypoxia. Upregulation of Parkin through administration of exogenous HGF may be a potential therapeutic strategy ptotecting myocytes during ischemia.

  12. The DNA replication licensing factor miniature chromosome maintenance 7 is essential for RNA splicing of epidermal growth factor receptor, c-Met, and platelet-derived growth factor receptor.

    Science.gov (United States)

    Chen, Zhang-Hui; Yu, Yan P; Michalopoulos, George; Nelson, Joel; Luo, Jian-Hua

    2015-01-16

    Miniature chromosome maintenance 7 (MCM7) is an essential component of DNA replication licensing complex. Recent studies indicate that MCM7 is amplified and overexpressed in a variety of human malignancies. In this report, we show that MCM7 binds SF3B3. The binding motif is located in the N terminus (amino acids 221-248) of MCM7. Knockdown of MCM7 or SF3B3 significantly increased unspliced RNA of epidermal growth factor receptor, platelet-derived growth factor receptor, and c-Met. A dramatic drop of reporter gene expression of the oxytocin exon 1-intron-exon 2-EGFP construct was also identified in SF3B3 and MCM7 knockdown PC3 and DU145 cells. The MCM7 or SF3B3 depleted cell extract failed to splice reporter RNA in in vitro RNA splicing analyses. Knockdown of SF3B3 and MCM7 leads to an increase of cell death of both PC3 and DU145 cells. Such cell death induction is partially rescued by expressing spliced c-Met. To our knowledge, this is the first report suggesting that MCM7 is a critical RNA splicing factor, thus giving significant new insight into the oncogenic activity of this protein.

  13. hHGF overexpression in myoblast sheets enhances their angiogenic potential in rat chronic heart failure.

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    Antti Siltanen

    Full Text Available After severe myocardial infarction (MI, heart failure results from ischemia, fibrosis, and remodeling. A promising therapy to enhance cardiac function and induce therapeutic angiogenesis via a paracrine mechanism in MI is myoblast sheet transplantation. We hypothesized that in a rat model of MI-induced chronic heart failure, this therapy could be further improved by overexpression of the antiapoptotic, antifibrotic, and proangiogenic hepatocyte growth factor (HGF in the myoblast sheets. We studied the ability of wild type (L6-WT and human HGF-expressing (L6-HGF L6 myoblast sheet-derived paracrine factors to stimulate cardiomyocyte, endothelial cell, or smooth muscle cell migration in culture. Further, we studied the autocrine effect of hHGF-expression on myoblast gene expression profiles by use of microarray analysis. We induced MI in Wistar rats by left anterior descending coronary artery (LAD ligation and allowed heart failure to develop for 4 weeks. Thereafter, we administered L6-WT (n = 15 or L6-HGF (n = 16 myoblast sheet therapy. Control rats (n = 13 underwent LAD ligation and rethoracotomy without therapy, and five rats underwent a sham operation in both surgeries. We evaluated cardiac function with echocardiography at 2 and 4 weeks after therapy, and analyzed cardiac angiogenesis and left ventricular architecture from histological sections at 4 weeks. Paracrine mediators from L6-HGF myoblast sheets effectively induced migration of cardiac endothelial and smooth muscle cells but not cardiomyocytes. Microarray data revealed that hHGF-expression modulated myoblast gene expression. In vivo, L6-HGF sheet therapy effectively stimulated angiogenesis in the infarcted and non-infarcted areas. Both L6-WT and L6-HGF therapies enhanced cardiac function and inhibited remodeling in a similar fashion. In conclusion, L6-HGF therapy effectively induced angiogenesis in the chronically failing heart. Cardiac function, however, was not further

  14. The angiogenic growth factors HGF and VEGF in serum and plasma from neuroblastoma patients.

    Science.gov (United States)

    Sköldenberg, Erik G; Larsson, Anders; Jakobson, Ake; Hedborg, Fredrik; Kogner, Per; Christofferson, Rolf H; Azarbayjani, Faranak

    2009-08-01

    To determine whether concentrations of the angiogenic growth factors hepatocyte growth factor (HGF) and vascular endothelial growth factor A (VEGF-A) correlate with clinical and genetic markers in samples taken at diagnosis in children with neuroblastoma (NB). Heparin plasma (P-) and serum (S-) samples of healthy controls (n=73, mean age +/- SD 3.5+/-2.1; females/males: 23/50) and patients with NB (n=62; 2.2+/-1.8; 26/36) were collected between 1988 and 1999. Clinical data included age at diagnosis, gender, stage, outcome, amplification of the oncogene MYCN, loss of heterozygosity at the short arm of chromosome 1 (1p LOH) and ploidy. HGF and S-VEGF-A were elevated in NB as compared to controls (38/62 patients, p<0.0001 and p<0.05, Mann-Whitney U test). HGF concentrations were higher in high-stage (stage 3-4) as compared to low-stage (stage 1-2) disease (p<0.01). P-HGF was elevated in patients with 1p LOH (p<0.01), MYCN amplification (p<0.001) and di- or tetraploidy (p<0.001). S-HGF concentration was elevated in patients MYCN-amplified tumors only. Plasma and S-HGF concentrations were higher in the deceased group (p<0.05), but not P or S-VEGF-A. This study showed that concentrations of HGF and S-VEGF-A are elevated in patients with NB. Furthermore, HGF and S-VEGF-A concentrations correlate to higher stage disease and HGF correlates to genetic markers known to indicate a poor outcome. These observations imply that HGF and VEGF-A have biological roles in NB and suggest the possibility of interference with HGF or VEGF-A signaling as a therapeutic strategy.

  15. The C. elegans Discoidin Domain Receptor DDR-2 Modulates the Met-like RTK-JNK Signaling Pathway in Axon Regeneration.

    Directory of Open Access Journals (Sweden)

    Naoki Hisamoto

    2016-12-01

    Full Text Available The ability of specific neurons to regenerate their axons after injury is governed by cell-intrinsic regeneration pathways. However, the signaling pathways that orchestrate axon regeneration are not well understood. In Caenorhabditis elegans, initiation of axon regeneration is positively regulated by SVH-2 Met-like growth factor receptor tyrosine kinase (RTK signaling through the JNK MAPK pathway. Here we show that SVH-4/DDR-2, an RTK containing a discoidin domain that is activated by collagen, and EMB-9 collagen type IV regulate the regeneration of neurons following axon injury. The scaffold protein SHC-1 interacts with both DDR-2 and SVH-2. Furthermore, we demonstrate that overexpression of svh-2 and shc-1 suppresses the delay in axon regeneration observed in ddr-2 mutants, suggesting that DDR-2 functions upstream of SVH-2 and SHC-1. These results suggest that DDR-2 modulates the SVH-2-JNK pathway via SHC-1. We thus identify two different RTK signaling networks that play coordinated roles in the regulation of axonal regeneration.

  16. The C. elegans Discoidin Domain Receptor DDR-2 Modulates the Met-like RTK-JNK Signaling Pathway in Axon Regeneration.

    Science.gov (United States)

    Hisamoto, Naoki; Nagamori, Yuki; Shimizu, Tatsuhiro; Pastuhov, Strahil I; Matsumoto, Kunihiro

    2016-12-01

    The ability of specific neurons to regenerate their axons after injury is governed by cell-intrinsic regeneration pathways. However, the signaling pathways that orchestrate axon regeneration are not well understood. In Caenorhabditis elegans, initiation of axon regeneration is positively regulated by SVH-2 Met-like growth factor receptor tyrosine kinase (RTK) signaling through the JNK MAPK pathway. Here we show that SVH-4/DDR-2, an RTK containing a discoidin domain that is activated by collagen, and EMB-9 collagen type IV regulate the regeneration of neurons following axon injury. The scaffold protein SHC-1 interacts with both DDR-2 and SVH-2. Furthermore, we demonstrate that overexpression of svh-2 and shc-1 suppresses the delay in axon regeneration observed in ddr-2 mutants, suggesting that DDR-2 functions upstream of SVH-2 and SHC-1. These results suggest that DDR-2 modulates the SVH-2-JNK pathway via SHC-1. We thus identify two different RTK signaling networks that play coordinated roles in the regulation of axonal regeneration.

  17. The C. elegans Discoidin Domain Receptor DDR-2 Modulates the Met-like RTK–JNK Signaling Pathway in Axon Regeneration

    Science.gov (United States)

    Shimizu, Tatsuhiro; Matsumoto, Kunihiro

    2016-01-01

    The ability of specific neurons to regenerate their axons after injury is governed by cell-intrinsic regeneration pathways. However, the signaling pathways that orchestrate axon regeneration are not well understood. In Caenorhabditis elegans, initiation of axon regeneration is positively regulated by SVH-2 Met-like growth factor receptor tyrosine kinase (RTK) signaling through the JNK MAPK pathway. Here we show that SVH-4/DDR-2, an RTK containing a discoidin domain that is activated by collagen, and EMB-9 collagen type IV regulate the regeneration of neurons following axon injury. The scaffold protein SHC-1 interacts with both DDR-2 and SVH-2. Furthermore, we demonstrate that overexpression of svh-2 and shc-1 suppresses the delay in axon regeneration observed in ddr-2 mutants, suggesting that DDR-2 functions upstream of SVH-2 and SHC-1. These results suggest that DDR-2 modulates the SVH-2–JNK pathway via SHC-1. We thus identify two different RTK signaling networks that play coordinated roles in the regulation of axonal regeneration. PMID:27984580

  18. RhoA/phosphatidylinositol 3-kinase/protein kinase B/mitogen-activated protein kinase signaling after growth arrest-specific protein 6/mer receptor tyrosine kinase engagement promotes epithelial cell growth and wound repair via upregulation of hepatocyte growth factor in macrophages.

    Science.gov (United States)

    Lee, Ye-Ji; Park, Hyun-Jung; Woo, So-Youn; Park, Eun-Mi; Kang, Jihee Lee

    2014-09-01

    Growth arrest-specific protein 6 (Gas6)/Mer receptor tyrosine kinase (Mer) signaling modulates cytokine secretion and helps to regulate the immune response and apoptotic cell clearance. Signaling pathways that activate an epithelial growth program in macrophages are still poorly defined. We report that Gas6/Mer/RhoA signaling can induce the production of epithelial growth factor hepatic growth factor (HGF) in macrophages, which ultimately promotes epithelial cell proliferation and wound repair. The RhoA/protein kinase B (Akt)/mitogen-activated protein (MAP) kinases, including p38 MAP kinase, extracellular signal-regulated protein kinase, and Jun NH2-terminal kinase axis in RAW 264.7 cells, was identified as Gas6/Mer downstream signaling pathway for the upregulation of HGF mRNA and protein. Conditioned medium from RAW 264.7 cells that had been exposed to Gas6 or apoptotic cells enhanced epithelial cell proliferation of the epithelial cell line LA-4 and wound closure. Cotreatment with an HGF receptor-blocking antibody or c-Met antagonist downregulated this enhancement. Inhibition of Mer with small interfering RNA (siRNA) or the RhoA/Rho kinase pathway by RhoA siRNA or Rho kinase pharmacologic inhibitor suppressed Gas6-induced HGF mRNA and protein expression in macrophages and blocked epithelial cell proliferation and wound closure induced by the conditioned medium. Our data provide evidence that macrophages can be reprogrammed by Gas6 to promote epithelial proliferation and wound repair via HGF, which is induced by the Mer/RhoA/Akt/MAP kinase pathway. Thus, defects in Gas6/Mer/RhoA signaling in macrophages may delay tissue repair after injury to the alveolar epithelium.

  19. The indole alkaloid meleagrin, from the olive tree endophytic fungus Penicillium chrysogenum, as a novel lead for the control of c-Met-dependent breast cancer proliferation, migration and invasion.

    Science.gov (United States)

    Mady, Mohamed S; Mohyeldin, Mohamed M; Ebrahim, Hassan Y; Elsayed, Heba E; Houssen, Wael E; Haggag, Eman G; Soliman, Randa F; El Sayed, Khalid A

    2016-01-15

    Fungi of the genus Penicillium produce unique and chemically diverse biologically active secondary metabolites, including indole alkaloids. The role of dysregulated hepatocyte growth factor (HGF) and its receptor, c-Met, in the development and progression of breast carcinoma is documented. The goal of this work is to explore the chemistry and bioactivity of the secondary metabolites of the endophytic Penicillium chrysogenum cultured from the leaf of the olive tree Olea europea, collected in its natural habitat in Egypt. This fungal extract showed good inhibitory activities against the proliferation and migration of several human breast cancer lines. The CH2Cl2 extract of P. chrysogenum mycelia was subjected to bioguided chromatographic separation to afford three known indole alkaloids; meleagrin (1), roquefortine C (2) and DHTD (3). Meleagrin inhibited the growth of the human breast cancer cell lines MDA-MB-231, MDA-468, BT-474, SK BR-3, MCF7 and MCF7-dox, while similar treatment doses were found to have no effect on the growth and viability of the non-tumorigenic human mammary epithelial cells MCF10A. Meleagrin also showed excellent ATP competitive c-Met inhibitory activity in Z-Lyte assay, which was further confirmed via molecular docking studies and Western blot analysis. In addition, meleagrin treatment caused a dose-dependent inhibition of HGF-induced cell migration, and invasion of breast cancer cell lines. Meleagrin treatment potently suppressed the invasive triple negative breast tumor cell growth in an orthotopic athymic nude mice model, promoting this unique natural product from hit to a lead rank. The indole alkaloid meleagrin is a novel lead c-Met inhibitory entity useful for the control of c-Met-dependent metastatic and invasive breast malignancies.

  20. 大肠癌细胞增殖中HGF/SF作用的观察%The function of HGF/SF in the proliferation of colorectal cancer cells

    Institute of Scientific and Technical Information of China (English)

    李宏武; 张趣; 梁健

    2006-01-01

    目的研究肝细胞生长因子/离散因子(HGF/SF)在诱导大肠癌细胞增殖中的作用.方法采用Western Blot方法,检测HGF的受体c-met在受检大肠癌细胞株Caco-2,Colo320中的表达;观察Caco-2,Colo320中HGF/SF活化p42/p44 MAPK和p3 8 MAPK的动态变化;应用[3H]-TdR,MTT方法观察p42/p44MAPK和p38MAPK传导通路阻滞剂PD98059和SB2035 80对HGF/SF诱导的大肠癌细胞增殖的抑制作用.结果(1)c-met在Caco-2和Colo320中有表达.(2)HGF/SF激活p42/p44MAPK,p3 8 MAPK:20ng/mL的HGF/SF处理细胞,p42/p44 MAPK磷酸化在10min达高峰(2.28±0.01);p3 8 MAPK变化与之相似(2.25±0.01).(3)HGF/SF诱导大肠癌细胞的DNA合成增加依赖于p42/p44MAPK的激活,在24h时点分别以20ng/mlHGF/SF,不同浓度(1μmol/L,5 μmol/L,1 0μmol/L)的PD98059和SB203 5 80处理细胞,HGF/SF使胸腺啶吸收增加(P<0.01);PD98059以浓度依赖性抑制胸腺啶的吸收(P<0.01).(4)HGF促进Caco-2细胞的增殖,而PD98059对这种增殖有抑制作用.结论HGF激活大肠癌细胞Caco-2和Colo320中p42/p44MAPK和p3 8MAPK:p42/p44MAPK参与HGF/SF诱导的大肠癌细胞Caco-2有丝分裂;HGF促进大肠癌细胞Caco-2增殖;HGF/SF和p42/p44MAPK在大肠癌细胞中发挥作用可能有细胞选择性.

  1. MMTV-PyMT and Derived Met-1 Mouse Mammary Tumor Cells as Models for Studying the Role of the Androgen Receptor in Triple-Negative Breast Cancer Progression.

    Science.gov (United States)

    Christenson, Jessica L; Butterfield, Kiel T; Spoelstra, Nicole S; Norris, John D; Josan, Jatinder S; Pollock, Julie A; McDonnell, Donald P; Katzenellenbogen, Benita S; Katzenellenbogen, John A; Richer, Jennifer K

    2017-04-01

    Triple-negative breast cancer (TNBC) has a faster rate of metastasis compared to other breast cancer subtypes, and no effective targeted therapies are currently FDA-approved. Recent data indicate that the androgen receptor (AR) promotes tumor survival and may serve as a potential therapeutic target in TNBC. Studies of AR in disease progression and the systemic effects of anti-androgens have been hindered by the lack of an AR-positive (AR+) immunocompetent preclinical model. In this study, we identified the transgenic MMTV-PyMT (mouse mammary tumor virus-polyoma middle tumor-antigen) mouse mammary gland carcinoma model of breast cancer and Met-1 cells derived from this model as tools to study the role of AR in breast cancer progression. AR protein expression was examined in late-stage primary tumors and lung metastases from MMTV-PyMT mice as well as in Met-1 cells by immunohistochemistry (IHC). Sensitivity of Met-1 cells to the AR agonist dihydrotestosterone (DHT) and anti-androgen therapy was examined using cell viability, migration/invasion, and anchorage-independent growth assays. Late-stage primary tumors and lung metastases from MMTV-PyMT mice and Met-1 cells expressed abundant nuclear AR protein, while negative for estrogen and progesterone receptors. Met-1 sensitivity to DHT and AR antagonists demonstrated a reliance on AR for survival, and AR antagonists inhibited invasion and anchorage-independent growth. These data suggest that the MMTV-PyMT model and Met-1 cells may serve as valuable tools for mechanistic studies of the role of AR in disease progression and how anti-androgens affect the tumor microenvironment.

  2. Human hepatocyte growth factor (hHGF-modified hepatic oval cells improve liver transplant survival.

    Directory of Open Access Journals (Sweden)

    Zhu Li

    Full Text Available Despite progress in the field of immunosuppression, acute rejection is still a common postoperative complication following liver transplantation. This study aims to investigate the capacity of the human hepatocyte growth factor (hHGF in modifying hepatic oval cells (HOCs administered simultaneously with orthotopic liver transplantation as a means of improving graft survival. HOCs were activated and isolated using a modified 2-acetylaminofluorene/partial hepatectomy (2-AAF/PH model in male Lewis rats. A HOC line stably expressing the HGF gene was established following stable transfection of the pBLAST2-hHGF plasmid. Our results demonstrated that hHGF-modified HOCs could efficiently differentiate into hepatocytes and bile duct epithelial cells in vitro. Administration of HOCs at the time of liver transplantation induced a wider distribution of SRY-positive donor cells in liver tissues. Administration of hHGF-HOC at the time of transplantation remarkably prolonged the median survival time and improved liver function for recipients compared to these parameters in the other treatment groups (P<0.05. Moreover, hHGF-HOC administration at the time of liver transplantation significantly suppressed elevation of interleukin-2 (IL-2, tumor necrosis factor-α (TNF-α and interferon-γ (IFN-γ levels while increasing the production of IL-10 and TGF-β1 (P<0.05. HOC or hHGF-HOC administration promoted cell proliferation, reduced cell apoptosis, and decreased liver allograft rejection rates. Furthermore, hHGF-modified HOCs more efficiently reduced acute allograft rejection (P<0.05 versus HOC transplantation only. Our results indicate that the combination of hHGF-modified HOCs with liver transplantation decreased host anti-graft immune responses resulting in a reduction of allograft rejection rates and prolonging graft survival in recipient rats. This suggests that HOC-based cell transplantation therapies can be developed as a means of treating severe liver

  3. 肝细胞生长因子研究进展%Progress of research on HGF/SF

    Institute of Scientific and Technical Information of China (English)

    张武; 陈文杰

    2001-01-01

    查阅近二十年国外有关HGF/SF文献,基本弄清了HGF/SF的分子结构及组织分布,说明了HGF/SF的调节和cmet受体及两者的关系,揭示了HGF/SF的生物活性、HGF/SF和肿瘤扩散以及与肝再生的关系.因此,HGF/SF在肝再生中起主要作用;是肾再生的关键因子;可促进伤口愈合;通过增加恶性细胞的侵袭性,HGF/SF可能作为肿瘤转移的重要因素之一.

  4. Clinical significance of MET in gastric cancer

    Institute of Scientific and Technical Information of China (English)

    Mikito; Inokuchi; Sho; Otsuki; Yoshitaka; Fujimori; Yuya; Sato; Masatoshi; Nakagawa; Kazuyuki; Kojima

    2015-01-01

    Chemotherapy has become the global standard treatment for patients with metastatic or unresectable gastric cancer(GC),although outcomes remain unfavorable.Many molecular-targeted therapies inhibiting signaling pathways of various tyrosine kinase receptors have been developed,and monoclonal antibodies targeting human epidermal growth factor receptor 2 or vascular endothelial growth factor receptor 2 have become standard therapy for GC.Hepatocyte growth factor and its receptor,c-MET(MET),play key roles in tumor growth through activated signaling pathways from receptor in GC cells.Genomic amplification of MET leads to the aberrant activation found in GC tumors and is related to survival in patients with GC.This review discusses the clinical significance of MET in GC and examines MET as a potential therapeutic target in patients with GC.Preclinical studies in animal models have shown that MET antibodies or smallmolecule MET inhibitors suppress tumor-cell proliferation and tumor progression in MET-amplified GC cells.These drugs are now being evaluated in clinical trials as treatments for metastatic or unresectable GC.

  5. Decreased Serum Hepatocyte Growth Factor (HGF) in Autistic Children with Severe Gastrointestinal Disease

    OpenAIRE

    Russo, A.J.; Krigsman, A; Jepson, B; Wakefield, Andrew

    2009-01-01

    Aim: To assess serum Hepatocyte Growth Factor (HGF) levels in autistic children with severe gastrointestinal (GI) disease and to test the hypothesis that there is a relationship between GI pathology and HGF concentration. Subjects and Methods: Serum from 29 autistic children with chronic digestive disease (symptoms for a minimum of 6–12 months), most with ileo-colonic lymphoid nodular hyperplasia (LNH—markedly enlarged lymphoid nodules) and inflammation of the colorectum, small bowel and/or s...

  6. Perioperative hepatocyte growth factor (HGF) infusions improve hepatic regeneration following portal branch ligation (PBL) in rodents.

    Science.gov (United States)

    Mangieri, Christopher W; McCartt, Jason C; Strode, Matthew A; Lowry, John E; Balakrishna, Prasad M

    2017-07-01

    As hepatic surgery has become safer and more commonly performed, the extent of hepatic resections has increased. When there is not enough expected hepatic reserve to facilitate primary resection of hepatic tumors, a clinical adjunct to facilitating primary resection is portal vein embolization (PVE). PVE allows the hepatic remnant to increase to an appropriate size prior to resection via hepatocyte regeneration; however, PVE is not always successful in facilitating adequate regeneration. One of the strongest trophic factors for hepatocyte regeneration is hepatocyte growth factor (HGF). The purpose of this study was to improve hepatic regeneration with perioperative HGF infusions in an animal model that mimics PVE. Portal branch ligation (PBL) in rodents is equivalent to PVE in humans. We performed left-sided PBL in Sprague-Dawley rodents with the experimental group receiving perioperative HGF infusions. Baseline and postoperative liver volumetrics were obtained with CT scanning methods as performed in clinical practice. Baseline and postoperative liver functions were assessed via indocyanine green (ICG) elimination testing. HGF infused rodents had statistically significant increase in all postoperative liver volumetrics. Most clinically relevant were increased right liver volumes (RLV), 14.10 versus 7.85 cm(3) (p value 0.0001), and increased degree of hypertrophy (DH %), 159.23 versus 47.11 % (p value 0.0079). HGF infused rodents also had a quick return to baseline liver function, 2.38 days compared to 6.13 days (p value 0.0001). Perioperative HGF infusions significantly increase hepatic regeneration following PBL in rodents. Perioperative HGF infusions following PVE are a possible adjunct to increase the amount of patients able to successfully undergo primary resection for hepatic tumors. Further basic science is warranted in examining the use of HGF infusions to increase hepatic regeneration and translating that basic science work to clinical practice.

  7. Chronic lymphocytic leukemia nurse-like cells express hepatocyte growth factor receptor (c-MET) and indoleamine 2,3-dioxygenase and display features of immunosuppressive type 2 skewed macrophages

    Science.gov (United States)

    Giannoni, Paolo; Pietra, Gabriella; Travaini, Giorgia; Quarto, Rodolfo; Shyti, Genti; Benelli, Roberto; Ottaggio, Laura; Mingari, Maria Cristina; Zupo, Simona; Cutrona, Giovanna; Pierri, Ivana; Balleari, Enrico; Pattarozzi, Alessandra; Calvaruso, Marco; Tripodo, Claudio; Ferrarini, Manlio; de Totero, Daniela

    2014-01-01

    Hepatocyte growth factor, produced by stromal and follicular dendritic cells, and present at high concentrations in the sera of patients with chronic lymphocytic leukemia, prolongs the survival of leukemic B cells by interacting with their receptor, c-MET. It is, however, unknown whether hepatocyte growth factor influences microenvironmental cells, such as nurse-like cells, which deliver survival signals to the leukemic clone. We evaluated the expression of c-MET on nurse-like cells and monocytes from patients with chronic lymphocytic leukemia and searched for phenotypic/functional features supposed to be influenced by the hepatocyte growth factor/c-MET interaction. c-MET is expressed at high levels on nurse-like cells and at significantly higher levels than normal on monocytes from patients. Moreover, the hepatocyte growth factor/c-MET interaction activates STAT3TYR705 phosphorylation in nurse-like cells. Indoleamine 2,3-dioxygenase, an enzyme modulating T-cell proliferation and induced on normal monocytes after hepatocyte growth factor treatment, was detected together with interleukin-10 on nurse-like cells, and on freshly-prepared patients’ monocytes. Immunohistochemical/immunostaining analyses demonstrated the presence of c-MET+ and indoleamine 2,3-dioxygenase+ cells in lymph node biopsies, co-expressed with CD68 and vimentin. Furthermore nurse-like cells and chronic lymphocytic monocytes significantly inhibited T-cell proliferation, prevented by anti-transforming growth factor beta and interleukin-10 antibodies and indoleamine 2,3-dioxygenase inhibitors, and supported CD4+CD25high+/FOXP3+ T regulatory cell expansion. We suggest that nurse-like cells display features of immunosuppressive type 2 macrophages: higher hepatocyte growth factor levels, produced by leukemic or other microenvironmental surrounding cells, may cooperate to induce M2 polarization. Hepatocyte growth factor may thus have a dual pathophysiological role: directly through enhancement of

  8. Tumor microenvironment elicits primary resistance to afatinib through HGF secretion%肿瘤微环境中肝细胞生长因子介导H1975肺癌细胞对afatinib产生原发耐药

    Institute of Scientific and Technical Information of China (English)

    康小红; 王立芳; 曹飞; 范方田; 徐振晔

    2013-01-01

    Objective To observe the effects of hepatocyte growth factor (HGF) derived from tumor microenvironment and/or afatinib on the growth of human lung adenocarcinoma H1975 cells and explore the potential mechanisms by which HGF induces primary resistance to afatinib.Methods The effects of HGF,TGF-α and afatinib on the growth of H1975 cells were evaluated by MTT assay.The HGF concentrations of normal human fetal lung fibroblasts MRC-5 cells and human lung adenocarcinoma H1975 cells co-cultured or separately cultured were determined by ELISA assay.Western blot was used to detect the expressions of EGFR and Met signal pathway-related proteins and epithelial-mesenchymal transition (EMT) markers in H1975 cells treated with HGF and/or afatinib.Results The MTT assay showed that H1975 cells were hyposensitive to afatinib in the presence of HGF.The ELISA assay showed that HGF production by H1975 cells was less than 0.1 ng/2.0 × 106 cells,but HGF production by MRC-5 cells was (151.37 ± 2.07) ng/2.0 × 106 cells incubated for 48 h.When H1975 cells and MRC-5 cells were co-cultured for 72 h,the concentration of HGF in the culture supematant was (61.13 ± 16.21) ng/ml.In the presence of HGF,the expression of p-Met,p-Akt and p-ERK proteins in the H1975 cells was markedly up-regulated.afatinib inhibited p-EGFR,but did not affect the expression of p-Met,p-Akt and p-ERK proteins.In the presence of afatinib,HGF up-regulated the expression of vimentin and down-regulated the expression of E-cadherin.Conclusions HGF secreted by stromal cells in the tumor micro-environment may confer resistance to afatinib in H1975 cells by activation of the Met/PI3K/Akt and Met/MAPK/ERK signaling pathways,and is involved in the epithelial-mesenchymal transition process.%目的 观察肿瘤微环境中肝细胞生长因子(HGF)和afatinib对H1975肺癌细胞增殖的影响,探讨肿瘤微环境中HGF介导afatinib耐药的机制.方法 采用四甲基偶氮唑蓝(MTT)法检测肿瘤微环境中HGF、

  9. Mouse hepatic oval cells require Met-dependent PI3K to impair TGF-β-induced oxidative stress and apoptosis.

    Directory of Open Access Journals (Sweden)

    Adoración Martínez-Palacián

    Full Text Available We have previously shown that oval cells harboring a genetically inactivated Met tyrosine kinase (Met(-/- oval cells are more sensitive to TGF-β-induced apoptosis than cells expressing a functional Met (Met(flx/flx, demonstrating that the HGF/Met axis plays a pivotal role in oval cell survival. Here, we have examined the mechanism behind this effect and have found that TGF-β induced a mitochondria-dependent apoptotic cell death in Met(flx/flx and Met(-/- oval cells, associated with a marked increase in levels of the BH3-only proteins Bim and Bmf. Bmf plays a key role during TGF-β-mediated apoptosis since knocking down of BMF significantly diminished the apoptotic response in Met(-/- oval cells. TGF-β also induced oxidative stress accompanied by NADPH oxidase 4 (Nox4 mRNA up-regulation and decreased protein levels of antioxidant enzymes. Antioxidants inhibit both TGF-β-induced caspase 3 activity and Bmf up-regulation, revealing an oxidative stress-dependent Bmf regulation by TGF-β. Notably, oxidative stress-related events were strongly amplified in Met(-/- oval cells, emphasizing the critical role of Met in promoting survival. Pharmacological inhibition of PI3K did impair HGF-driven protection from TGF-β-induced apoptosis and increased sensitivity of Met(flx/flx oval cells to TGF-ß by enhancing oxidative stress, reaching apoptotic indices similar to those obtained in Met(-/- oval cells. Interestingly, both PI3K inhibition and/or knockdown itself resulted in caspase-3 activation and loss of viability in Met(flx/flx oval cells, whereas no effect was observed in Met(-/- oval cells. Altogether, results presented here provide solid evidences that both paracrine and autocrine HGF/Met signaling requires PI3K to promote mouse hepatic oval cell survival against TGF-β-induced oxidative stress and apoptosis.

  10. The HgF2 Ionic Switch: A Triumph of Electrostatics against Relativistic Odds.

    Science.gov (United States)

    Donald, Kelling J; Kretz, William J; Omorodion, Oluwarotimi

    2015-11-16

    A remarkable transition in the chemical bonding in (HgF2)n clusters as a function of n is identified and characterized. HgF2 is a fascinating material. Certain significant consequences of relativistic effects on the structure of the HgF2 molecule, dimer, and trimer disappear in the extended solid. Relativistic effects in Hg ensure that HgX2 molecules (X≡F, Cl, Br, and I) are linear, rigid, and form weakly bound dimers and trimers held together by weak electrostatic and van der Waals-type forces (unlike ZnX2 and CdX2 systems in which the intermonomer contacts are strong polar covalent bonds). For HgF2, the location and nature of an apparent transition from weak interactions in the smallest (HgF2)n clusters to ionic bonding in the (fluorite) HgF2 extended solid has remained a mystery. Computational evidence obtained at the M06-2X, B97D3, and MP2 levels of theory and reported herein indicate that polar covalent bonding in (HgF2)n begins as early as n=5. For n=2 through to n=13, the transition or switch from weak (primarily dipole-dipole-type) intermonomer interactions to a preference for polar covalent bonding occurs within the range 5

  11. Integrin-linked kinase (ILK) modulates wound healing through regulation of hepatocyte growth factor (HGF)

    Energy Technology Data Exchange (ETDEWEB)

    Serrano, Isabel; Diez-Marques, Maria L.; Rodriguez-Puyol, Manuel [Department of Physiology, University of Alcala, Alcala de Henares, Madrid (Spain); Red de Investigacion Renal Cooperativa (RedinRen) (Spain); Instituto Reina Sofia de Investigacion Nefrologica (Spain); Herrero-Fresneda, Inmaculada [Nephrology Unit, IDIBELL, Hospital de Bellvitge, Barcelona (Spain); Red de Investigacion Renal Cooperativa (RedinRen) (Spain); Garcia del Moral, Raimundo [Department of Pathology, University of Granada (Spain); Red de Investigacion Renal Cooperativa (RedinRen) (Spain); Dedhar, Shoukat [Department of Integrative Oncology, BC Cancer Research Center, Vancouver, BC (Canada); Ruiz-Torres, Maria P., E-mail: mpiedad.ruiz@uah.es [Department of Physiology, University of Alcala, Alcala de Henares, Madrid (Spain); Red de Investigacion Renal Cooperativa (RedinRen) (Spain); Instituto Reina Sofia de Investigacion Nefrologica (Spain); Rodriguez-Puyol, Diego [Nephrology Unit, Hospital Universitario Principe de Asturias, Alcala de Henares, Madrid (Spain); Red de Investigacion Renal Cooperativa (RedinRen) (Spain); Instituto Reina Sofia de Investigacion Nefrologica (Spain)

    2012-11-15

    Integrin-linked kinase (ILK) is an intracellular effector of cell-matrix interactions and regulates many cellular processes, including growth, proliferation, survival, differentiation, migration, invasion and angiogenesis. The present work analyzes the role of ILK in wound healing in adult animals using a conditional knock-out of the ILK gene generated with the tamoxifen-inducible Cre-lox system (CRE-LOX mice). Results show that ILK deficiency leads to retarded wound closure in skin. Intracellular mechanisms involved in this process were analyzed in cultured mouse embryonic fibroblast (MEF) isolated from CRE-LOX mice and revealed that wounding promotes rapid activation of phosphatidylinositol 3-kinase (PI3K) and ILK. Knockdown of ILK resulted in a retarded wound closure due to a decrease in cellular proliferation and loss of HGF protein expression during the healing process, in vitro and in vivo. Alterations in cell proliferation and wound closure in ILK-deficient MEF or mice could be rescued by exogenous administration of human HGF. These data demonstrate, for the first time, that the activation of PI3K and ILK after skin wounding are critical for HGF-dependent tissue repair and wound healing. -- Highlights: Black-Right-Pointing-Pointer ILK deletion results in decreased HGF expression and delayed scratch wound repair. Black-Right-Pointing-Pointer PI3K/ILK/AKT pathway signals through HGF to regulate wound healing. Black-Right-Pointing-Pointer An ILK-dependent increase in HGF expression is responsible for wound healing in vivo. Black-Right-Pointing-Pointer ILK-KO mice are used to confirm the requirement for ILK function in wound healing. Black-Right-Pointing-Pointer Human HGF treatment restores delayed wound closure in vitro and in vivo.

  12. Evaluation of serum HGF and CK18 levels in patients with esophageal cancer.

    Science.gov (United States)

    Kilic-Baygutalp, N; Ozturk, N; Orsal-Ibisoglu, E; Gündogdu, B; Ozgeris, F B; Bakan, N; Bakan, E; Kilic, A F

    2016-08-29

    Cytokeratins are thought to play a role in apoptosis. Cytokeratin 18 (CK18) is involved in the formation of intracellular cytoskeleton, and has been considered a promising apoptosis marker in gastrointestinal carcinomas. Growth factors, including hepatocyte growth factor (HGF), may provide a microenvironment for malignant cells. In this study, we aimed to compare serum HGF and CK18 levels between esophageal squamous cell carcinoma patients and healthy controls. The study included 41 adult patients (20 male, 21 female) diagnosed with esophageal squamous cell carcinoma, with a mean age of 63.54 ± 10.88 years (range, 41-82 years). We also recruited 39 age and gender-matched healthy control subjects. Venous blood samples were taken; serum HGF and CK18 concentrations were determined via ELISA. Results indicated that serum HGF levels were higher in patients (1.37 ± 0.63 ng/mL) as compared to the healthy subjects (0.41 ± 0.29 ng/mL). Similarly, serum CK18 levels were higher in the patient group (2.53 ± 1.33 ng/mL) than in the control group (0.34 ± 0.23 ng/mL) (P < 0.001). In addition, serum HGF and CK18 levels were positively correlated with metastasis stage, tumor stage, and disease stage of esophageal squamous cell carcinoma. To our knowledge, this is the first study to evaluate serum HGF and CK18 levels in patients with esophageal squamous cell carcinoma. The results suggest that serum CK18 and HGF levels may be used as prognostic and disease monitoring biomarkers of esophageal squamous cell carcinoma.

  13. COMT Val(158) met genotype and striatal D(2/3) receptor binding in adults with 22q11 deletion syndrome.

    LENUS (Irish Health Repository)

    Boot, Erik

    2011-09-01

    Although catechol-O-methyltransferase (COMT) activity evidently affects dopamine function in prefrontal cortex, the contribution is assumed less significant in striatum. We studied whether a functional polymorphism in the COMT gene (Val(158) Met) influences striatal D(2\\/3) R binding ratios (D(2\\/3) R BP(ND) ) in 15 adults with 22q11 deletion syndrome and hemizygous for this gene, using single photon emission computed tomography and the selective D(2\\/3) radioligand [(123) I]IBZM. Met hemizygotes had significantly lower mean D(2\\/3) R BPND than Val hemizygotes. These preliminary data suggest that low COMT activity may affect dopamine levels in striatum in humans and this may have implications for understanding the contribution of COMT activity to psychiatric disorders.

  14. The role of the microtubular system in the cell response to HGF/SF.

    Science.gov (United States)

    Dugina, V B; Alexandrova, A Y; Lane, K; Bulanova, E; Vasiliev, J M

    1995-04-01

    The effects of the microtubular drugs colcemid and taxol on the morphological changes induced by hepatocyte growth factor/scatter factor (HGF/SF) in MDCK cells were studied. Dynamic changes in the area and shape of individual cells were assessed by morphometric methods whereas alterations of the cytoskeleton were assessed by immunomorphological methods. The results suggest that there are two components in the response to HGF/SF: (a) activation of the extension of lamellae leading to cell spreading; and (b) reorganization of microtubules leading to polarization of cell shape. The latter response is highly sensitive to microtubular drugs, especially taxol. HGF/SF induced spreading in taxol-treated MDCK cells but these cells retained a non-polarized discoid shape and a pattern of actin microfilament bundles characteristic of the untreated cells. Colcemid and taxol did not prevent HGF/SF-induced migration of cells in Boyden chambers but completely inhibited the outgrowth of multicellular strands and tubules from cell aggregates in collagen gels. These results show that enhanced lamella formation in response to HGF/SF without polarization of cell shape is sufficient to induce cell motility. In contrast, microtubule-dependent polarization is essential for complex morphogenetic responses such as tubulogenesis in collagen gels.

  15. HGF Gene Modification in Mesenchymal Stem Cells Reduces Radiation-Induced Intestinal Injury by Modulating Immunity.

    Directory of Open Access Journals (Sweden)

    Hua Wang

    Full Text Available Effective therapeutic strategies to address intestinal complications after radiation exposure are currently lacking. Mesenchymal stem cells (MSCs, which display the ability to repair the injured intestine, have been considered as delivery vehicles for repair genes. In this study, we evaluated the therapeutic effect of hepatocyte growth factor (HGF-gene-modified MSCs on radiation-induced intestinal injury (RIII.Female 6- to 8-week-old mice were radiated locally at the abdomen with a single 13-Gy dose of radiation and then treated with saline control, Ad-HGF or Ad-Null-modified MSCs therapy. The transient engraftment of human MSCs was detected via real-time PCR and immunostaining. The therapeutic effects of non- and HGF-modified MSCs were evaluated via FACS to determine the lymphocyte immunophenotypes; via ELISA to measure cytokine expression; via immunostaining to determine tight junction protein expression; via PCNA staining to examine intestinal epithelial cell proliferation; and via TUNEL staining to detect intestinal epithelial cell apoptosis.The histopathological recovery of the radiation-injured intestine was significantly enhanced following non- or HGF-modified MSCs treatment. Importantly, the radiation-induced immunophenotypic disorders of the mesenteric lymph nodes and Peyer's patches were attenuated in both MSCs-treated groups. Treatment with HGF-modified MSCs reduced the expression and secretion of inflammatory cytokines, including tumor necrosis factor alpha (TNF-α and interferon-gamma (IFN-γ, increased the expression of the anti-inflammatory cytokine IL-10 and the tight junction protein ZO-1, and promoted the proliferation and reduced the apoptosis of intestinal epithelial cells.Treatment of RIII with HGF-gene-modified MSCs reduces local inflammation and promotes the recovery of small intestinal histopathology in a mouse model. These findings might provide an effective therapeutic strategy for RIII.

  16. Monitoring of TNFR1, IL-2Rα, HGF, CCL8, IL-8 and IL-12p70 following HSCT and their role as GVHD biomarkers in paediatric patients.

    Science.gov (United States)

    Berger, M; Signorino, E; Muraro, M; Quarello, P; Biasin, E; Nesi, F; Vassallo, E; Fagioli, F

    2013-09-01

    No predictive factors are currently available to establish patient-specific GVHD risk. A panel of six serum cytokines (TNF receptor 1, IL-2 receptor alfa (IL-2Rα), hepatocyte growth factor (HGF), monocyte chemo-attractant protein-2, IL-8, IL-12p70) were monitored at established time points (days -1, +1, +7, +14, +21, +28 and +60) in 170 paediatric hematopoietic SCT (HSCT) recipients. We found that higher concentrations of IL-2Rα on days +14 and +21 together with HGF on days +14 and +21 were significantly associated at a higher probability of both grade II-IV GVHD (on day +14 it was: 60% vs 28%, P=0.007) and grade III-IV (on day +14 it was: 40% vs 15%, P=0.001). The higher IL-8 serum concentration on day +28 was associated with a lower probability of chronic GVHD being 4% vs 29% (P=0.01) for patients with higher vs lower IL-8 serum concentration. These findings were confirmed when the analysis was restricted to the the matched unrelated donor group. In conclusion, even if the serum cytokine levels were related to several variables associated with HSCT, we identified two cytokines as predictors of GVHD II-IV and III-IV, translating into a higher TRM risk (17% vs 3%, P=0.004).

  17. Cancer-Associated Fibroblasts Regulate Tumor-Initiating Cell Plasticity in Hepatocellular Carcinoma through c-Met/FRA1/HEY1 Signaling

    Directory of Open Access Journals (Sweden)

    Eunice Yuen Ting Lau

    2016-05-01

    Full Text Available Like normal stem cells, tumor-initiating cells (T-ICs are regulated extrinsically within the tumor microenvironment. Because HCC develops primarily in the context of cirrhosis, in which there is an enrichment of activated fibroblasts, we hypothesized that cancer-associated fibroblasts (CAFs would regulate liver T-ICs. We found that the presence of α-SMA(+ CAFs correlates with poor clinical outcome. CAF-derived HGF regulates liver T-ICs via activation of FRA1 in an Erk1,2-dependent manner. Further functional analysis identifies HEY1 as a direct downstream effector of FRA1. Using the STAM NASH-HCC mouse model, we find that HGF-induced FRA1 activation is associated with the fibrosis-dependent development of HCC. Thus, targeting the CAF-derived, HGF-mediated c-Met/FRA1/HEY1 cascade may be a therapeutic strategy for the treatment of HCC.

  18. HGF/SF increases number of skin melanocytes but does not alter quality or quantity of follicular melanogenesis.

    Directory of Open Access Journals (Sweden)

    Agnieszka Wolnicka-Glubisz

    Full Text Available Melanins are an important factor determining the vulnerability of mammalian skin to UV radiation and thus to UV-induced skin cancers. Transgenic mice overexpressing hepatocyte growth factor/scatter factor (HGF/SF have extra-follicular dermal melanocytes, notably in the papillary upper dermis, and are susceptible to UV-induced melanoma. Pigmented HGF/SF neonatal mice are more susceptible than albino HGF/SF animals to UVA -induced melanoma, indicating an involvement of melanin in melanoma formation. This raises the question of the effect of transgenic HGF/SF on melanization. We developed a methodology to accurately quantitate both the production of melanin and the efficiency of melanogenesis in normal, and HGF/SF transgenic mice in vivo. Skin and hair shafts of 5 day old and adult (3 week old C57BL/6-HGF/SF and corresponding C57BL/6 wild type mice were investigated by electron paramagnetic resonance spectroscopy (EPR to quantitate melanin, by transmission electron microscopy (TEM for the presence of melanosomes, and by standard histology and by Western blotting and zymography to determine the expression and activity of melanogenesis-related proteins. Eumelanin but no phaeomelanin was detected in transgenic C57BL/6-HGF and C57BL/6 wild type mice. Transgenic HGF/SF overexpression did not change the type of melanin produced in the skin or hair, did not affect the terminal content of melanin production in standard samples of hair and did not influence hair cycle/morphogenesis-related changes in skin thickness. No melanocytes were found in the epidermis and no melanosomes were found in epidermal keratinocytes. HGF/SF transgenic mice thus lack the epidermal melanin UV-protection found in constitutively dark human skin. We conclude that melanocytes in the HGF/SF transgenic mouse, particularly in the papillary dermis, are vulnerable to UVA which interacts with eumelanin but not phaeomelanin to induce melanoma.

  19. Stimulatory effect of HGF-overexpressing adipose tissue-derived mesenchymal stem cells on thymus regeneration in a rat thymus involution model.

    Science.gov (United States)

    Jung, Woo-Sung; Han, Sei-Myoung; Kim, Sung-Min; Kim, Mi-Eun; Lee, Jun-Sik; Seo, Kyoung-Won; Youn, Hwa-Young; Lee, Hee-Woo

    2014-10-01

    The thymus is the central lymphoid organ providing a unique and essential microenvironment for T-cell precursor development into mature functionally competent T-lymphocytes. Thus, it is important to develop the strategies for enhancing thymic regeneration from involution induced by a variety of clinical treatments and conditions. Hepatocyte growth factor (HGF) promotes proliferation in a variety of cell types. We have used stem cell-based HGF gene therapy to enhance regeneration from acute thymic involution. HGF-overexpressing human adipose tissue-derived mesenchymal stem cells (HGF-hATMSCs) were generated by liposomal transfection with the pMEX expression vector, constructed by inserting the HGF gene. Significantly increased HGF expression in these cells was confirmed by reverse transcription-polymerase chain reaction and an enzyme-linked immunosorbent assay. HGF produced by HGF-hATMSCs enhanced the proliferation of a mouse thymic epithelial cell line and the expression of interleukin-7 in vitro. We also examined the effect of HGF-hATMSCs on thymic regeneration in rats with acute thymic involution. Significant increases in thymus size and weight, as well as the number of thymocytes (especially, early thymocyte progenitors), were seen in the HGF-hATMSCs-treated rats compared to saline-treated control animals. A stimulatory effect of HGF-hATMSCs on thymic regeneration has therefore been shown, highlighting the clinical value of HGF-hATMSCs for treating thymic involution.

  20. MET exon 14 juxtamembrane splicing mutations: clinical and therapeutical perspectives for cancer therapy

    Science.gov (United States)

    Pilotto, Sara; Gkountakos, Anastasios; Carbognin, Luisa; Scarpa, Aldo; Tortora, Giampaolo

    2017-01-01

    The MET proto-oncogene plays crucial roles in cell growth and proliferation, survival and apoptosis, epithelial-mesenchymal transition (EMT) and invasion, potentially conditioning the development and progression of the carcinogenesis process. The MET-associated aberrant signaling could be triggered by a variety of mechanisms, such as mutations, gene amplification, increased gene copy number and Met/HGF protein expression. Among the various MET alterations, MET exon 14 splicing abnormalities, causing the loss of the Met juxtamembrane (JM) domain, recently emerged as a new potential oncogenic driver and have been identified and validated across different cancer and histology subtypes. Moreover, this aberration was found to be mutually exclusive with other recognized drivers, thus strongly nominating its potential oncogenic role. Recently, the clinical activity of anti-Met-targeted therapy was demonstrated particularly in patients harboring MET exon 14 skipping lung cancer, resulting in a renewed enthusiasm to further test MET precision therapy in prospective trials. In this review, the key preclinical and clinical data regarding MET exon 14 skipping splicing variants as an actionable genomic aberration in cancer are described, and the perspectives deriving from the validation of such alteration as a potential target, which may further allow driving the therapeutic approach in this molecularly selected patients’ subgroup, are explored. PMID:28164087

  1. MET exon 14 juxtamembrane splicing mutations: clinical and therapeutical perspectives for cancer therapy.

    Science.gov (United States)

    Pilotto, Sara; Gkountakos, Anastasios; Carbognin, Luisa; Scarpa, Aldo; Tortora, Giampaolo; Bria, Emilio

    2017-01-01

    The MET proto-oncogene plays crucial roles in cell growth and proliferation, survival and apoptosis, epithelial-mesenchymal transition (EMT) and invasion, potentially conditioning the development and progression of the carcinogenesis process. The MET-associated aberrant signaling could be triggered by a variety of mechanisms, such as mutations, gene amplification, increased gene copy number and Met/HGF protein expression. Among the various MET alterations, MET exon 14 splicing abnormalities, causing the loss of the Met juxtamembrane (JM) domain, recently emerged as a new potential oncogenic driver and have been identified and validated across different cancer and histology subtypes. Moreover, this aberration was found to be mutually exclusive with other recognized drivers, thus strongly nominating its potential oncogenic role. Recently, the clinical activity of anti-Met-targeted therapy was demonstrated particularly in patients harboring MET exon 14 skipping lung cancer, resulting in a renewed enthusiasm to further test MET precision therapy in prospective trials. In this review, the key preclinical and clinical data regarding MET exon 14 skipping splicing variants as an actionable genomic aberration in cancer are described, and the perspectives deriving from the validation of such alteration as a potential target, which may further allow driving the therapeutic approach in this molecularly selected patients' subgroup, are explored.

  2. Quantitative analysis of HGF and EGF-dependent phosphotyrosine signaling networks

    DEFF Research Database (Denmark)

    Hammond, Dean E; Hyde, Russell; Kratchmarova, Irina;

    2010-01-01

    549 lung adenocarcinoma cells with EGF or HGF. In total, we obtained quantitative information for 274 proteins, which respond to either or both stimuli by >1.5 fold changes in enrichment, following immuno-precipitation with antiphosphotyrosine antibodies. The data reveal a high degree of overlap...

  3. nMET, A New Target in Recurrent Cancer.

    Science.gov (United States)

    Xie, Yingqiu; Istayeva, Sholpan; Chen, Zhanlin; Tokay, Tursonjan; Zhumadilov, Zhaxybay; Wu, Denglong; Hortelano, Gonzalo; Zhang, Jinfu

    2016-01-01

    Membranous Met is classically identified with its role in cancer metastases, while nuclear Met is associated with a more invasive, aggressive and proliferative form of cancer. Full-length Met or N-terminal transmembrane domain cleaved Met can translocate into nucleus in a cell growth and pH dependent but both ligand-dependent (full length Met) and -independent (cleaved Met) manner. nMET may play greater essential roles in cancer recurrence than membranous Met. For example, in prostate cancer, it has been found that androgen receptor (AR) may inhibit the expression of membranous Met so anti-androgen based prostate cancer therapy may promote the expression of nuclear Met (nMET). We recently found a novel nMET/SOX9/ β-Catenin/AR pathway in relapsed prostate cancer which may contribute to the formation of the feedback loop of AR reactivation via MET/nMET. Emerging evidence suggests the possibility of nMET as a prognostic marker in relapsed cancer. This review summarizes recent findings about nMET and its unique role in recurrent cancer.

  4. Combined MET inhibition and topoisomerase I inhibition block cell growth of small cell lung cancer.

    Science.gov (United States)

    Rolle, Cleo E; Kanteti, Rajani; Surati, Mosmi; Nandi, Suvobroto; Dhanasingh, Immanuel; Yala, Soheil; Tretiakova, Maria; Arif, Qudsia; Hembrough, Todd; Brand, Toni M; Wheeler, Deric L; Husain, Aliya N; Vokes, Everett E; Bharti, Ajit; Salgia, Ravi

    2014-03-01

    Small cell lung cancer (SCLC) is a devastating disease, and current therapies have not greatly improved the 5-year survival rates. Topoisomerase (Top) inhibition is a treatment modality for SCLC; however, the response is short lived. Consequently, our research has focused on improving SCLC therapeutics through the identification of novel targets. Previously, we identified MNNG HOS transforming gene (MET) to be overexpressed and functional in SCLC. Herein, we investigated the therapeutic potential of combinatorial targeting of MET using SU11274 and Top1 using 7-ethyl-10-hydroxycamptothecin (SN-38). MET and TOP1 gene copy numbers and protein expression were determined in 29 patients with limited (n = 11) and extensive (n = 18) disease. MET gene copy number was significantly increased (>6 copies) in extensive disease compared with limited disease (P = 0.015). Similar TOP1 gene copy numbers were detected in limited and extensive disease. Immunohistochemical staining revealed a significantly higher Top1 nuclear expression in extensive (0.93) versus limited (0.15) disease (P = 0.04). Interestingly, a significant positive correlation was detected between MET gene copy number and Top1 nuclear expression (r = 0.5). In vitro stimulation of H82 cells revealed hepatocyte growth factor (HGF)-induced nuclear colocalization of p-MET and Top1. Furthermore, activation of the HGF/MET axis enhanced Top1 activity, which was abrogated by SU11274. Combination of SN-38 with SU11274 dramatically decreased SCLC growth as compared with either drug alone. Collectively, these findings suggest that the combinatorial inhibition of MET and Top1 is a potentially efficacious treatment strategy for SCLC. ©2013 AACR.

  5. Nisine geholpen met hordentechnologie

    NARCIS (Netherlands)

    Jong, de L.S.

    2001-01-01

    Een combinatie van nisine met carvacrol, thymol of carvon leidde tot een synergistische reductie van het aantal levensvatbare cellen van Listeria monocytogenes en Bacillus cereus. Verslag van een promotieonderzoek

  6. Sterren scoren met airbag

    NARCIS (Netherlands)

    Slütter, M.

    2010-01-01

    De praktijktest voor het airbagsysteem voor fietsers begint deze maand in Den Haag en Utrecht. Autofabrikanten hebben nu al interesse getoond. Dat is niet verwonderlijk, want met deze airbag kunnen ze sterren verdienen in de botsproeven van EuroNCAP.

  7. Zuinig met antibiotica

    NARCIS (Netherlands)

    Kuipers, A.; Wemmenhove, H.

    2011-01-01

    Het antibioticagebruik op melkveebedrijven is in beeld gebracht. Hoe benutten we deze gegevens om zuiniger met antibiotica om te gaan en hoe denken dierenartsen hierop in te spelen? Speelt de keuze voor verschillende middelen een rol?

  8. When Historiography Met Epistemology

    Directory of Open Access Journals (Sweden)

    Jean-François Stoffel

    2017-06-01

    Full Text Available Review of Bordoni, Stefano. When historiography met epistemology: Sophisticated histories and philosophies of science in French-speaking countries in the second half of the nineteenth century. Reviewed by Jean-François Stoffel.

  9. Oral fibroblasts produce more HGF and KGF than skin fibroblasts in response to co-culture with keratinocytes

    DEFF Research Database (Denmark)

    Grøn, Birgitte; Stoltze, Kaj; Andersson, Anders

    2002-01-01

    The production of hepatocyte growth factor (HGF) and keratinocyte growth factor (KGF) in subepithelial fibroblasts from buccal mucosa, periodontal ligament, and skin was determined after co-culture with keratinocytes. The purpose was to detect differences between the fibroblast subpopulations...... that could explain regional variation in epithelial growth and wound healing. Normal human fibroblasts were cultured on polystyrene or maintained in collagen matrix and stimulated with keratinocytes cultured on membranes. The amount of HGF and KGF protein in the culture medium was determined every 24 h for 5...... days by ELISA. When cultured on polystyrene, the constitutive level of KGF and HGF in periodontal fibroblasts was higher than the level in buccal and skin fibroblasts. In the presence of keratinocytes, all three types of fibroblasts in general increased their HGF and KGF production 2-3 times. When...

  10. Rekenen met vercijferde data

    NARCIS (Netherlands)

    Veugen, P.J.M.

    2011-01-01

    Een nieuwe techniek om bestaande en nieuwe toepassingen ‘privacy vriendelijk’ te maken is gebaseerd op het concept ‘rekenen met vercijferde data’. In dit artikel wordt dit mysterieuze idee uit de doeken gedaan en wordt de kracht ervan duidelijk gemaakt.

  11. BacMet

    DEFF Research Database (Denmark)

    Pal, Chandan; Bengtsson-Palme, Johan; Rensing, Christopher Günther T;

    2014-01-01

    -selection. Information on metal and biocide resistance genes, including their sequences and molecular functions, is, however, scattered. Here, we introduce BacMet (http://bacmet.biomedicine.gu.se) - a manually curated database of antibacterial biocide- and metal-resistance genes based on an in-depth review...

  12. Pionieren met informeel overleg

    NARCIS (Netherlands)

    Doornbos, N.

    2012-01-01

    Conflicthanteringspalet’, ‘escalatieladder’, ‘keukentafelgesprek’… Het zogenoemde pioniersproject van het Ministerie van Binnenlandse Zaken en Koninkrijksrelaties ‘Prettig contact met de overheid’ heeft de woordenschat aardig wat aangevuld. Zelfs de term LSD krijgt een nieuwe inhoud: luisteren - sam

  13. Pionieren met informeel overleg

    NARCIS (Netherlands)

    Doornbos, N.

    2012-01-01

    Conflicthanteringspalet’, ‘escalatieladder’, ‘keukentafelgesprek’… Het zogenoemde pioniersproject van het Ministerie van Binnenlandse Zaken en Koninkrijksrelaties ‘Prettig contact met de overheid’ heeft de woordenschat aardig wat aangevuld. Zelfs de term LSD krijgt een nieuwe inhoud: luisteren -

  14. Mechanische onkruidbestrijding met perspectief

    NARCIS (Netherlands)

    Bleeker, P.O.

    2011-01-01

    Intra-rijwieders met schoffels, lichtsensoren en camera’s: deze intelligente machines bestrijden het onkruid in de gewasrij mechanisch. Ze zijn ontwikkeld voor de biologische landbouw. De sensoren en camera’s bepalen de plaats van het gewas, waarna de schoffels per rij het onkruid tussen de planten

  15. Pionieren met informeel overleg

    NARCIS (Netherlands)

    Doornbos, N.

    2012-01-01

    Conflicthanteringspalet’, ‘escalatieladder’, ‘keukentafelgesprek’… Het zogenoemde pioniersproject van het Ministerie van Binnenlandse Zaken en Koninkrijksrelaties ‘Prettig contact met de overheid’ heeft de woordenschat aardig wat aangevuld. Zelfs de term LSD krijgt een nieuwe inhoud: luisteren - sam

  16. Ad-HGF improves the cardiac remodeling of rat following myocardial infarction by upregulating autophagy and necroptosis and inhibiting apoptosis

    Science.gov (United States)

    Liu, Jiabao; Wu, Peng; Wang, Yunle; Du, Yingqiang; A, Nan; Liu, Shuiyuan; Zhang, Yiming; Zhou, Ningtian; Xu, Zhihui; Yang, Zhijian

    2016-01-01

    Cell death in MI is the most critical determinant of subsequent left ventricular remodeling and heart failure. Besides apoptosis, autophagy and necroptosis have been recently found to be another two regulated cell death styles. HGF has been reported to have a protective role in MI, but its impact on the three death styles remains unclear. Thus, our study was performed to investigate the distribution of autophagy, apoptosis and necroptosis in cardiac tissues after MI and explore the role and mechanism of Ad-HGF on cardiac remodeling by regulating the three death styles. We firstly showed the distribution of autophagy, apoptosis and necroptosis differs in temporal and spatial context after MI using immunofluorescence. Notably, Ad-HGF treatment improves the cardiac remodeling of SD rats following MI by preserving the heart function, reducing the scar size and aggresomes. Further mechanism study reveals Ad-HGF promotes autophagy and necroptosis and inhibits apoptosis in vivo and in vitro. Co-immunoprecipitation assays showed Ad-HGF treatment significantly decreased the binding of Bcl-2 to Beclin1 but enhanced Bcl-2 binding to Bax in H9c2 cells under hypoxia. Moreover, HGF-induced sequestration of Bax by Bcl-2 allows Bax to become inactive, thereby inhibiting apoptosis. In addition, Ad-HGF markedly increased the formation of Beclin1-Vps34-Atg14L complex, which accounted for promoting autophagy. Both the western blot and activity assay showed Ad-HGF significantly decreased the caspase 8 protein and activity levels, which obligated the cell to undergo necroptosis under hypoxia and block apoptosis. Thus, our findings offer new evidence and strategies for the treatment of MI and post-MI cardiac remodeling. PMID:27904666

  17. CONSTRUCTION OF RECOMBINANT PLASMID PIRES-BAX-HGF%pIRES-Bax-HGF重组质粒的构建

    Institute of Scientific and Technical Information of China (English)

    黄涛; 常青; 徐平

    2011-01-01

    Objective To construct the plasmid vector of pIRES-Bax-HGF. Methods The Bax gene sequence was cloned from ovarian cancer samples, and HGF gene sequence from pBluescript Ⅱ SK+HGF plasmid derived from ATCC. Bax and HGF coding sequence were inserted into pIRES plasmid by step double enzyme digestion. Results Enzyme digestion and sequencing indicated that the construction of recombinant pIRES-Bax-HGF plasmid was successful. Conclusion Obtaining the coding genes of both Bax and HGF, and successfully creating the plasmid vector of plRES-Bax-HGF establish a foundation for further study of the effects of HGF and Bax on vascular endothelial cells, smooth muscle cells, and fibrocytes, which steps out an important step to treat post-CABG restenosis at gene level.%目的 构建pIRES-Bax-HGF质粒载体.方法 采用RT-PCR方法从卵巢癌标本中克隆Bax的基因序列,从ATCC来源的pBlueseriptⅡ SK+HGF质粒中克隆HGF的基因序列.分步双酶切插入到plRES载体质粒中.结果 酶切鉴定及测序表明,重组pIRES-Bax-HGF质粒构建成功.结论 获取HGF及Bax编码基因并成功构建重组pIRES-Bax-HGF质粒载体,为进一步研究HGF及Bax对血管内皮细胞、平滑肌细胞、纤维细胞等的影响奠定了基础,也向基因水平干预冠状动脉旁路移植术术后再狭窄的形成迈出了重要一步.

  18. Effects of HGF gene polymorphisms and protein expression on transhepatic arterial chemotherapeutic embolism efficacy and prognosis in patients with primary liver cancer

    Science.gov (United States)

    Chen, Hai-Yong; Chen, Yao-Min; Wu, Jian; Yang, Fu-Chun; Lv, Zhen; Qian, Yi-Gang; Zheng, Shu-Sen

    2017-01-01

    Objective To investigate the correlations of two hepatocyte growth factor (HGF) gene polymorphisms (rs5745652 and rs2074725) and their protein expression levels with the efficacy of transhepatic arterial chemotherapeutic embolism (TACE) and prognosis in patients with primary liver cancer (PLC). Methods From March 2011 to June 2012, 109 PLC patients (the case group) who chose TACE as primary treatment and 80 healthy people (the control group) who had undergone physical examination in The First Affiliated Hospital, Zhejiang University were selected during the same period. Gene polymorphisms of HGF rs5745652 and HGF rs2074725 were detected. Serum HGF level, treating efficacy, survival quality, and 3-year survival rate for PLC patients who received TACE were observed. Results There were significant differences in genotype and allele frequencies of HGF rs5745652 and HGF rs2074725, between the case and control groups (all PCancer stage were independent prognostic factors for PLC (Pprognosis after TACE treatment.

  19. Metsään.fi-metsäsuunnitelma OTSO Metsäpalveluissa

    OpenAIRE

    Karimo, Jussi

    2016-01-01

    Opinnäytetyön lähtökohtana oli OTSO Metsäpalveluiden halu kehittää Metsään.fi-palvelusta saatavan tiedon perusteella tehtävä metsäsuunnitelmatuote. Metsäsuunnitelmatuotteella tarkoitettiin uudenlaista metsäsuunnitelmaa, joka tehtäisiin Metsään.fi-palvelun tietoa hyödyntäen. Opinnäytetyön tarkoituksena oli kartoittaa OTSOn metsäpalveluhenkilöstön näkemyksiä Metsään.fi-palvelusta, jotta selviäisi, kannattaako heidän mielestään Metsään.fi-palvelua hyödyntää metsäsuunnitelmatyökaluna. Lisäksi hal...

  20. Effects of HGF gene polymorphisms and protein expression on transhepatic arterial chemotherapeutic embolism efficacy and prognosis in patients with primary liver cancer

    Directory of Open Access Journals (Sweden)

    Chen HY

    2017-02-01

    Full Text Available Hai-Yong Chen,1,2 Yao-Min Chen,3 Jian Wu,1,2 Fu-Chun Yang,1,2 Zhen Lv,1,2 Yi-Gang Qian,1,2 Shu-Sen Zheng1,2 1Department of Surgery, Division of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University, 2Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, 3Department of Breast Surgery, The First Affiliated Hospital, Zhejiang University, Hangzhou, Zhejiang, People’s Republic of China Objective: To investigate the correlations of two hepatocyte growth factor (HGF gene polymorphisms (rs5745652 and rs2074725 and their protein expression levels with the efficacy of transhepatic arterial chemotherapeutic embolism (TACE and prognosis in patients with primary liver cancer (PLC. Methods: From March 2011 to June 2012, 109 PLC patients (the case group who chose TACE as primary treatment and 80 healthy people (the control group who had undergone physical examination in The First Affiliated Hospital, Zhejiang University were selected during the same period. Gene polymorphisms of HGF rs5745652 and HGF rs2074725 were detected. Serum HGF level, treating efficacy, survival quality, and 3-year survival rate for PLC patients who received TACE were observed. Results: There were significant differences in genotype and allele frequencies of HGF rs5745652 and HGF rs2074725, between the case and control groups (all P<0.05. Compared with CT+TT genotype of HGF rs5745652, patients carrying CC genotype had lower serum HGF levels, higher efficacy, better survival quality, and prolonged 3-year survival rate (all P<0.05. In rs2074725, patients carrying CA+AA genotype had lower serum HGF levels, higher efficacy, better survival quality, and prolonged 3-year survival rate compared with patients carrying rs2074725 CC genotype (all P<0.05. Gene polymorphisms of HGF rs5745652 and HGF rs2074725, tumor size, and Barcelona Clinic Liver Cancer stage were independent prognostic factors for PLC (P<0.05. Conclusion: Our

  1. La metáfora

    DEFF Research Database (Denmark)

    Agustin, Oscar Garcia

    2007-01-01

    La función de la metáfora ha sido revisada desde distintas disciplinas. Desde la hermenéutica, se destaca la naturaleza tensional de la metáfora y el modo en que contribuye a crear significaciones nuevas, que rehacen los órdenes semánticos preexistentes. Desde el cognitivismo, la metáfora...

  2. Met inactivation by S-allylcysteine suppresses the migration and invasion of nasopharyngeal cancer cells induced by hepatocyte growth factor

    Energy Technology Data Exchange (ETDEWEB)

    Cho, O Yeon; Hwang, Hye Sook; Lee, Bok Soon; Oh, Young Taek; Kim, Chul Ho; Chun, Mi Son [Ajou University School of Medicine, Suwon (Korea, Republic of)

    2015-12-15

    Past studies have reported that S-allylcysteine (SAC) inhibits the migration and invasion of cancer cells through the restoration of E-cadherin, the reduction of matrix metalloproteinase (MMP) and Slug protein expression, and inhibition of the production of reactive oxygen species (ROS). Furthermore, evidence is emerging that shows that ROS induced by radiation could increase Met activation. Following on these reports of SAC and Met, we investigated whether SAC could suppress Met activation. Wound healing, invasion, 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium (MTT), soft agar colony forming, western blotting, and gelatin zymography assays were performed in the human nasopharyngeal cancer cell lines HNE1 and HONE1 treated with SAC (0, 10, 20, or 40 mM) and hepatocyte growth factor (HGF). This study showed that SAC could suppress the migration and invasion of HNE1 and HONE1 cell lines by inhibiting p-Met. An increase of migration and invasion induced by HGF and its decrease in a dose dependent manner by SAC in wound healing and invasion assays was observed. The reduction of p-Met by SAC was positively correlated with p-focal adhesion kinase (p-FAK) and p-extracellular related kinase (p-ERK in both cell lines). SAC reduced Slug, MMP2, and MMP9 involved in migration and invasion with the inhibition of Met-FAK signaling. These results suggest that SAC inhibited not only Met activation but also the downstream FAK, Slug, and MMP expression. Finally, SAC may be a potent anticancer compound for nasopharyngeal cancer treated with radiotherapy.

  3. Absence of tpr-met and expression of c-met in human gastric mucosa and carcinoma.

    Science.gov (United States)

    Heideman, D A; Snijders, P J; Bloemena, E; Meijer, C J; Offerhaus, G J; Meuwissen, S G; Gerritsen, W R; Craanen, M E

    2001-08-01

    The c-met proto-oncogene, encoding the hepatocyte growth factor receptor, can be activated by various mechanisms. These include, among others, gene amplification with concomitant overexpression and the tpr-met oncogenic rearrangement. In the case of gastric cancer, contradictory results on the presence of the tpr-met oncogenic rearrangement have been published. The current study aimed therefore to assess the prevalence of tpr-met expression in Caucasian gastric adenocarcinomas, to evaluate the importance of this oncogene in their carcinogenesis. In addition, the level of c-met expression was determined, to evaluate the role of this alternative mode of activation of the proto-oncogene. A series of Caucasian gastric adenocarcinomas (n=43) and normal gastric mucosal samples (n=14) was analysed for tpr-met and c-met expression. Expression of tpr-met mRNA in the samples was performed by two reverse transcriptase polymerase chain reaction (RT-PCR) assays, with excellent correlation. The specificity of both methods was confirmed by direct sequencing of the PCR products of the MNNG-HOS cell line, which is known to contain the rearrangement. The level of c-met expression was assessed using semi-quantitative RT-PCR assays and immunohistochemistry (IHC). None of the normal gastric mucosal or gastric adenocarcinoma samples expressed tpr-met mRNA, as determined by both RT-PCR assays. Seventy per cent of the adenocarcinomas showed overexpression of c-met, according to elevated c-met mRNA levels, compared with the expression level of normal gastric mucosa. A significant correlation was found between the level of c-met mRNA and protein expression. In conclusion, these results strongly suggest that tpr-met activation does not play a role in Caucasian gastric carcinogenesis, while overexpression of the c-met gene occurs in the majority of Caucasian gastric adenocarcinomas.

  4. Expression of Factors in the Hepatocyte Growth Factor (HGF) Pathway in Whole Bone Marrow Biopsies in Association to the Osteolytic Bone Disease of Multiple Myeloma

    DEFF Research Database (Denmark)

    Kristensen, Ida Bruun; Christensen, Jacob Haaber; Lyng, Maria Bibi

    Expression of Factors in the Hepatocyte Growth Factor (HGF) Pathway in Whole Bone Marrow Biopsies in Association to the Osteolytic Bone Disease of Multiple Myeloma......Expression of Factors in the Hepatocyte Growth Factor (HGF) Pathway in Whole Bone Marrow Biopsies in Association to the Osteolytic Bone Disease of Multiple Myeloma...

  5. Gene expression alterations during HGF-induced dedifferentiation of a renal tubular epithelial cell line (MDCK) using a novel canine DNA microarray.

    Science.gov (United States)

    Balkovetz, Daniel F; Gerrard, Edward R; Li, Shixiong; Johnson, David; Lee, James; Tobias, John W; Rogers, Katherine K; Snyder, Richard W; Lipschutz, Joshua H

    2004-04-01

    Hepatocyte growth factor (HGF) elicits a broad spectrum of biological activities, including epithelial cell dedifferentiation. One of the most widely used and best-studied polarized epithelial cell lines is the Madin-Darby canine kidney (MDCK) cell line. Here, we describe and validate the early response of polarized monolayers of MDCK cells stimulated with recombinant HGF using a novel canine DNA microarray designed to query 12,473 gene sequences. In our survey, eight genes previously implicated in the HGF signaling pathway were differentially regulated, demonstrating that the system was responsive to HGF. Also identified were 117 genes not previously known to be involved in the HGF pathway. The results were confirmed by real-time PCR or Western blot analysis for 38 genes. Of particular interest were the large number of differentially regulated genes encoding small GTPases, proteins involved in endoplasmic reticulum translation, proteins involved in the cytoskeleton, the extracellular matrix, and the hematopoietic and prostaglandin systems.

  6. Vroegtijdig Phytophthora opsporen met biosensor

    NARCIS (Netherlands)

    Jansen, R.M.C.

    2003-01-01

    Phytophthora kan vroegtijdig worden opgespoord met biosensoren. Bij de Leerstoelgroep Agrarische Bedrijfstechnologie van Wageningen Universiteit wordt verder gekeken naar praktische toepassingen van deze techniek

  7. Plexin B1 inhibits MET through direct association and regulates Shp2 expression in melanocytes.

    Science.gov (United States)

    Soong, Joanne; Scott, Glynis

    2013-01-15

    Plexin B1, the receptor for Semaphorin 4D (Sema4D), is expressed by melanocytes in the skin. We recently showed that Sema4D suppresses activation of the hepatocyte growth factor receptor, MET, in melanocytes, and that knockdown of Plexin B1 results in activation of MET. MET signaling mediates proliferation, survival and migration in melanocytes, and its activation is associated with transformation of melanocytes to melanoma. In this report we investigated the mechanism by which Plexin B1 inhibits MET activation. Our results show that Plexin B1 and MET exist as an oligomeric receptor-receptor complex in melanocytes, and that receptor association is increased by Sema4D. MET and Plexin B1 receptor complexes were identified along the cell body of melanocytes, and Sema4D increased receptor association on dendrites, suggesting that Sema4D regulates MET-dependent processes at precise locations on the melanocyte. Despite activation of MET, Plexin B1 knockdowns proliferated slowly and showed increased apoptosis compared with controls. Shp2, a non-receptor protein tyrosine phosphatase, translates growth and survival signals from MET and other receptor tyrosine kinases. Plexin B1 knockdowns had markedly lower levels of Shp2 compared with controls, and Sema4D upregulated Shp2 expression at the protein and message level in normal melanocytes. Functional studies showed that blockade of Shp2 activity abrogated MET-dependent activation of Erk1/Erk2 and Akt in melanocytes. These results suggest a complex role for Sema4D and Plexin B1 in orchestrating signaling from the MET receptor in melanocytes. Because Shp2 is a downstream adaptor protein for multiple receptors, Sema4D may control the effects of several growth factors on melanocytes through regulation of Shp2.

  8. Monovalency Unleashes the Full Therapeutic Potential of the DN-30 Anti-Met Antibody*

    Science.gov (United States)

    Pacchiana, Giovanni; Chiriaco, Cristina; Stella, Maria C.; Petronzelli, Fiorella; De Santis, Rita; Galluzzo, Maria; Carminati, Paolo; Comoglio, Paolo M.; Michieli, Paolo; Vigna, Elisa

    2010-01-01

    Met, the high affinity receptor for hepatocyte growth factor, is one of the most frequently activated tyrosine kinases in human cancer and a validated target for cancer therapy. We previously developed a mouse monoclonal antibody directed against the extracellular portion of Met (DN-30) that induces Met proteolytic cleavage (receptor “shedding”) followed by proteasome-mediated receptor degradation. This translates into inhibition of hepatocyte growth factor/Met-mediated biological activities. However, DN-30 binding to Met also results in partial activation of the Met kinase due to antibody-mediated receptor homodimerization. To safely harness the therapeutic potential of DN-30, its shedding activity must be disassociated from its agonistic activity. Here we show that the DN-30 Fab fragment maintains high affinity Met binding, elicits efficient receptor shedding and down-regulation, and does not promote kinase activation. In Met-addicted tumor cell lines, DN-30 Fab displays potent cytostatic and cytotoxic activity in a dose-dependent fashion. DN-30 Fab also inhibits anchorage-independent growth of several tumor cell lines. In mouse tumorigenesis assays using Met-addicted carcinoma cells, intratumor administration of DN-30 Fab or systemic delivery of a chemically stabilized form of the same molecule results in reduction of Met phosphorylation and inhibition of tumor growth. These data provide proof of concept that monovalency unleashes the full therapeutic potential of the DN-30 antibody and point at DN-30 Fab as a promising tool for Met-targeted therapy. PMID:20833723

  9. Monovalency unleashes the full therapeutic potential of the DN-30 anti-Met antibody.

    Science.gov (United States)

    Pacchiana, Giovanni; Chiriaco, Cristina; Stella, Maria C; Petronzelli, Fiorella; De Santis, Rita; Galluzzo, Maria; Carminati, Paolo; Comoglio, Paolo M; Michieli, Paolo; Vigna, Elisa

    2010-11-12

    Met, the high affinity receptor for hepatocyte growth factor, is one of the most frequently activated tyrosine kinases in human cancer and a validated target for cancer therapy. We previously developed a mouse monoclonal antibody directed against the extracellular portion of Met (DN-30) that induces Met proteolytic cleavage (receptor "shedding") followed by proteasome-mediated receptor degradation. This translates into inhibition of hepatocyte growth factor/Met-mediated biological activities. However, DN-30 binding to Met also results in partial activation of the Met kinase due to antibody-mediated receptor homodimerization. To safely harness the therapeutic potential of DN-30, its shedding activity must be disassociated from its agonistic activity. Here we show that the DN-30 Fab fragment maintains high affinity Met binding, elicits efficient receptor shedding and down-regulation, and does not promote kinase activation. In Met-addicted tumor cell lines, DN-30 Fab displays potent cytostatic and cytotoxic activity in a dose-dependent fashion. DN-30 Fab also inhibits anchorage-independent growth of several tumor cell lines. In mouse tumorigenesis assays using Met-addicted carcinoma cells, intratumor administration of DN-30 Fab or systemic delivery of a chemically stabilized form of the same molecule results in reduction of Met phosphorylation and inhibition of tumor growth. These data provide proof of concept that monovalency unleashes the full therapeutic potential of the DN-30 antibody and point at DN-30 Fab as a promising tool for Met-targeted therapy.

  10. A novel rabbit anti-hepatocyte growth factor monoclonal neutralizing antibody inhibits tumor growth in prostate cancer cells and mouse xenografts

    Energy Technology Data Exchange (ETDEWEB)

    Yu, Yanlan; Chen, Yicheng; Ding, Guoqing; Wang, Mingchao; Wu, Haiyang; Xu, Liwei; Rui, Xuefang; Zhang, Zhigen, E-mail: srrshurology@163.com

    2015-08-14

    The hepatocyte growth factor and its receptor c-Met are correlated with castration-resistance in prostate cancer. Although HGF has been considered as an attractive target for therapeutic antibodies, the lack of cross-reactivity of monoclonal antibodies with human/mouse HGFs is a major obstacle in preclinical developments. We generated a panel of anti-HGF RabMAbs either blocking HGF/c-Met interaction or inhibiting c-Met phosphorylation. We selected one RabMAb with mouse cross-reactivity and demonstrated that it blocked HGF-stimulated downstream activation in PC-3 and DU145 cells. Anti-HGF RabMAb inhibited not only the growth of PC-3 cells but also HGF-dependent proliferation in HUVECs. We further demonstrated the efficacy and potency of the anti-HGF RabMAb in tumor xenograft mice models. Through these in vitro and in vivo experiments, we explored a novel therapeutic antibody for advanced prostate cancer. - Highlights: • HGF is an attractive target for castration-refractory prostate cancer. • We generated and characterized a panel of anti-HGF rabbit monoclonal antibodies. • More than half of these anti-HGF RabMAbs was cross-reactive with mouse HGF. • Anti-HGF RabMAb blocks HGF-stimulated phosphorylation and cell growth in vitro. • Anti-HGF RabMAb inhibits tumor growth and angiogenesis in xenograft mice.

  11. The Impact of Chain Length and Flexibility in the Interaction between Sulfated Alginates and HGF and FGF-2.

    Science.gov (United States)

    Arlov, Øystein; Aachmann, Finn L; Feyzi, Emadoldin; Sundan, Anders; Skjåk-Bræk, Gudmund

    2015-11-09

    Alginate is a promising polysaccharide for use in biomaterials as it is biologically inert. One way to functionalize alginate is by chemical sulfation to emulate sulfated glycosaminoglycans, which interact with a variety of proteins critical for tissue development and homeostasis. In the present work we studied the impact of chain length and flexibility of sulfated alginates for interactions with FGF-2 and HGF. Both growth factors interact with defined sequences of heparan sulfate (HS) at the cell surface or in the extracellular matrix. Whereas FGF-2 interacts with a pentasaccharide sequence containing a critical 2-O-sulfated iduronic acid, HGF has been suggested to require a highly sulfated HS/heparin octasaccharide. Here, oligosaccharides of alternating mannuronic and guluronic acid (MG) were sulfated and assessed by their relative efficacy at releasing growth factor bound to the surface of myeloma cells. 8-mers of sulfated MG (SMG) alginate showed significant HGF release compared to shorter fragments, while the maximum efficacy was achieved at a chain length average of 14 monosaccharides. FGF-2 release required a higher concentration of the SMG fragments, and the 14-mer was less potent compared to an equally sulfated high-molecular weight SMG. Sulfated mannuronan (SM) was subjected to periodate oxidation to increase chain flexibility. To assess the change in flexibility, the persistence length was estimated by SEC-MALLS analysis and the Bohdanecky approach to the worm-like chain model. A high degree of oxidation of SM resulted in approximately twice as potent HGF release compared to the nonoxidized SM alginate. The release of FGF-2 also increased with the degree of oxidation, but to a lower degree compared to that of HGF. It was found that the SM alginates were more efficient at releasing FGF-2 than the SMG alginates, indicating a greater dependence on monosaccharide identity and charge orientation over chain flexibility and charge density.

  12. Targeting MET Amplification as a New Oncogenic Driver

    Energy Technology Data Exchange (ETDEWEB)

    Kawakami, Hisato [Department of Medical Oncology, Kinki University Faculty of Medicine, 377-2 Ohno-higashi, Osaka-Sayama, Osaka 589-8511 (Japan); Okamoto, Isamu, E-mail: okamotoi@kokyu.med.kyushu-u.ac.jp [Department of Medical Oncology, Kinki University Faculty of Medicine, 377-2 Ohno-higashi, Osaka-Sayama, Osaka 589-8511 (Japan); Center for Clinical and Translational Research, Kyushu University Hospital, 3-1-1 Maidashi, Higashiku, Fukuoka 812-8582 (Japan); Okamoto, Wataru [Department of Medical Oncology, Kinki University Faculty of Medicine, 377-2 Ohno-higashi, Osaka-Sayama, Osaka 589-8511 (Japan); Division of Transrlational Research, Exploratory Oncology Research & Clinical Trial Center, National Cancer Center, 6-5-1 Kashiwanoha, Kashiwa, Chiba 277-8577 (Japan); Tanizaki, Junko [Department of Medical Oncology, Kinki University Faculty of Medicine, 377-2 Ohno-higashi, Osaka-Sayama, Osaka 589-8511 (Japan); Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, HIM223, 450 Brookline Avenue, Boston, MA 02215 (United States); Nakagawa, Kazuhiko [Department of Medical Oncology, Kinki University Faculty of Medicine, 377-2 Ohno-higashi, Osaka-Sayama, Osaka 589-8511 (Japan); Nishio, Kazuto [Department of Genome Biology, Kinki University Faculty of Medicine, 377-2 Ohno-higashi, Osaka-Sayama, Osaka 589-8511 (Japan)

    2014-07-22

    Certain genetically defined cancers are dependent on a single overactive oncogene for their proliferation and survival, a phenomenon known as “oncogene addiction”. A new generation of drugs that selectively target such “driver oncogenes” manifests a clinical efficacy greater than that of conventional chemotherapy in appropriate genetically defined patients. MET is a proto-oncogene that encodes a receptor tyrosine kinase, and aberrant activation of MET signaling occurs in a subset of advanced cancers as result of various genetic alterations including gene amplification, polysomy, and gene mutation. Our preclinical studies have shown that inhibition of MET signaling either with the small-molecule MET inhibitor crizotinib or by RNA interference targeted to MET mRNA resulted in marked antitumor effects in cancer cell lines with MET amplification both in vitro and in vivo. Furthermore, patients with non-small cell lung cancer or gastric cancer positive for MET amplification have shown a pronounced clinical response to crizotinib. Accumulating preclinical and clinical evidence thus suggests that MET amplification is an “oncogenic driver” and therefore a valid target for treatment. However, the prevalence of MET amplification has not been fully determined, possibly in part because of the difficulty in evaluating gene amplification. In this review, we provide a rationale for targeting this genetic alteration in cancer therapy.

  13. Targeting MET Amplification as a New Oncogenic Driver

    Directory of Open Access Journals (Sweden)

    Hisato Kawakami

    2014-07-01

    Full Text Available Certain genetically defined cancers are dependent on a single overactive oncogene for their proliferation and survival, a phenomenon known as “oncogene addiction”. A new generation of drugs that selectively target such “driver oncogenes” manifests a clinical efficacy greater than that of conventional chemotherapy in appropriate genetically defined patients. MET is a proto-oncogene that encodes a receptor tyrosine kinase, and aberrant activation of MET signaling occurs in a subset of advanced cancers as result of various genetic alterations including gene amplification, polysomy, and gene mutation. Our preclinical studies have shown that inhibition of MET signaling either with the small-molecule MET inhibitor crizotinib or by RNA interference targeted to MET mRNA resulted in marked antitumor effects in cancer cell lines with MET amplification both in vitro and in vivo. Furthermore, patients with non-small cell lung cancer or gastric cancer positive for MET amplification have shown a pronounced clinical response to crizotinib. Accumulating preclinical and clinical evidence thus suggests that MET amplification is an “oncogenic driver” and therefore a valid target for treatment. However, the prevalence of MET amplification has not been fully determined, possibly in part because of the difficulty in evaluating gene amplification. In this review, we provide a rationale for targeting this genetic alteration in cancer therapy.

  14. Microbewerking met behulp van lasers

    NARCIS (Netherlands)

    Ezendam, M.M.M.

    1994-01-01

    Het bewerken van materialen met behulp van lasers staat momenteel enorm in de belangstelling, en terecht. De ontwikkeling van bestaande en nieuwe typen lasers staat alles behalve stil. Ontwikkelingen bevinden zich met name in het gebied van hogere vermogens, betere bundelkwaliteit en hogere

  15. Enhanced antioxidant capacity of dental pulp-derived iPSC-differentiated hepatocytes and liver regeneration by injectable HGF-releasing hydrogel in fulminant hepatic failure.

    Science.gov (United States)

    Chiang, Chih-Hung; Wu, Wai-Wah; Li, Hsin-Yang; Chien, Yueh; Sun, Cho-Chin; Peng, Chi-Hsien; Lin, Alex Tong-Long; Huang, Chi-Shuan; Lai, Ying-Hsiu; Chiou, Shih-Hwa; Hung, Shuen-Iu; Chang, Yuh-Lih; Lan, Yuan-Tzu; Liu, Dean-Mo; Chien, Chian-Shiu; Huo, Teh-Ia; Lee, Shou-Dong; Wang, Chien-Ying

    2015-01-01

    Acute hepatic failure (AHF) is a severe liver injury leading to sustained damage and complications. Induced pluripotent stem cells (iPSCs) may be an alternative option for the treatment of AHF. In this study, we reprogrammed human dental pulp-derived fibroblasts into iPSCs, which exhibited pluripotency and the capacity to differentiate into tridermal lineages, including hepatocyte-like cells (iPSC-Heps). These iPSC-Heps resembled human embryonic stem cell-derived hepatocyte-like cells in gene signature and hepatic markers/functions. To improve iPSC-Heps engraftment, we next developed an injectable carboxymethyl-hexanoyl chitosan hydrogel (CHC) with sustained hepatocyte growth factor (HGF) release (HGF-CHC) and investigated the hepatoprotective activity of HGF-CHC-delivered iPSC-Heps in vitro and in an immunocompromised AHF mouse model induced by thioacetamide (TAA). Intrahepatic delivery of HGF-CHC-iPSC-Heps reduced the TAA-induced hepatic necrotic area and rescued liver function and recipient viability. Compared with PBS-delivered iPSC-Heps, the HGF-CHC-delivered iPSC-Heps exhibited higher antioxidant and antiapoptotic activities that reduced hepatic necrotic area. Importantly, these HGF-CHC-mediated responses could be abolished by administering anti-HGF neutralizing antibodies. In conclusion, our findings demonstrated that HGF mediated the enhancement of iPSC-Hep antioxidant/antiapoptotic capacities and hepatoprotection and that HGF-CHC is as an excellent vehicle for iPSC-Hep engraftment in iPSC-based therapy against AHF.

  16. Gezondheidsrisico's in verband met het werken met Polychloorbifenylen : een onderzoek

    NARCIS (Netherlands)

    Geuskens, R.B.M.; Nossent, S.M.; Koëter, H.B.W.M.; Dreef-van der Meulen, H.C.; Stijkel, A.; Zielhuis, R.L.

    1989-01-01

    Met behulp van gegevens verkregen uit een werkplekinventarisatie naar gegevens over produktie/gebruik, risicopopulatie en (mogelijke) blootstelling aan polychloorbifenylen (PCB's), en een literatuurstudie naar mogelijke schadelijke eigenschappen van PCB's op het reproductiesysteem en/of nageslacht (

  17. Mesenchymal stem cells and myoblast differentiation under HGF and IGF-1 stimulation for 3D skeletal muscle tissue engineering.

    Science.gov (United States)

    Witt, R; Weigand, A; Boos, A M; Cai, A; Dippold, D; Boccaccini, A R; Schubert, D W; Hardt, M; Lange, C; Arkudas, A; Horch, R E; Beier, J P

    2017-02-28

    Volumetric muscle loss caused by trauma or after tumour surgery exceeds the natural regeneration capacity of skeletal muscle. Hence, the future goal of tissue engineering (TE) is the replacement and repair of lost muscle tissue by newly generating skeletal muscle combining different cell sources, such as myoblasts and mesenchymal stem cells (MSCs), within a three-dimensional matrix. Latest research showed that seeding skeletal muscle cells on aligned constructs enhance the formation of myotubes as well as cell alignment and may provide a further step towards the clinical application of engineered skeletal muscle. In this study the myogenic differentiation potential of MSCs upon co-cultivation with myoblasts and under stimulation with hepatocyte growth factor (HGF) and insulin-like growth factor-1 (IGF-1) was evaluated. We further analysed the behaviour of MSC-myoblast co-cultures in different 3D matrices. Primary rat myoblasts and rat MSCs were mono- and co-cultivated for 2, 7 or 14 days. The effect of different concentrations of HGF and IGF-1 alone, as well as in combination, on myogenic differentiation was analysed using microscopy, multicolour flow cytometry and real-time PCR. Furthermore, the influence of different three-dimensional culture models, such as fibrin, fibrin-collagen-I gels and parallel aligned electrospun poly-ε-caprolacton collagen-I nanofibers, on myogenic differentiation was analysed. MSCs could be successfully differentiated into the myogenic lineage both in mono- and in co-cultures independent of HGF and IGF-1 stimulation by expressing desmin, myocyte enhancer factor 2, myosin heavy chain 2 and alpha-sarcomeric actinin. An increased expression of different myogenic key markers could be observed under HGF and IGF-1 stimulation. Even though, stimulation with HGF/IGF-1 does not seem essential for sufficient myogenic differentiation. Three-dimensional cultivation in fibrin-collagen-I gels induced higher levels of myogenic differentiation

  18. Cahier Welzijnsgids. Omgaan met beroepsgeheim

    Directory of Open Access Journals (Sweden)

    Hilde Vlaeminck

    2016-03-01

    Full Text Available Bernard Hubeau, Jos Mertens, Johan Put, Rudi Roose, Kris Stas, Freya Vander Laenen (Eds.. Cahier Welzijnsgids. Omgaan met beroepsgeheim. Mechelen: Kluwer, 182 p., €31,60. ISBN 978 90 4655 475 3

  19. Compost voor biggen met diarree

    NARCIS (Netherlands)

    Gommers, T.

    1990-01-01

    Het geven van compost aan biggen met diarree zorgt op het Proefstation voor de Varkenshouderij voor minder medicijngebruik. De biggen krijgen de compost van groente-, fruit- en tuinafval vanaf de tweede dag na de geboorte, zodra de diarreeverschijnselen zichtbaar zijn.

  20. Metallurgical Laboratory (MET-LAB)

    Data.gov (United States)

    Federal Laboratory Consortium — The MET-LAB can perform materials characterization for all types of metallic components and systems to any industry-specific or military standard. Capabilities: The...

  1. The HGF/c-MET Axis as a Critical Driver of Resistance to Androgen Suppression in Metastatic Castrate-Resistant Prostate Cancer

    Science.gov (United States)

    2015-10-01

    aspirates from 5 patients. We have obtained 6 blood samples for CTC analyses from 4 patients on abiraterone and 3 blood samples from 2 patients on...bone marrow aspirates has been slower than anticipated. We have addressed this in a number of ways, including pre- screening clinics for eligible...a graphene oxide based microfluidic device (GO Chip) to prostate cancer circulating tumor cell capture and analysis, AACR, 2015. *Patnaik, A

  2. Astragalus mongholicus ameliorates renal fibrosis by modulating HGF and TGF-β in rats with unilateral ureteral obstruction

    Institute of Scientific and Technical Information of China (English)

    Chuan ZUO; Xi-sheng XIE; Hong-yu QIU; Yao DENG; Da ZHU; Jun-ming FAN

    2009-01-01

    Astragalus mongholicus (AM) derived from the dry root of Astragalus membranaceus Bge. var. mongolicus (Bge.) Hsiao is a widely used traditional Chinese medicine. The present study investigated the potential role of AM on renal fibrosis on a rat model of unilateral ureteral obstruction (UUO). We divided 48 Sprague-Dawley rats randomly into 4 groups: sham-operated group (Sham), untreated UUO group, AM-treated (10 g/(kg.d)) UUO group, and losartan-treated (20 mg/(kg.d)) UUO group as positive control. Haematoxylin & eosin (HE) and Masson staining were used to study the dynamic histological changes of the kidneys 7 and 14 d after operation. The expressions of fibronectin (FN), type I collagen (coII), hepatocyte growth factor (HGF), transforming growth factor-pi (TGF-βl), and a-smooth muscle actin (a-SMA) were analyzed by real-time polymerase chain reaction (PCR), immunohistochemistry staining, and Western blot. Results show that, similar to losartan, AM alleviated the renal damage and decreased the deposition of FN and colI from UUO by reducing the expressions of TGF-pi and a-SMA (P<0.05), whereas HGF increased greatly with AM treatment (P<0.05). Our findings reveal that AM could retard the progression of renal fibrosis. The renoprotective effect of AM might be related to inhibition of myofibroblast activation, inducing of HGF and reducing of TGF-β1 expression.

  3. ETS2 mediated tumor suppressive function and MET oncogene inhibition in human non-small cell lung cancer

    Science.gov (United States)

    Kabbout, Mohamed; Garcia, Melinda M.; Fujimoto, Junya; Liu, Diane D.; Woods, Denise; Chow, Chi-Wan; Mendoza, Gabriela; Momin, Amin A.; James, Brian P.; Solis, Luisa; Behrens, Carmen; Lee, J. Jack

    2013-01-01

    PURPOSE The ETS2 transcription factor is an evolutionarily conserved gene that is deregulated in cancer. We analyzed the transcriptome of lung adenocarcinomas and normal lung tissue by expression profiling and found that ETS2 was significantly down-regulated in adenocarcinomas. In this study, we probed the yet unknown functional role of ETS2 in lung cancer pathogenesis. EXPERIMENTAL DESIGN Lung adenocarcinomas (n=80) and normal lung tissues (n=30) were profiled using the Affymetrix Human Gene 1.0 ST platform. Immunohistochemical (IHC) analysis was performed to determine ETS2 protein expression in NSCLC histological tissue specimens (n=201). Patient clinical outcome, based on ETS2 IHC expression, was statistically assessed using the log-rank and Kaplan-Meier tests. RNA interference and over-expression strategies were employed to assess effects of ETS2 expression on the transcriptome and on various malignant phenotypes. RESULTS ETS2 expression was significantly reduced in lung adenocarcinomas compared to normal lung (precurrence in NSCLC (p=0.009, HR=1.89) and adenocarcinoma (p=0.03, HR=1.86). Moreover, ETS2 was found to significantly inhibit lung cancer cell growth, migration and invasion (p<0.05), and microarray and pathways analysis revealed significant (p<0.001) activation of the HGF pathway following ETS2 knockdown. In addition, ETS2 was found to suppress MET phosphorylation and knockdown of MET expression significantly attenuated (p<0.05) cell invasion mediated by ETS2-specific siRNA. Furthermore, knockdown of ETS2 augmented HGF-induced MET phosphorylation, cell migration and invasion. CONCLUSION(S) Our findings point to a tumor suppressor role for ETS2 in human NSCLC pathogenesis through inhibition of the MET proto-oncogene. PMID:23659968

  4. Loss of embryonic MET signaling alters profiles of hippocampal interneurons.

    Science.gov (United States)

    Martins, Gabriela J; Plachez, Céline; Powell, Elizabeth M

    2007-01-01

    Hippocampal interneurons arise in the ventral forebrain and migrate dorsally in response to cues, including hepatocyte growth factor/scatter factor which signals via its receptor MET. Examination of the hippocampus in adult mice in which MET had been inactivated in the embryonic proliferative zones showed an increase in parvalbumin-expressing cells in the dentate gyrus, but a loss of these cells in the CA3 region. An overall loss of calretinin-expressing cells was seen throughout the hippocampus. A similar CA3 deficit of parvalbumin and calretinin cells was observed when MET was eliminated only in postmitotic cells. These data suggest that MET is required for the proper hippocampal development, and embryonic perturbations lead to long-term anatomical defects with possible learning and memory dysfunction.

  5. Rapportage gewasbescherming 2007 Telen met toekomst - Bloembollen

    NARCIS (Netherlands)

    Haan, de J.J.

    2008-01-01

    Dit is het vierde rapportage gewasbescherming van het praktijknetwerk Telen met toekomst voor de open teelten. Het praktijknetwerk Telen met toekomst organiseert groepen praktijkbedrijven met hun relaties rond de ontwikkeling van meer duurzame productiesystemen (milieutechnisch, ecologisch en

  6. Leven met Inflammatory Bowel Disease

    NARCIS (Netherlands)

    Duijvendijk J. van, [No Value

    2004-01-01

    Leven met Inflammatory Bowel Disease Inflammatory bowel disease (IBD) is de verzamelnaam voor Colitis ulcerosa en de ziekte van Crohn. Het zijn chronische darmontstekingen, waarvan de ziekteactiviteit wisselt en zich niet laat voorspellen. Door de lichamelijke klachten en het onvoorspelbare karakter

  7. Water zuiveren met drijvende planten

    NARCIS (Netherlands)

    Keizer-Vlek, H.E.; Verdonschot, P.F.M.; Verdonschot, R.C.M.; Dekkers, T.B.M.

    2013-01-01

    Drijvende moerassystemen met helofyten, ook wel floating treatment wetlands of floatlands genoemd, worden in Nederland uitsluitend toegepast om natuurbeleving te stimuleren en de biodiversiteit van het oppervlaktewater te vergroten. Floatlands zijn echter mogelijk ook geschikt om nutriënten uit het

  8. Fijnstof te lijf met koolzaadolie

    NARCIS (Netherlands)

    Ogink, N.W.M.

    2010-01-01

    Wageningen UR Livestock Research onderzoekt een reeks aan maatregelen die de uitstoot van fijnstof bij pluimveebedrijven kunnen verminderen. Iedere dag wat koolzaadolie vernevelen is tot nu toe het meest hoopgevend, met als bijkomend voordeel dat het stalklimaat verbetert voor mens en dier.

  9. Water zuiveren met drijvende planten

    OpenAIRE

    Keizer-Vlek, H.E.; Verdonschot, P. F. M.; Verdonschot, R.C.M.; Dekkers, T.B.M.

    2013-01-01

    Drijvende moerassystemen met helofyten, ook wel floating treatment wetlands of floatlands genoemd, worden in Nederland uitsluitend toegepast om natuurbeleving te stimuleren en de biodiversiteit van het oppervlaktewater te vergroten. Floatlands zijn echter mogelijk ook geschikt om nutriënten uit het oppervlaktewater te verwijderen. Vooral in het stedelijk gebied is dit een aantrekkelijke optie. De gele lis is er uitermate voor geschikt.

  10. Leven met Inflammatory Bowel Disease

    NARCIS (Netherlands)

    Duijvendijk J. van, [No Value

    2004-01-01

    Leven met Inflammatory Bowel Disease Inflammatory bowel disease (IBD) is de verzamelnaam voor Colitis ulcerosa en de ziekte van Crohn. Het zijn chronische darmontstekingen, waarvan de ziekteactiviteit wisselt en zich niet laat voorspellen. Door de lichamelijke klachten en het onvoorspelbare karakter

  11. Steeds preciezer met de sensor

    NARCIS (Netherlands)

    Houweling, van P.; PPO Akkerbouw, Groene Ruimte en Vollegrondsgroente

    2014-01-01

    Maurits Bax uit Luyksgestel werkt met de Yara N-sensor. Zo spuit hij minder dan een derde van de voorgeschreven dosering voor loofdodingsmiddel in aardappelen. Andere toepassingen zijn minder praktijkrijp, zoals aardappelen bijmesten. Daarvoor lijkt een app, ontwikkeld door het PPO, uitkomst te gaan

  12. Mogelijkheden voor notenteelt met tussengewas

    NARCIS (Netherlands)

    Oosterbaan, A.; Schepers, H.

    2005-01-01

    Er zijn enkele presentaties gehouden over de ervaringen met de teelt van walnoten in Nederland tijdens het vijfde Internationale Walnotencongres in Sorrento, Italië, gehouden in november 2004. De productie van walnoten in Nederland stelt nog niet veel voor. Er is dus ruimte voor eigen productie

  13. Expression of the proto-oncogenes c-met and c-kit and their ligands, hepatocyte growth factor/scatter factor and stem cell factor, in SCLC cell lines and xenografts

    DEFF Research Database (Denmark)

    Rygaard, K; Nakamura, T; Spang-Thomsen, M

    1993-01-01

    We examined a panel of 25 small cell lung cancer (SCLC) cell lines and nude mouse xenografts for expression of the proto-oncogenes c-met and c-kit, and for expression of the corresponding ligands, hepatocyte growth factor (HGF) (also known as scatter factor (SF)), and stem cell factor (SCF......), respectively. Expression of mRNA was detected by Northern blotting, and c-met and c-kit protein expression was detected by Western blotting and immunocytochemistry. c-met and c-kit mRNA was expressed in 22 of the examined cell lines or xenografts, and coexpression of the two proto-oncogenes was observed in 20...... tumours. Expression of c-met and c-kit protein paralleled in the mRNA expression. HGF/SF mRNA was expressed in two of the examined tumours, and only one of these also expressed the c-met proto-oncogene. SCF mRNA was expressed in 19 of the examined tumours, and in 18 of these coexpression of c-kit and SCF...

  14. Gezondheidsrisico's in verband met het werken met Dieldrin : een onderzoek

    OpenAIRE

    Geuskens, R.B.M.; Nossent, S.M.; Koëter, H.B.W.M.; Dreef-van der Meulen, H.C.; Stijkel, A; Zielhuis, R.L.

    1989-01-01

    Op basis van gegevens verkregen uit een oriënterende werkplekinventarisatie naar gegevens over produktie/gebruik, risicopopulatie en (mogelijke) blootstelling aan dieldrin en een literatuurstudie naar mogelijke schadelijke eigenschappen van dieldrin op het reproduktiesysteem en/of nageslacht (6000S-AIST-73/2) is een evaluatie gemaakt van het gezondheidsrisico van werken met dieldrin. Er zijn aanwijzingen voor reproduktierisico's m.b.t. tot blootstelling van volwassenen. Voor vrouwen in de vru...

  15. La metáfora

    DEFF Research Database (Denmark)

    Agustin, Oscar Garcia

    2007-01-01

    cuestionamiento de la lógica y de las leyes establecidas se corresponde con lo que denominamos autonomía. Así pues, el proceso de autonomía zapatista consiste, por un lado, en la declaración y aplicación de los derechos indígenas y, por otro, en la creación de un sentido alternativo, donde la metáfora juega un...

  16. La metáfora

    DEFF Research Database (Denmark)

    Agustin, Oscar Garcia

    2007-01-01

    cuestionamiento de la lógica y de las leyes establecidas se corresponde con lo que denominamos autonomía. Así pues, el proceso de autonomía zapatista consiste, por un lado, en la declaración y aplicación de los derechos indígenas y, por otro, en la creación de un sentido alternativo, donde la metáfora juega un...

  17. Met induces diverse mammary carcinomas in mice and is associated with human basal breast cancer

    OpenAIRE

    Graveel, Carrie R.; DeGroot, Jack D.; Su, Yanli; Koeman, Julie; Dykema, Karl; Leung, Samuel; Snider, Jacqueline; Davies, Sherri R.; Swiatek, Pamela J.; Cottingham, Sandra; Watson, Mark A.; Matthew J Ellis; Sigler, Robert E.; Furge, Kyle A.; Vande Woude, George F

    2009-01-01

    Understanding the signaling pathways that drive aggressive breast cancers is critical to the development of effective therapeutics. The oncogene MET is associated with decreased survival in breast cancer, yet the role that MET plays in the various breast cancer subtypes is unclear. We describe a knockin mouse with mutationally activated Met (Metmut) that develops a high incidence of diverse mammary tumors with basal characteristics, including metaplasia, absence of progesterone receptor and E...

  18. Gene expression of hepatocyte growth factor and its receptor in HCC and nontumorous liver tissues

    Institute of Scientific and Technical Information of China (English)

    1999-01-01

    AIM To study the changes of gene expression of hepatocyte growth factor (HGF) and hepatocyte growth factor receptor (HGFr) in hepatocellular carcinoma (HCC) tissue and nontumorous liver tissue and the relationship between these changes and the biological behavior of the tumor.METHODS Gene expression of HGF and HGFr in 26 cases of HCC tissue and their adjacent nontumorous liver tissues was determined with digoxigenin-labeled DNA probes.RESULTS Positive expression of HGF in HCC tissue was similar to that in the adjacent nontumorous liver tissue, but positive rate of HGF expression was lower than HGFr gene expression. However, HGFr expression was higher in the metastatic cases than in those without metastasis. It was found that HGFr was overexpressed in HCC tissue as well as in the adjacent nontumorous liver tissue.CONCLUSION There seems to be a close relationship between overexpression of HGFr gene and tumor metastasis, and the HGF and HGFr system plays an important role in regulating tumor growth and metastasis.

  19. Fatty Acid Synthase Activity as a Target for c-Met Driven Prostate Cancer

    Science.gov (United States)

    2013-07-01

    Sharma, and H.E. Bazan , Association of protein tyrosine phosphatases (PTPs)-1B with c-Met receptor and modulation of corneal epithelial wound healing...Luteolin Post-Transcriptionally Downregulates c-Met Expression Independent of Proteosomal/Lysosomal Degradation. Mol. Cancer. Ther. 2009 Jan 1; 8(1

  20. receptores

    Directory of Open Access Journals (Sweden)

    Salete Regina Daronco Benetti

    2006-01-01

    Full Text Available Se trata de un estudio etnográfico, que tuvo lo objetivo de interpretar el sistema de conocimiento y del significado atribuidos a la sangre referente a la transfusión sanguínea por los donadores y receptores de un banco de sangre. Para la colecta de las informaciones se observaron los participantes y la entrevista etnográfica se realizó el análisis de dominio, taxonómicos y temáticos. Los dominios culturales fueron: la sangre es vida: fuente de vida y alimento valioso; creencias religiosas: fuentes simbólicas de apoyos; donación sanguínea: un gesto colaborador que exige cuidarse, gratifica y trae felicidad; donación sanguínea: fuente simbólica de inseguridad; estar enfermo es una condición para realizar transfusión sanguínea; transfusión sanguínea: esperanza de vida; Creencias populares: transfusión sanguínea como riesgo para la salud; donadores de sangre: personas benditas; donar y recibir sangre: como significado de felicidad. Temática: “líquido precioso que origina, sostiene, modifica la vida, provoca miedo e inseguridad”.

  1. Rapportage gewasbescherming 2007 Telen met toekomst - Champignons

    NARCIS (Netherlands)

    Haan, de J.J.

    2008-01-01

    Het praktijknetwerk Telen met toekomst organiseert groepen praktijkbedrijven met hun relaties rond de ontwikkeling van meer duurzame productiesystemen (milieutechnisch, ecologisch en economisch) in de plantaardige sectoren. Deze rapportage geeft het resultaat van een inventarisatie van de status van

  2. Groepshuisvesting zeugen: brijvoedering met lange trog

    NARCIS (Netherlands)

    Hoofs, A.I.J.; Mheen, van der H.

    2003-01-01

    Brijvoedering via een lange trog combineert de managementvoordelen van gelijktijdig vreten, en stabiele groepen met de economische voordelen van het voeren van brijvoedering met brijproducten. Dit voersysteem geniet dan ook veel belangstelling vanuit de praktijk.

  3. Computergestuurde circulatieregelingen : optimaal bewaarklimaat met minimaal energieverbruik

    NARCIS (Netherlands)

    Wildschut, J.; Janssen, H.J.J.; Sapounas, A.; Gieling, T.H.

    2011-01-01

    Bij het bewaren van bloembollen in kuubskisten gestapeld voor een systeemwand in een bewaarcel wordt voor de ventilatie met buitenlucht, en voor de circulatie met cellucht veel energie verbruikt. Door het ventilatiedebiet met de klimaatcomputer te sturen op basis van ethyleenmeting wordt bij het bew

  4. Comparative study of effects of bone marrow cell vs. Ad5-HGF administration via non infarct-related artery injection in myocardial infarction in swine

    Institute of Scientific and Technical Information of China (English)

    Liansheng Wang; Jun Huang; Zhijian Yang; Wei Wang; Dongchao Ma; Shunlin Xu; Yuqing Zhang; Fang Zhou; Bo Chen; Kejiang Cao

    2007-01-01

    Objective: To evaluate the effect of transplanting bone marrow-derived mesenchymal stem cells (BM-MSCs) or adenovirus5-hepatocyte growth factor(Ad5-HGF) via non-infarct-related artery injection in swine myocardial infarction models. Methods :BMMSCs were obtained from swine bone marrow and expanded in vitro to a purity of >50%. A myocardial infarction(MI) was created by ligating the distal left anterior descending artery in swine. Either BM-MSCs (5 × 106/ml) or Ad5-HGF (4 × 109 pfu) were transfused via the right coronary artery (non-infarcted artery) four weeks after MI. Gate-controled cardiac perfusion imaging was performed at the end of four and seven weeks after LAD ligation, to evaluate heart function and cardiac perfusion. Morphologic and histologic characteristics of the hearts were also studied. Results: (1)The gate-controlled cardiac perfusion imaging showed that the improvement in LVEF was greater in both treatment groups than in control group at the 4th weeks. (2)In both treatment groups, capillary density was significantly higher than that of control group (P < 0.05). Conclusion:BM-MSCs or Ad5-HGF transplantation via non-infarcted artery administration can stimulate angiogenesis and improve heart function, but there was no difference in therapeutic efficacy between BM-MSCs and Ad5-HGF.

  5. Mutant MMP-9 and HGF gene transfer enhance resolution of CCl4-induced liver fibrosis in rats: role of ASH1 and EZH2 methyltransferases repression.

    Directory of Open Access Journals (Sweden)

    Hussein Atta

    Full Text Available Hepatocyte growth factor (HGF gene transfer inhibits liver fibrosis by regulating aberrant cellular functions, while mutant matrix metalloproteinase-9 (mMMP-9 enhances matrix degradation by neutralizing the elevated tissue inhibitor of metalloproteinase-1 (TIMP-1. It was shown that ASH1 and EZH2 methyltransferases are involved in development of liver fibrosis; however, their role in the resolution phase of liver fibrosis has not been investigated. This study evaluated the role of ASH1 and EZH2 in two mechanistically different therapeutic modalities, HGF and mMMP-9 gene transfer in CCl4 induced rat liver fibrosis. Liver fibrosis was induced in rats with twice a week intraperitoneal injection of CCl4 for 8 weeks. Adenovirus vectors encoding mMMP-9 or HGF genes were injected through tail vein at weeks six and seven and were sacrificed one week after the second injection. A healthy animal group was likewise injected with saline to serve as a negative control. Rats treated with mMMP-9 showed significantly lower fibrosis score, less Sirius red stained collagen area, reduced hydroxyproline and ALT concentration, decreased transforming growth factor beta 1 (TGF-β1 mRNA and lower labeling indices of α smooth muscle actin (α-SMA and proliferating cell nuclear antigen (PCNA stained cells compared with HGF- or saline-treated rats. Furthermore, TIMP-1 protein expression in mMMP-9 group was markedly reduced compared with all fibrotic groups. ASH1 and EZH2 protein expression was significantly elevated in fibrotic liver and significantly decreased in mMMP-9- and HGF-treated compared to saline-treated fibrotic livers with further reduction in the mMMP-9 group.Gene transfer of mMMP-9 and HGF reduced liver fibrosis in rats. ASH1 and EZH2 methyltransferases are significantly reduced in mMMP-9 and HGF treated rats which underlines the central role of these enzymes during fibrogenesis. Future studies should evaluate the role of selective pharmacologic inhibitors

  6. Evidence for an LKB1/AMPK/eNOS Cascade Regulated by HGF, S-Adenosylmethionine and NO in Hepatocyte Proliferation

    Science.gov (United States)

    Vázquez, Mercedes; Ariz, Usue; Varela-Rey, Marta; Embade, Nieves; Martínez, Nuria; Fernández, David; Gómez, Laura; Lamas, Santiago; Lu, Shelly C; Martínez-Chantar, M Luz; Mato, José M

    2008-01-01

    S-Adenosylmethionine (SAMe) is involved in numerous complex hepatic processes such as hepatocyte proliferation, death, inflammatory responses, and anti-oxidant defense. One of the most relevant actions of SAMe is the inhibition of hepatocyte proliferation during liver regeneration. In hepatocytes, SAMe regulates the levels of cytoplasmic HuR, an RNA-binding protein that increases the half-life of target mRNA such as cyclin D1 and A2, via inhibition of HGF-mediated AMP-activated protein kinase (AMPK) phosphorylation. Because AMPK is activated by the tumor suppressor kinase LKB1, and AMPK activates endothelial nitric oxide (NO) synthase (eNOS), and NO synthesis is of great importance for hepatocyte proliferation, we hypothesized that in hepatocytes HGF may induce the phosphorylation of LKB1, AMPK and eNOS through a process regulated by SAMe, and that this cascade might be crucial for hepatocyte growth. Here we demonstrate that the proliferative response of hepatocytes involves eNOS phosphorylation via HGF-mediated LKB1 and AMPK phosphorylation, and that this process is regulated by SAMe and NO. We also show that knockdown of LKB1, AMPK, or eNOS with specific iRNA inhibits HGF-mediated hepatocyte proliferation. Finally, we found that the LKB1/AMPK/eNOS cascade is activated during liver regeneration after partial hepatectomy and that this process is impaired in mice treated with SAMe before hepatectomy, in knockout mice deficient in hepatic SAMe, and in eNOS knockout mice. Conclusion We have identified an LKB1/AMPK/eNOS cascade regulated by HGF, SAMe and NO that functions as a critical determinant of hepatocyte proliferation during liver regeneration after partial hepatectomy. PMID:19177591

  7. The (PrS/HGF-pDNA) multilayer films for gene-eluting stent coating: Gene-protecting, anticoagulation, antibacterial properties, and in vivo antirestenosis evaluation.

    Science.gov (United States)

    Chang, Hao; Ren, Ke-feng; Zhang, He; Wang, Jin-lei; Wang, Bai-liang; Ji, Jian

    2015-02-01

    Vascular gene-eluting stents (GES) is a promising strategy for treatment of cardiovascular disease. Very recently, we have proved that the (protamine sulfate/plasmid DNA encoding hepatocyte growth factor) (PrS/HGF-pDNA) multilayer can serve as a powerful tool for enhancing competitiveness of endothelial cell over smooth muscle cell, which opens perspectives for the regulation of intercellular competitiveness in the field of interventional therapy. However, before the gene multilayer films could be used in vascular stents for real clinical application, the preservation of gene bioactivity during the industrial sterilization and the hemocompatibility of film should be taken into account. Actually, both are long been ignored issues in the field of gene coating for GES. In this study, we demonstrate that the (PrS/HGF-pDNA) multilayer film exhibits the good gene-protecting abilities, which is confirmed by using the industrial sterilizations (gamma irradiation and ethylene oxide) and a routine storage condition (dry state at 4°C for 30 days). Furthermore, hemocompatible measurements (such as platelet adhesion and whole blood coagulation) and antibacterial assays (bacteria adhesion and growth inhibition) indicate the good anticoagulation and antibacterial properties of the (PrS/HGF-pDNA) multilayer film. The in vivo preliminary data of angiography and histological analysis suggest that the (PrS/HGF-pDNA) multilayer coated stent can reduce the in-stent restenosis. This work reveals that the (PrS/HGF-pDNA) multilayer film could be a promising candidate as coating for GES, which is of great potential in future clinic application.

  8. Damnacanthal, a noni anthraquinone, inhibits c-Met and is a potent antitumor compound against Hep G2 human hepatocellular carcinoma cells.

    Science.gov (United States)

    García-Vilas, Javier A; Quesada, Ana R; Medina, Miguel A

    2015-01-26

    Damnacanthal, an anthraquinone present in noni plants, targets several tyrosine kinases and has antitumoral effects. This study aims at getting additional insight on the potential of damnacanthal as a natural antitumor compound. The direct effect of damnacanthal on c-Met was tested by in vitro activity assays. Additionally, Western blots of c-Met phosphorylation in human hepatocellular carcinoma Hep G2 cells were performed. The antitumor effects of damnacanthal were tested by using cell growth, soft agar clonogenic, migration and invasion assays. Their mechanisms were studied by Western blot, and cell cycle, apoptosis and zymographic assays. Results show that damnacanthal targets c-Met both in vitro and in cell culture. On the other hand, damnacanthal also decreases the phosphorylation levels of Akt and targets matrix metalloproteinase-2 secretion in Hep G2 cells. These molecular effects are accompanied by inhibition of the growth and clonogenic potential of Hep G2 hepatocellular carcinoma cells, as well as induction of Hep G2 apoptosis. Since c-Met has been identified as a new potential therapeutical target for personalized treatment of hepatocellular carcinoma, damnacanthal and noni extract supplements containing it could be potentially interesting for the treatment and/or chemoprevention of hepatocellular carcinoma through its inhibitory effects on the HGF/c-Met axis.

  9. KAI1 inhibits HGF-induced invasion of pancreatic cancer by sphingosine kinase activity

    Institute of Scientific and Technical Information of China (English)

    Xu Liu; Xiao-Zhong Guo; Wei-Wei Zhang; Zhuo-Zhuang Lu; Qun-Wei Zhang; Hai-Feng Duan; d Li-Sheng Wang

    2011-01-01

    BACKGROUND: KAI1/CD82 has been reported to attenuate the process of metastases in a variety of tumors; however, its mechanism of action in invasion has not been fully elucidated. The present study aimed to investigate the importance of KAI1 in invasion and its correlation with activation of sphingosine kinase (SPK) in human pancreatic cancer PANC1 and Miapaca-2 cell lines. METHODS: The expression of KAI1 in PANC1 and Miapaca-2 cells,whichwasmediatedbyrecombinantadenovirus(Ad-KAI1), was assessed by a flow cytometer and Western blotting. After successful infection was established, in vitro growth curve and invasive ability in Boyden Chamber assay were studied. The presence of KAI1 correlating with c-Met and SPK was detected by co-immunoprecipitationand[γ-32P]ATPincorporation. RESULTS: KAI1 genes had no significant effects on the curve representing cell growth. After infection with the KAI1 gene, decreased invasive ability in the Boyden Chamber assay was observed in PANC1 and Miapaca-2 cells that were induced by hepatocyte growth factor. Over-expression of KAI1 in the cells led to the deactivation of SPK and a decreased level of intracellular sphingosine-1-phosphate. No correlation was observed between c-Met and KAI1 during co-immunoprecipitation. CONCLUSION: The results of this study for the first time demonstrated a regulatory role for KAI1 in SPK activation, which leads to decreased invasive ability in disease progression of human pancreatic cancer.

  10. Hepatocyte growth factor in renal failure: promise and reality.

    Science.gov (United States)

    Vargas, G A; Hoeflich, A; Jehle, P M

    2000-04-01

    Can science discover some secrets of Greek mythology? In the case of Prometheus, we can now suppose that his amazing hepatic regeneration was caused by a peptide growth factor called hepatocyte growth factor (HGF). Increasing evidence indicates that HGF acts as a multifunctional cytokine on different cell types. This review addresses the molecular mechanisms that are responsible for the pleiotropic effects of HGF. HGF binds with high affinity to its specific tyrosine kinase receptor c-met, thereby stimulating not only cell proliferation and differentiation, but also cell migration and tumorigenesis. The three fundamental principles of medicine-prevention, diagnosis, and therapy-may be benefited by the rational use of HGF. In renal tubular cells, HGF induces mitogenic and morphogenetic responses. In animal models of toxic or ischemic acute renal failure, HGF acts in a renotropic and nephroprotective manner. HGF expression is rapidly up-regulated in the remnant kidney of nephrectomized rats, inducing compensatory growth. In a mouse model of chronic renal disease, HGF inhibits the progression of tubulointerstitial fibrosis and kidney dysfunction. Increased HGF mRNA transcripts were detected in mesenchymal and tubular epithelial cells of rejecting kidney. In transplanted patients, elevated HGF levels may indicate renal rejection. When HGF is considered as a therapeutic agent in human medicine, for example, to stimulate kidney regeneration after acute injury, strategies need to be developed to stimulate cell regeneration and differentiation without an induction of tumorigenesis.

  11. Berekeningsresultaten met het model galvanisch bedrijf

    NARCIS (Netherlands)

    Ros; J.P.M.

    1986-01-01

    Met het model galvanisch bedrijf zijn computerberekeningen uitgevoerd aan 24 modelbedrijven. Daarbij is met name nagegaan, welke kosten moeten worden gemaakt om welk rendement te verkrijgen bij diverse saneringsvarianten. Het blijkt, dat tegen kosten tussen nul en 300 gulden per verwijderde kilo

  12. Werken met een inflammatoire darmziekte in Nederland.

    NARCIS (Netherlands)

    Netjes, J.; Borst, J. de; Rijken, M.

    2011-01-01

    Mensen met de ziekte van Crohn of colitis ulcerosa zijn net zo vaak actief op de arbeidsmarkt als andere Nederlanders. Wel werken ze minder vaak fulltime en heeft het merendeel meer of minder last van de ziekte bij hun werk als gevolg van vermoeidheid, stress of spanning. Mensen met een chronische

  13. XML: De eend met de gouden eieren?

    NARCIS (Netherlands)

    Keulen, van Maurice

    2001-01-01

    XML is al een tijdje één van de hypes. Alles moet met XML. Als kritisch informaticus begint het dan bij mij te kriebelen. Hoezo alles moet met XML? Klinkt een beetje als ik heb een hamer en alles ziet er ineens uit als een spijker. Het kan toch niet waar zijn dat men werkelijk iets heeft uitgevonden

  14. Werken met een inflammatoire darmziekte in Nederland.

    NARCIS (Netherlands)

    Netjes, J.; Borst, J. de; Rijken, M.

    2011-01-01

    Mensen met de ziekte van Crohn of colitis ulcerosa zijn net zo vaak actief op de arbeidsmarkt als andere Nederlanders. Wel werken ze minder vaak fulltime en heeft het merendeel meer of minder last van de ziekte bij hun werk als gevolg van vermoeidheid, stress of spanning. Mensen met een chronische

  15. Bespuiten met calcium kan neusrot voorkomen

    NARCIS (Netherlands)

    Zandstra, G.B.; Marcelis, L.F.M.

    2000-01-01

    Oorzaak van neusrot bij paprika is een calciumtekort in de vrucht. Een bespuiting met calcium vlak na de bloei heeft een zeer gunstig effect. In bijgaande tabel gegevens over het effect van spuiten met calcium op het optreden van neusrot bij paprika

  16. Biobrandstof met het gemak van benzine

    NARCIS (Netherlands)

    Klein Lankhorst, R.M.

    2015-01-01

    Onderzoekers in Wageningen werken aan brandstoffen voor voertuigen die hernieuwbaar zijn en tegelijk hetzelfde gemak kennen als benzine en diesel. In het BioSolar Cellsconsortium werken ze met technieken die geïnspireerd zijn op fotosynthese in planten. Van water wordt met zonlicht waterstof gemaakt

  17. Met apps op eigen benen leren staan

    NARCIS (Netherlands)

    Jan-Pieter Teunisse

    2012-01-01

    Mensen met autisme kunnen in de toekomst zelfstandiger wonen, werken en studeren met behulp van `digitale coaches' op hun mobieltje, iPad of iPod. Bij het testen van deze apps en andere nieuwe technologische hulpmiddelen, is ook de HAN betrokken. `ICT-oplossingen kunnen iemand helpen om meer regie

  18. Indazoles as potential c-Met inhibitors: design, synthesis and molecular docking studies.

    Science.gov (United States)

    Ye, Lianbao; Ou, Xiaomin; Tian, Yuanxin; Yu, Bangwei; Luo, Yan; Feng, Binghong; Lin, Hansen; Zhang, Jiajie; Wu, Shuguang

    2013-07-01

    Deregulation of the receptor tyrosine kinase c-Met has been implicated in several human cancers and is considered as an attractive target for small molecule drug discovery. In this study, a series of indazoles were designed, synthesized and evaluated as novel c-Met inhibitors. The results showed that the majority of the compounds exhibited significant inhibition on c-Met and compound 4d showed highest activity against c-Met with IC50 value of 0.17 μM in TR-FRET-based assay and IC50 value of 5.45 μM in cell-based assay as compared to other tested compounds. Molecular docking experiments verified the results and explained the molecular mechanism of pretty activities to c-Met.

  19. Germline met mutations in mice reveal mutation- and background-associated differences in tumor profiles.

    Directory of Open Access Journals (Sweden)

    Carrie R Graveel

    Full Text Available BACKGROUND: The receptor tyrosine kinase Met is involved in the progression and metastasis of numerous human cancers. Although overexpression and autocrine activation of the Met signaling pathway are commonly found in human cancers, mutational activation of Met has been observed in small cell and non-small cell lung cancers, lung adenocarcinomas, renal carcinomas, and mesotheliomas. METHODOLOGY/PRINCIPAL FINDINGS: To investigate the influence of mutationally activated Met in tumorigenesis, we utilized a novel mouse model. Previously, we observed that various Met mutations developed unique mutation-specific tumor spectra on a C57BL/6 background. Here, we assessed the effect of genetic background on the tumorigenic potential of mutationally activated Met. For this purpose, we created congenic knock-in lines of the Met mutations D1226N, M1248T, and Y1228C on the FVB/N background. Consistent with the mutation-specific tumor spectra, several of the mutations were associated with the same tumor types as observed on C57BL/6 background. However, on the FVB/N background most developed a high incidence of mammary carcinomas with diverse histopathologies. CONCLUSIONS/SIGNIFICANCE: This study demonstrates that on two distinct mouse backgrounds, Met is able to initiate tumorigenesis in multiple cell types, including epithelial, hematopoietic, and endothelial. Furthermore, these observations emphasize that even a modest increase in Met activation can initiate tumorigenesis with both the Met mutational spectra and host background having profound influence on the type of tumor generated. Greater insight into the interaction of genetic modifiers and Met signaling will significantly enhance our ability to tailor combination therapies for Met-driven cancers.

  20. The BDNF Val66Met polymorphism enhances glutamatergic transmission but diminishes activity-dependent synaptic plasticity in the dorsolateral striatum.

    Science.gov (United States)

    Jing, Deqiang; Lee, Francis S; Ninan, Ipe

    2017-01-01

    The Val66Met polymorphism in the brain-derived neurotrophic factor (BDNF) gene disrupts the activity-dependent release of BDNF, which might underlie its involvement in several neuropsychiatric disorders. Consistent with the potential role of regulated release of BDNF in synaptic functions, earlier studies have demonstrated that the BDNF Val66Met polymorphism impairs NMDA receptor-mediated synaptic transmission and plasticity in the hippocampus, the medial prefrontal cortex and the central amygdala. However, it is unknown whether the BDNF Val66Met polymorphism affects synapses in the dorsal striatum, which depends on cortical afferents for BDNF. Electrophysiological experiments revealed an enhanced glutamatergic transmission in the dorsolateral striatum (DLS) of knock-in mice containing the variant polymorphism (BDNF(Met/Met)) compared to the wild-type (BDNF(Val/Val)) mice. This increase in glutamatergic transmission is mediated by a potentiation in glutamate release and NMDA receptor transmission in the medium spiny neurons without any alterations in non-NMDA receptor-mediated transmission. We also observed an impairment of synaptic plasticity, both long-term potentiation and depression in the DLS neurons, in BDNF(Met/Met) mice. Thus, the BDNF Val66Met polymorphism exerts an increase in glutamatergic transmission but impairs synaptic plasticity in the dorsal striatum, which might play a role in its effect on neuropsychiatric symptoms. This article is part of the Special Issue entitled 'Ionotropic glutamate receptors'.

  1. Hepatocyte growth factor/scatter factor modulates cell motility, proliferation, and proteoglycan synthesis of chondrocytes.

    Science.gov (United States)

    Takebayashi, T; Iwamoto, M; Jikko, A; Matsumura, T; Enomoto-Iwamoto, M; Myoukai, F; Koyama, E; Yamaai, T; Matsumoto, K; Nakamura, T

    1995-06-01

    Hepatocyte growth factor/scatter factor (HGF/SF) is a multifunctional growth factor that promotes proliferation, motility, and morphogenesis in epithelial cells. Recently the HGF receptor, c-met protooncogene product, has been shown to be expressed in developing limb buds (Sonnenberg, E., D. Meyer, M. Weidner, and C. Birchmeiyer, 1993. J. Cell Biol. 123: 223-235), suggesting that some populations of mesenchymal cells in limb buds respond to HGF/SF. To test the possibility that HGF/SF is involved in regulation of cartilage development, we isolated chondrocytes from knee joints and costal cartilages of 23-d embryonic and 4-wk-old rabbits, and analyzed the effects of HGF/SF on migration and proliferation of these cells. We found that HGF/SF stimulated migration of cultured articular chondrocytes but did not scatter limb mesenchymal fibroblasts or synovial fibroblasts in culture. HGF/SF also stimulated proliferation of chondrocytes; a maximum three-fold stimulation in DNA synthesis was observed at the concentration of 3 ng/ml of HGF/SF. Moreover, HGF/SF had the ability to enhance proteoglycan synthesis in chondrocytes. The responsiveness of chondrocytes to HGF/SF was also supported by the observation that they expressed the HGF/SF receptor. Addition of the neutralizing antibody to rat HGF/SF affected neither DNA synthesis nor proteoglycan synthesis in rat chondrocytes, suggesting a paracine mechanism of action of HGF/SF on these cells. In situ hybridization analysis showed that HGF/SF mRNA was restrictively expressed in the areas of future joint regions in developing limb buds and in the intercostal spaces of developing costal cartilages. These findings suggest that HGF/SF plays important roles in cartilage development through its multiple activities.

  2. Hepatocyte growth factor/scatter factor modulates cell motility, proliferation, and proteoglycan synthesis of chondrocytes

    Science.gov (United States)

    1995-01-01

    Hepatocyte growth factor/scatter factor (HGF/SF) is a multifunctional growth factor that promotes proliferation, motility, and morphogenesis in epithelial cells. Recently the HGF receptor, c-met protooncogene product, has been shown to be expressed in developing limb buds (Sonnenberg, E., D. Meyer, M. Weidner, and C. Birchmeiyer, 1993. J. Cell Biol. 123: 223-235), suggesting that some populations of mesenchymal cells in limb buds respond to HGF/SF. To test the possibility that HGF/SF is involved in regulation of cartilage development, we isolated chondrocytes from knee joints and costal cartilages of 23-d embryonic and 4-wk-old rabbits, and analyzed the effects of HGF/SF on migration and proliferation of these cells. We found that HGF/SF stimulated migration of cultured articular chondrocytes but did not scatter limb mesenchymal fibroblasts or synovial fibroblasts in culture. HGF/SF also stimulated proliferation of chondrocytes; a maximum three-fold stimulation in DNA synthesis was observed at the concentration of 3 ng/ml of HGF/SF. Moreover, HGF/SF had the ability to enhance proteoglycan synthesis in chondrocytes. The responsiveness of chondrocytes to HGF/SF was also supported by the observation that they expressed the HGF/SF receptor. Addition of the neutralizing antibody to rat HGF/SF affected neither DNA synthesis nor proteoglycan synthesis in rat chondrocytes, suggesting a paracine mechanism of action of HGF/SF on these cells. In situ hybridization analysis showed that HGF/SF mRNA was restrictively expressed in the areas of future joint regions in developing limb buds and in the intercostal spaces of developing costal cartilages. These findings suggest that HGF/SF plays important roles in cartilage development through its multiple activities. PMID:7775584

  3. Opioid Receptors.

    Science.gov (United States)

    Stein, Christoph

    2016-01-01

    Opioids are the oldest and most potent drugs for the treatment of severe pain. Their clinical application is undisputed in acute (e.g., postoperative) and cancer pain, but their long-term use in chronic pain has met increasing scrutiny. This article reviews mechanisms underlying opioid analgesia and other opioid actions. It discusses the structure, function, and plasticity of opioid receptors; the central and peripheral sites of analgesic actions and side effects; endogenous and exogenous opioid receptor ligands; and conventional and novel opioid compounds. Challenging clinical situations, such as the tension between chronic pain and addiction, are also illustrated.

  4. Analysis of peeling decoder for MET ensembles

    CERN Document Server

    Hinton, Ryan

    2009-01-01

    The peeling decoder introduced by Luby, et al. allows analysis of LDPC decoding for the binary erasure channel (BEC). For irregular ensembles, they analyze the decoder state as a Markov process and present a solution to the differential equations describing the process mean. Multi-edge type (MET) ensembles allow greater precision through specifying graph connectivity. We generalize the the peeling decoder for MET ensembles and derive analogous differential equations. We offer a new change of variables and solution to the node fraction evolutions in the general (MET) case. This result is preparatory to investigating finite-length ensemble behavior.

  5. Mars MetNet Mission Payload Overview

    Science.gov (United States)

    Harri, A.-M.; Haukka, H.; Alexashkin, S.; Guerrero, H.; Schmidt, W.; Genzer, M.; Vazquez, L.

    2012-09-01

    A new kind of planetary exploration mission for Mars is being developed in collaboration between the Finnish Meteorological Institute (FMI), Lavochkin Association (LA), Space Research Institute (IKI) and Institutio Nacional de Tecnica Aerospacial (INTA). The Mars MetNet mission [1] is based on a new semi-hard landing vehicle called MetNet Lander (MNL). The scientific payload of the Mars MetNet Precursor mission is divided into three categories: Atmospheric instruments, Optical devices and Composition and structure devices. Each of the payload instruments will provide crucial scientific data about the Martian atmospheric phenomena.

  6. LINE-1 ORF-1p functions as a novel HGF/ETS-1 signaling pathway co-activator and promotes the growth of MDA-MB-231 cell.

    Science.gov (United States)

    Yang, Qian; Feng, Fan; Zhang, Fan; Wang, Chunping; Lu, Yinying; Gao, Xudong; Zhu, Yunfeng; Yang, Yongping

    2013-12-01

    Long interspersed nucleotide element (LINE)-1 ORF-1p is encoded by the human pro-oncogene LINE-1. It is involved in the development and progression of several human carcinomas, such as hepatocellular carcinoma and lung and breast cancers. The hepatocyte growth factor (HGF)/ETS-1 signaling pathway is involved in regulation of cancer cell proliferation, metastasis and invasion. The biological function of the interaction between LINE-1 ORF-1p and the HGF/ETS-1 signaling pathway in regulation of human breast cancer proliferation remains largely unknown. Here, we showed that LINE-1 ORF-1p enhanced ETS-1 transcriptional activity and increased expression of downstream genes of ETS-1. Interaction between ETS-1 and LINE-1 ORF-1p was identified by immunoprecipitation assays. LINE-1 ORF-1p modulated ETS-1 activity through cytoplasm/nucleus translocation and recruitment to the ETS-1 binding element in the MMP1 gene promoter. We also showed that LINE-1 ORF-1p promoted proliferation and anchorage-independent growth of MDA-MB-231 breast cancer cells. By investigating a novel role of the LINE-1 ORF-1p in the HGF/ETS-1 signaling pathway and MDA-MB-231 cells, we demonstrated that LINE-1 ORF-1p may be a novel ETS-1 coactivator and molecular target for therapy of human triple negative breast cancer. © 2013.

  7. The role of FGF-2/HGF and fibronectin matrix on pleomorphic adenoma myoepithelial cell morphology and immunophenotype: an in vitro study.

    Science.gov (United States)

    Silva, Carolina Amália Barcellos; Nardello, Laura Cristina Leite; Garcia, Frederico Windlin; Araújo, Ney Soares de; Montalli, Victor Angelo; Araújo, Vera Cavalcanti de; Martinez, Elizabeth Ferreira

    2015-02-01

    Myoepithelial cells play a central role in glandular tumors, regulating the progression of in situ to invasive neoplasias, with the tumor microenvironment being shown to be involved in both initiation and progression. This study aimed to analyze the in vitro effects of fibroblast growth factor-2 (FGF-2) and hepatocyte growth factor (HGF) in myoepithelial cells under the influence of the fibronectin matrix extracellular protein. Benign myoepithelial cells were obtained from pleomorphic adenoma and cultured on a fibronectin substratum. FGF-2 and HGF were supplemented at different concentrations and time intervals, in order to evaluate cell proliferation, morphology and immunophenotype. Individually, FGF-2 and HGF supplementation did not alter myoepithelial cell proliferation, morphology or immunophenotype. The fibronectin substratum provoked an increase in cell proliferation and immunopositivity for α-smooth muscle actin and FGF-2. The myoepithelial cell morphology changed when the fibronectin substratum and FGF-2 acted together, highlighting the importance of the fibronectin extracellular matrix protein on the behavior of these cells.

  8. Acetylcholinesterase converts Met5-enkephalin-containing peptides to Met5-enkephalin.

    Science.gov (United States)

    Dowton, M; Boelen, M

    1988-11-22

    Acetylcholinesterase (AChE; E.C. 3.1.1.7) was incubated with a number of enkephalin-containing neuropeptides found in the bovine adrenal medulla. Met5-enkephalin and Leu5-enkephalin were the most stable of the peptides studied, while precursors of Met5-enkephalin were converted to Met5-enkephalin. AChE is therefore capable of limited peptidase activity on Met5-enkephalin precursors. The enzyme hydrolysed the Met5-enkephalin precursor BAM-12P on the C-terminal side of the pair of basic amino acid residues, and cleaved basic amino acids from the carboxy-terminal of Met5-enkephalin-Arg6 and Met5-enkephalin-Arg6-Arg7. These results indicate that AChE, acting alone, is capable of the same pattern of enkephalin processing as that observed in the adrenal medulla.

  9. RNAi technology and lentiviral delivery as a powerful tool to suppress Tpr-Met-mediated tumorigenesis.

    Science.gov (United States)

    Taulli, Riccardo; Accornero, Paolo; Follenzi, Antonia; Mangano, Tony; Morotti, Alessandro; Scuoppo, Claudio; Forni, Paolo E; Bersani, Francesca; Crepaldi, Tiziana; Chiarle, Roberto; Naldini, Luigi; Ponzetto, Carola

    2005-05-01

    Tpr-Met, the oncogenic counterpart of the Met receptor, has been detected in gastric cancers, as well as in precursor lesions and in the adjacent normal gastric mucosa. This has prompted the suggestion that Tpr-Met may predispose to the development of gastric tumors. Given the sequence specificity of RNA interference, oncogenes activated by point mutation or rearrangements can be targeted while spearing the product of the wild-type allele. In this work, we report specific suppression of Tpr-Met expression and inhibition of Tpr-Met-mediated transformation and tumorigenesis by means of a short interfering RNA (siRNA) directed toward the Tpr-Met junction (anti-TM2). When delivered by a lentiviral vector, anti-TM2 siRNA was effective also in mouse embryonal fibroblasts or epithelial cells expressing high levels of Tpr-Met. Our results suggest that lentiviral-mediated delivery of anti-TM2 siRNA may be developed into a powerful tool to treat Tpr-Met-positive cancers.

  10. Involvement of lipid rafts in adhesion-induced activation of Met and EGFR

    Directory of Open Access Journals (Sweden)

    Lu Ying-Che

    2011-10-01

    Full Text Available Abstract Background Cell adhesion has been shown to induce activation of certain growth factor receptors in a ligand-independent manner. However, the mechanism for such activation remains obscure. Methods Human epidermal carcinoma A431 cells were used as a model to examine the mechanism for adhesion-induced activation of hepatocyte growth factor receptor Met and epidermal growth factor receptor (EGFR. The cells were suspended and replated on culture dishes under various conditions. The phosphorylation of Met at Y1234/1235 and EGFR at Y1173 were used as indicators for their activation. The distribution of the receptors and lipid rafts on the plasma membrane were visualized by confocal fluorescent microscopy and total internal reflection microscopy. Results We demonstrate that Met and EGFR are constitutively activated in A431 cells, which confers proliferative and invasive potentials to the cells. The ligand-independent activation of Met and EGFR in A431 cells relies on cell adhesion to a substratum, but is independent of cell spreading, extracellular matrix proteins, and substratum stiffness. This adhesion-induced activation of Met and EGFR cannot be attributed to Src activation, production of reactive oxygen species, and the integrity of the cytoskeleton. In addition, we demonstrate that Met and EGFR are independently activated upon cell adhesion. However, partial depletion of Met and EGFR prevents their activation upon cell adhesion, suggesting that overexpression of the receptors is a prerequisite for their self-activation upon cell adhesion. Although Met and EGFR are largely distributed in 0.04% Triton-insoluble fractions (i.e. raft fraction, their activated forms are detected mainly in 0.04% Triton-soluble fractions (i.e. non-raft fraction. Upon cell adhesion, lipid rafts are accumulated at the cell surface close to the cell-substratum interface, while Met and EGFR are mostly excluded from the membrane enriched by lipid rafts. Conclusions

  11. Prof. Zhu Zuoyan Met with ISI Delegation

    Institute of Scientific and Technical Information of China (English)

    Liu Xiuping; Chen Huai

    2007-01-01

    @@ On March 27, Prof. Zhu Zuoyan, Vice President of NSFC, met with a three-member delegation from the Institute for Scientific Information (ISI), USA headed by Dr. James Testa, Director of Editorial Development of ISI.

  12. Palmzaadkever opsporen met lichtval en alcohol

    NARCIS (Netherlands)

    Bloemhard, C.M.J.

    2006-01-01

    De palmzaadkever houdt er een verborgen levenswijze op na. Met een lichtval zijn de volwassenen, vliegende vrouwtjes goed te vangen. Tijdige signalering verbetert de bestrijding, maar vooral schoon uitgangsmateriaal importeren verlaagt de infectiedruk

  13. Ervaringen en perspectieven van zaadcoating met pesticiden

    NARCIS (Netherlands)

    Ester, A.; Huiting, H.; Putter, de H.

    2005-01-01

    Zaadbehandeling is doorgaans een uitgelezen kans om gebruik van gewasbeschermingsmiddelen fors terug te dringen. Coating van het zaad met insecticiden kan in een aantal situaties een effectieve bestrijdingsmethode zijn. Doordat de volvelds-, kweekplaat-, plantvoetbehandeling en soms een gewasbehande

  14. Roestvrij stalen trog met opstap voldoet goed

    NARCIS (Netherlands)

    Hoofs, A.

    1995-01-01

    Uit onderzoek op het Varkensproefbedrijf in Sterksel blijkt dat de roestvrij stalen trog met opstap en schuine voorkant, ondanks het hogere investeringsbedrag, perspectieven biedt voor toepassing in de vleesvarkenshouderij.

  15. Mars MetNet Precursor Mission Status

    Science.gov (United States)

    Harri, A.-M.; Aleksashkin, S.; Guerrero, H.; Schmidt, W.; Genzer, M.; Vazquez, L.; Haukka, H.

    2013-09-01

    We are developing a new kind of planetary exploration mission for Mars in collaboration between the Finnish Meteorological Institute (FMI), Lavochkin Association (LA), Space Research Institute (IKI) and Institutio Nacional de Tecnica Aerospacial (INTA). The Mars MetNet mission is based on a new semi-hard landing vehicle called MetNet Lander (MNL). The scientific payload of the Mars MetNet Precursor [1] mission is divided into three categories: Atmospheric instruments, Optical devices and Composition and structure devices. Each of the payload instruments will provide significant insights in to the Martian atmospheric behavior. The key technologies of the MetNet Lander have been qualified and the electrical qualification model (EQM) of the payload bay has been built and successfully tested.

  16. Mars MetNet Mission Status

    Science.gov (United States)

    Harri, A.-M.; Aleksashkin, S.; Arruego, I.; Schmidt, W.; Genzer, M.; Vazquez, L.; Haukka, H.; Palin, M.; Nikkanen, T.

    2015-10-01

    New kind of planetary exploration mission for Mars is under development in collaboration between the Finnish Meteorological Institute (FMI), Lavochkin Association (LA), Space Research Institute (IKI) and Institutio Nacional de Tecnica Aerospacial (INTA). The Mars MetNet mission is based on a new semihard landing vehicle called MetNet Lander (MNL). The scientific payload of the Mars MetNet Precursor [1] mission is divided into three categories: Atmospheric instruments, Optical devices and Composition and structure devices. Each of the payload instruments will provide significant insights in to the Martian atmospheric behavior. The key technologies of the MetNet Lander have been qualified and the electrical qualification model (EQM) of the payload bay has been built and successfully tested.

  17. Afvangen van fosfaat uit bloembollensector met ijzerzand

    NARCIS (Netherlands)

    Chardon, W.J.; Groenenberg, J.E.; Jansen, S.; Buijert, A.; Talens, R.; Krol, A.F.

    2014-01-01

    In het oppervlaktewater van de Bollenstreek is de fosfaatconcentratie veel hoger dan de norm van de Europese Kaderrichtlijn Water. Met ijzerzand, een nevenproduct van drinkwaterproductie, kan fosfaat worden afgevangen. Het hoogheemraadschap van Rijnland heeft drie maatregelen op basis van ijzerzand

  18. Met een Happy Meal duurzaam leren handelen

    NARCIS (Netherlands)

    Noorduyn, L.; Wals, A.E.J.

    2010-01-01

    Afgestudeerden van groene opleidingen moeten over duurzaamheidscompetenties beschikken, willen ze problemen echt op kunnen lossen. Bijvoorbeeld “omgaan met onzekerheid” en “inleven in een ander”. Maar hoe breng je een student die competenties bij?

  19. MMPM - Mars MetNet Precursor Mission

    Science.gov (United States)

    Harri, A.-M.; Schmidt, W.; Pichkhadze, K.; Linkin, V.; Vazquez, L.; Uspensky, M.; Polkko, J.; Genzer, M.; Lipatov, A.; Guerrero, H.; Alexashkin, S.; Haukka, H.; Savijarvi, H.; Kauhanen, J.

    2008-09-01

    We are developing a new kind of planetary exploration mission for Mars - MetNet in situ observation network based on a new semi-hard landing vehicle called the Met-Net Lander (MNL). The eventual scope of the MetNet Mission is to deploy some 20 MNLs on the Martian surface using inflatable descent system structures, which will be supported by observations from the orbit around Mars. Currently we are working on the MetNet Mars Precursor Mission (MMPM) to deploy one MetNet Lander to Mars in the 2009/2011 launch window as a technology and science demonstration mission. The MNL will have a versatile science payload focused on the atmospheric science of Mars. Detailed characterization of the Martian atmospheric circulation patterns, boundary layer phenomena, and climatology cycles, require simultaneous in-situ measurements by a network of observation posts on the Martian surface. The scientific payload of the MetNet Mission encompasses separate instrument packages for the atmospheric entry and descent phase and for the surface operation phase. The MetNet mission concept and key probe technologies have been developed and the critical subsystems have been qualified to meet the Martian environmental and functional conditions. Prototyping of the payload instrumentation with final dimensions was carried out in 2003-2006.This huge development effort has been fulfilled in collaboration between the Finnish Meteorological Institute (FMI), the Russian Lavoschkin Association (LA) and the Russian Space Research Institute (IKI) since August 2001. Currently the INTA (Instituto Nacional de Técnica Aeroespacial) from Spain is also participating in the MetNet payload development. To understand the behavior and dynamics of the Martian atmosphere, a wealth of simultaneous in situ observations are needed on varying types of Martian orography, terrain and altitude spanning all latitudes and longitudes. This will be performed by the Mars MetNet Mission. In addition to the science aspects the

  20. MetNet - Martian Network Mission

    Science.gov (United States)

    Harri, A.-M.

    2009-04-01

    We are developing a new kind of planetary exploration mission for Mars - MetNet in situ observation network based on a new semi-hard landing vehicle called the Met-Net Lander (MNL). The actual practical mission development work started in January 2009 with participation from various countries and space agencies. The scientific rationale and goals as well as key mission solutions will be discussed. The eventual scope of the MetNet Mission is to deploy some 20 MNLs on the Martian surface using inflatable descent system structures, which will be supported by observations from the orbit around Mars. Currently we are working on the MetNet Mars Precursor Mission (MMPM) to deploy one MetNet Lander to Mars in the 2009/2011 launch window as a technology and science demonstration mission. The MNL will have a versatile science payload focused on the atmospheric science of Mars. Detailed characterization of the Martian atmospheric circulation patterns, boundary layer phenomena, and climatology cycles, require simultaneous in-situ measurements by a network of observation posts on the Martian surface. The scientific payload of the MetNet Mission encompasses separate instrument packages for the atmospheric entry and descent phase and for the surface operation phase. The MetNet mission concept and key probe technologies have been developed and the critical subsystems have been qualified to meet the Martian environmental and functional conditions. This development effort has been fulfilled in collaboration between the Finnish Meteorological Institute (FMI), the Russian Lavoschkin Association (LA) and the Russian Space Research Institute (IKI) since August 2001. Currently the INTA (Instituto Nacional de Técnica Aeroespacial) from Spain is also participating in the MetNet payload development.

  1. Mars MetNet Mission Status

    Science.gov (United States)

    Harri, Ari-Matti; Aleksashkin, Sergei; Arruego, Ignacio; Schmidt, Walter; Genzer, Maria; Vazquez, Luis; Haukka, Harri

    2015-04-01

    New kind of planetary exploration mission for Mars is under development in collaboration between the Finnish Meteorological Institute (FMI), Lavochkin Association (LA), Space Research Institute (IKI) and Institutio Nacional de Tecnica Aerospacial (INTA). The Mars MetNet mission is based on a new semi-hard landing vehicle called MetNet Lander (MNL). The scientific payload of the Mars MetNet Precursor [1] mission is divided into three categories: Atmospheric instruments, Optical devices and Composition and structure devices. Each of the payload instruments will provide significant insights in to the Martian atmospheric behavior. The key technologies of the MetNet Lander have been qualified and the electrical qualification model (EQM) of the payload bay has been built and successfully tested. 1. MetNet Lander The MetNet landing vehicles are using an inflatable entry and descent system instead of rigid heat shields and parachutes as earlier semi-hard landing devices have used. This way the ratio of the payload mass to the overall mass is optimized. The landing impact will burrow the payload container into the Martian soil providing a more favorable thermal environment for the electronics and a suitable orientation of the telescopic boom with external sensors and the radio link antenna. It is planned to deploy several tens of MNLs on the Martian surface operating at least partly at the same time to allow meteorological network science. 2. Scientific Payload The payload of the two MNL precursor models includes the following instruments: Atmospheric instruments: 1. MetBaro Pressure device 2. MetHumi Humidity device 3. MetTemp Temperature sensors Optical devices: 1. PanCam Panoramic 2. MetSIS Solar irradiance sensor with OWLS optical wireless system for data transfer 3. DS Dust sensor The descent processes dynamic properties are monitored by a special 3-axis accelerometer combined with a 3-axis gyrometer. The data will be sent via auxiliary beacon antenna throughout the

  2. Mars MetNet Mission Payload Overview

    Science.gov (United States)

    Haukka, H.; Harri, A.-M.; Alexashkin, S.; Guerrero, H.; Schmidt, W.; Genzer, M.; Vazquez, L.

    2012-04-01

    A new kind of planetary exploration mission for Mars is being developed in collaboration between the Finnish Meteorological Institute (FMI), Lavochkin Association (LA), Space Research Institute (IKI) and Institutio Nacional de Tecnica Aerospacial (INTA). The Mars MetNet mission is based on a new semi-hard landing vehicle called MetNet Lander (MNL). The main idea behind the MetNet landing vehicles is to use a state-of-the-art inflatable entry and descent system instead of rigid heat shields and parachutes as earlier semi-hard landing devices have used. This way the ratio of the payload mass to the overall mass is optimized and more mass and volume resources are spared for the science payload. The vehicle decelerates its entry speed using the inflatable structure and final landing sequence includes a cone headed body penetrating the Martian soil. It is planned to deploy several tens of MNLs on the Martian surface operating at least partly at the same time to allow meteorological network science. The payload of the two MNL precursor models includes the following instruments: Atmospheric instruments: - Pressure device (MetBaro): mass 100g, measurement range 0..1015 hPa. - Humidity device (MetHumi): mass 15g, measurement range 0..100%RH. - Temperature sensors (MetTemp): mass 2g each, measurement range -110C..+30C. Optical devices: - Panoramic camera (PanCam): mass 100g, FOV 4 lenses mounted at 90 deg - Solar irradiance sensor (MetSIS) with optical wireless system (OWLS) for data transfer: mass 115g (MetSIS) and 7g (OWLS module), wavelength range 190..1100nm. MetSIS equipped with 28 optical detectors, two temperature sensors and two solar incidence angle detectors. - Dust sensor (DS): mass 42g, resolution: 10 particles / cm3. Composition and structure device: - Magnetometer (MOURA): mass 80g, measurement range: ±30uT. MetNet Mission payload instruments are specially designed to operate in very low power conditions. MNL flexible solar panels provides a total of

  3. Dynamic soluble changes in sVEGFR1, HGF, and VEGF promote chemotherapy and bevacizumab resistance: A prospective translational study in the BECOX (GEMCAD 09-01) trial.

    Science.gov (United States)

    Pineda, Estela; Salud, A; Vila-Navarro, E; Safont, M J; Llorente, Beatriz; Aparicio, J; Vera, R; Escudero, P; Casado, E; Bosch, C; Bohn, U; Pérez-Carrión, R; Carmona, A; Ayuso, J R; Ripollés, T; Bouzas, R; Gironella, M; García-Albéniz, X; Feliu, J; Maurel, J

    2017-06-01

    Despite initial responsiveness, acquired resistance to both bevacizumab and chemotherapy in metastatic colorectal cancer is universal. We have recently published that in vitro, chronically oxaliplatin resistance upregulates soluble vascular endothelial growth factor receptor 1, downregulates vascular endothelial growth factor, and also promotes c-MET, b-catenin/transcription factor 4, and AKT activation. We tested whether variation in three serum biomarkers such as the natural c-MET ligand (hepatocyte growth factor), soluble vascular endothelial growth factor receptor 1, and vascular endothelial growth factor-A was associated with efficacy in metastatic colorectal cancer patients treated in the prospective BECOX study. Serum levels of vascular endothelial growth factor-A165, soluble vascular endothelial growth factor receptor 1, and hepatocyte growth factor were assessed by enzyme-linked immunosorbent assay method basally and every 3 cycles (at the time of computed tomography evaluation) in a preplanned translational study in the first-line BECOX trial in metastatic colorectal cancer patients treated with CAPOX plus bevacizumab. Response was evaluated by routine contrast-enhanced computed tomography by RECIST 1.1 by investigator assessment and by three blinded independent radiologists. Ratios between soluble vascular endothelial growth factor receptor 1/vascular endothelial growth factor-A and hepatocyte growth factor/vascular endothelial growth factor-A were established and variations through time were related to RECIST 1.1 by investigator assessment and independent radiologist. The BECOX trial included 68 patients, and 27 patients were analyzed in the translational trial. A total of 80 RECIST 1.1 evaluations were done by investigator assessment and 56 by independent radiologist. We found that a 3.22-fold increase in soluble vascular endothelial growth factor receptor 1/vascular endothelial growth factor-A by investigator assessment and a 3.06-fold increase in

  4. Glucocorticoid receptor haplotype and metabolic syndrome : the Lifelines cohort study

    NARCIS (Netherlands)

    Wester, Vincent L.; Koper, Jan W.; van den Akker, Erica L. T.; Franco, Oscar H.; Stolk, Ronald P.; van Rossum, Elisabeth F. C.

    2016-01-01

    Objective: An excess of glucocorticoids (Cushing's syndrome) is associated with metabolic syndrome (MetS) features. Several single-nucleotide polymorphisms (SNPs) in the glucocorticoid receptor (GR) gene influence sensitivity to glucocorticoids and have been associated with aspects of MetS. However,

  5. Hepatocyte growth factor and alternative splice variants - expression, regulation and implications in osteogenesis and bone health and repair.

    Science.gov (United States)

    Frisch, Rachel N; Curtis, Kevin M; Aenlle, Kristina K; Howard, Guy A

    2016-09-01

    Bone marrow-derived mesenchymal stem cells (MSCs) can differentiate into multiple cell types, including osteoblasts, chondrocytes, and adipocytes. These pluripotent cells secrete hepatocyte growth factor (HGF), which regulates cell growth, survival, motility, migration, mitogenesis and is important for tissue development/regeneration. HGF has four splice variants, NK1, NK2, NK3, and NK4 which have varying functions and affinities for the HGF receptor, cMET. HGF promotes osteoblastic differentiation of MSCs into bone forming cells, playing a role in bone development, health and repair. This review will focus on the effects of HGF in osteogenesis, bone repair and bone health, including structural and functional insights into the role of HGF in the body. Approximately 6.2 million Americans experience a fracture annually, with 5-10% being mal- or non-union fractures. HGF is important in priming MSCs for osteogenic differentiation in vitro and is currently being studied to assess its role during bone repair in vivo. Due to the high turnover rate of systemic HGF, non-classic modes of HGF-treatment, including naked-plasmid HGF delivery and the use of HGF splice variants (NK1 & NK2) are being studied to find safe and efficacious treatments for bone disorders, such as mal- or non-union fractures.

  6. Putative PPAR target genes express highly in skeletal muscle of insulin-resistant MetS model SHR/NDmc-cp rats.

    Science.gov (United States)

    Hariya, Natsuyo; Miyake, Kunio; Kubota, Takeo; Goda, Toshinao; Mochizuki, Kazuki

    2015-01-01

    It is known that insulin resistance in skeletal muscle induces subsequent metabolic diseases such as metabolic syndrome (MetS). However, which genes are altered in the skeletal muscle by development of insulin resistance in animal models has not been examined. In this study, we performed microarray and subsequent real-time RT-PCR analyses using total RNA extracted from the gastrocnemius muscle of the MetS model, spontaneously hypertensive corpulent congenic (SHR/NDmc-cp) rats, and control Wistar Kyoto (WKY) rats. SHR/NDmc-cp rats displayed overt insulin resistance relative to WKY rats. The expression of many genes related to fatty acid oxidation was higher in SHR/NDmc-cp rats than in WKY rats. Among 18 upregulated genes, putative peroxisome proliferator responsive elements were found in the upstream region of 15 genes. The protein expression of ACOX2, an upregulated gene, and peroxisome proliferator-activated receptor (PPAR) G1, but not of PPARG2, PPARA or PPARD, was higher in the gastrocnemius muscle of SHR/NDmc-cp rats than that in WKY rats. These results suggest that insulin resistance in the MetS model, SHR/NDmc-cp rats, is positively associated with the expression of fatty acid oxidation-related genes, which are presumably PPARs’ targets, in skeletal muscle.

  7. MEK inhibitors against MET-amplified non-small cell lung cancer

    Science.gov (United States)

    Chiba, Masato; Togashi, Yosuke; Tomida, Shuta; Mizuuchi, Hiroshi; Nakamura, Yu; Banno, Eri; Hayashi, Hidetoshi; Terashima, Masato; De Velasco, Marco A.; Sakai, Kazuko; Fujita, Yoshihiko; Mitsudomi, Tetsuya; Nishio, Kazuto

    2016-01-01

    Several receptor tyrosine kinases (RTKs) including EGFR, ALK, and MET have been identified as therapeutic targets in non-small cell lung cancer (NSCLC). Among the downstream pathways of RTKs, the MAPK pathway is particularly important for cancer cell proliferation, differentiation, and survival. In this study, the effects of MEK inhibitors (trametinib and PD0325901) in several NSCLC cell lines with driver gene alterations, especially RTK genes, were tested in vitro using an MTT assay, and a wide range of sensitivities was found. In particular, all the EGFR-mutated cell lines were resistant to MEK inhibitors, whereas all the MET-amplified cell lines were sensitive. A bioinformatics technique and western blot analyses showed that the PI3K/AKT pathway is more activated in EGFR-mutated NSCLC than in MET-amplified NSCLC, and a PI3K inhibitor enhanced the sensitivity to trametinib in the EGFR-mutated cell lines, suggesting that this pathway is associated with resistance to MEK inhibitors. Although the HCC827 cell line (EGFR mutation) was resistant to MEK inhibitors, the HCC827CNXR cell line, whose driver gene shifts from EGFR to MET, exhibited enhanced sensitivity to MEK inhibitors, indicating the biological importance of the MAPK pathway for MET-amplified NCSLC. Furthermore, a synergistic effect of crizotinib (a MET inhibitor) and trametinib was observed in MET-amplified NCLC cell lines. Our findings indicate that the MAPK pathway is biologically important for MET-amplified NSCLC and strongly encourage the development of combination therapy with a MET inhibitor and a MEK inhibitor against MET-amplified NSCLC. PMID:27748834

  8. Targeting Met and VEGFR Axis in Metastatic Castration-Resistant Prostate Cancer: 'Game Over'?

    Science.gov (United States)

    Modena, Alessandra; Massari, Francesco; Ciccarese, Chiara; Brunelli, Matteo; Santoni, Matteo; Montironi, Rodolfo; Martignoni, Guido; Tortora, Giampaolo

    2016-08-01

    Despite recent advances that have been made in the therapeutic landscape of metastatic castration-resistant prostate cancer (mCRPC), effective management of bone metastases remains a key goal not yet reached. The receptor tyrosine kinase MET and the vascular endothelial growth factor receptor (VEGFR) seem to play an important role in prostate cancer progression and pathological bone turnover, representing potential targets for improving clinical outcomes in mCRPC. Studies evaluating agents that target one or both these pathways have demonstrated modest activity but no improvement in overall survival. Nevertheless, this therapeutic strategy seems to still be a promising and engaging area of prostate cancer research and the interest in better understanding the MET/VEGFR axis and the mechanism of action of these inhibitors is growing. This review describes the rationale for targeting MET and VEGFR pathway in mCRPC and provides the clinical data available to date and an update on ongoing trials.

  9. Chronisch zieken bij de bedrijfsarts: ervaringen met en oordeel over samenwerking met de huisarts.

    NARCIS (Netherlands)

    Baanders, A.N.

    2004-01-01

    Dit artikel beschrijft de ervaringen met en het oordeel over arbocuratieve samenwerking (ACS) vanuit het perspectief van mensen met somatische chronische aandoeningen. Dit geeft een indruk van de mogelijkheden die ACS volgens chronisch zieken kan hebben bij het terugdringen van ziekteverzuimen en

  10. Portale hypertensie : een experimenteel model met dimethylnitrosamine

    NARCIS (Netherlands)

    O.T. Terpstra (Onno)

    1979-01-01

    textabstractDe behandeling van patiënten met een bloeding uit slokdarmvarices ten gevolge van portale hypertensie levert nog steeds geen bevredigende resultaten op (Sherlock 1978). Operaties die de druk in de vena portae verlagen, zoals een portocavale shunt, zijn effectief wanneer het er om gaat ee

  11. Paprika nog moeilijk te sturen met groeilicht

    NARCIS (Netherlands)

    Hogendonk, L.

    2005-01-01

    De resultaten van een op een paprikabedrijf uitgevoerde proef met drie belichtingssystemen van 5 duizend lux zijn in de afgelopen maanden omgezet in een aantal conclusies. Eén uitkomst was dat de effecten van vaste en bewegende belichting elkaar niet veel ontlopen. Een andere conclusie die kon

  12. Met uitloop meer kans op parasitaire infecties

    NARCIS (Netherlands)

    Eijck, I.A.J.M.

    2003-01-01

    Parasitaire infecties vormen een belangrijk probleem in de biologische- en scharrelhouderij. In een veldinventarisatie van het Praktijkonderzoek van ASG werden meer Ascaris suum (spoelwormen), coccidiën en Toxoplasma gondii gevonden op bedrijven met uitloop dan op bedrijven zonder uitloop. Nader ond

  13. A brief report on mets system

    Digital Repository Service at National Institute of Oceanography (India)

    Fernandes, W.A.

    Mets system is basically a gas monitoring system, used for the detection of underwater gas. The system consists of a sensor, datalogger and energy module. The sensor works on the diffusion techniques. The system can be deployed to a water depth...

  14. Inkoper Innoveer! : Kansen grijpen met innoveren

    NARCIS (Netherlands)

    Reijniers, J.J.A.M.; Gaspersz, J.B.R.; Marijnen, Y.; Roddeman, J.

    2009-01-01

    Dit boek biedt inkopers nieuwe perspectieven, praktische adviezen en kansrijke ideeën om succesvoller te zijn en bij te dragen aan de vernieuwingskracht van hun organisatie. Daarnaast bieden de auteurs een visie waarmee de kansen met inkoop volop zijn te benutten: innovatietalent van leveranciers, s

  15. Allergische consument is tevreden met Santana

    NARCIS (Netherlands)

    Maas, van der M.P.; Schenk, M.F.

    2008-01-01

    Nederland had twee jaar geleden de primeur: Santana, een hyperallergeen appelras voor mensen met appelallergie. Wageningen UR heeft de ervaringen van de consumenten over 2006 en 2007 onderzocht. De vermindering van de allergische reactie is ongeveer volgens verwachting en de tevredenheid blijkt hoog

  16. Met gezonde bijen naar de heide

    NARCIS (Netherlands)

    Cornelissen, B.; Calis, J.

    2010-01-01

    Op 22 maart 2010 kwam een bont gezelschap van bijenhouders van ABTB, ANI en NBV bijeen in Hoenderloo. Het onderwerp die avond was de vraag: “Hoe combineer ik varroabestrijding met de heidedracht?” Hieronder het antwoord en wel in de vorm van de basisprincipes van varroa bestrijding plus een concrete

  17. Consistentie met MS-DOS software

    NARCIS (Netherlands)

    Olsthoorn TN

    1988-01-01

    Zonder de keuze van een zekere standaard-lijn ten aanzien van de software die men zelf gebruikt, kan nauwelijks efficient met een computer worden gewerkt. Onder UNIX en op de Macintosh is het gebruik van programma's en de uitwisseling van gegevens daartussen gestandaardiseerd. Onder MS-DOS

  18. Behandeling non-vitale pulpa met formocresol

    NARCIS (Netherlands)

    Wijk, Pieter Harm

    1971-01-01

    Het principe van de endodontische behandeling volgens de richtlijnen van De Boer is gebaseerd op de gedachte dat het niet nodig is het gehele wortelkanaal te reinigen, mits men er voor zorgt dat de achtergelaten noxen met behulp van een chemischestof - in dit geval formaldehyde - onschadelijk worden

  19. Hepatocyte growth factor activates several transduction pathways in rat pancreatic acini.

    Science.gov (United States)

    Aparicio, I M; Garcia-Marin, L J; Andreolotti, A G; Bodega, G; Jensen, R T; Bragado, M J

    2003-12-07

    The receptor of hepatocyte growth factor (HGF), c-met induces different physiological responses in several cell types. Little is known about the role of HGF in exocrine pancreas. However, abnormal HGF signaling has been strongly implicated in pancreatic tumorigenesis and association of HGF with pancreatitis has been demonstrated. We have studied the presence of c-met and activation of their intracellular pathways associated in rat pancreatic acini in comparison with cholecystokinin (CCK) and epidermal growth factor (EGF). C-met expression in rat exocrine pancreas was identified by immunohistochemistry and immunoprecipitation followed by Western analysis. Tyrosine phosphorylation of c-met is strongly stimulated as well as kinase pathways leading to ERK1/2 cascade. HGF, but not CCK or EGF, selectively caused a consistent increase in the amount of p85 regulatory subunit of PI3-K present in anti-phosphotyrosine immunoprecipitates. Downstream of PI3-K, HGF increased Ser473 phosphorylation of Akt selectively, as CCK or EGF did not affect it. HGF selectively stimulated tyrosine phosphorylation of phosphatase PTP1D. HGF failed to promote the well-known CCK effects in pancreatic acini such as amylase secretion and intracellular calcium mobilization. Although HGF shares activation of ERK1/2 with CCK, we demonstrate that it promotes the selective activation of intracellular pathways not regulated by CCK or EGF. Our results suggest that HGF is an in vivo stimulus of pancreatic acini and provide novel insight into the transduction pathways and effects of c-met/HGF in normal pancreatic acinar cells.

  20. OH-induced oxidation of cyclo-Met-Met. A search for a complexed OH-radical

    DEFF Research Database (Denmark)

    Holcman, J.; Bobrowski, K.; Schöneich, C.;

    1991-01-01

    In the OH radical-induced oxidation of cyclo-Met-Met an OH adduct, cyclo-Met-Met(S therefore OH), absorbing at lambda-max = 390 nm with epsilon-390 cyclo-Met-Met(S therefore OH) = 4500 dm3 mol-1 cm-1 is formed. This adduct reversibly eliminates hydroxide ion, pK(b) = 5.4 +/- 0.1, forming correspo...

  1. The Expression and Significance of HGF and MMP-9 in Lichen Planus%HGF和MMP-9在扁平苔藓皮损中的表达及意义

    Institute of Scientific and Technical Information of China (English)

    何肖; 白莉

    2011-01-01

    目的 检测扁平苔藓皮损中肝细胞生长因子(HGF)和基质金属蛋白酶-9(MMP-9)的表达情况,探讨其在扁平苔藓发病中的意义.方法 应用免疫组化法和RT-PCR法测定30例扁平苔藓及30例正常皮肤组织中HGF和MMP-9的表达水平.结果 扁平苔藓组中HGF和MMP-9的表达率均高于正常对照组(P<0.01),且二者在扁平苔藓皮损中的表达呈正相关(r1=0.391,P1=0.032;r2=0.375,P2=0.041).结论 HGF和MMP-9的高表达可能参与了扁平苔藓的发病.%Objective To explore the expression of hepatocyte growth factor( HGF ) and metalloproteinase - 9( MMP - 9 ) in lichen planus,and investigate the function in pathogenesis of lichen planus.Methods The expression of HGF and MMP - 9 was assayed by RT - PCR and immunohistochemistry in 30 LP lesions and 30 normal skins.Results The expression of HGF and MMP - 9 in LP lesions was stronger than that in normal skins( P <0.01 ),and HGF was positively related to the expression of MMP -9 in LP lesions ( r1 =0.391 ,P1 = 0.032; r2 = 0.375, P2 = 0.041 ).Conclusion The increased expression of HGF and MMP -9 may contribute to the formation and progression of lichen planus.

  2. Angular MET sensor for precise azimuth determination

    Science.gov (United States)

    Zaitsev, Dmitry; Antonov, Alexander; Krishtop, Vladimir

    2016-12-01

    This paper describes using a MET-based low-noise angular motion sensor to precisely determine azimuth direction in a dynamic-scheme method of measuring Earth's rotation velocity vector. The scheme includes installing a sensor on a rotating platform so that it could scan a space and seek for the position of highest Earth's rotation vector projection on its axis. This method is very efficient provided a low-noise sensor is used. We take a low-cost angular sensor based on MET (molecular electronic transduction) technology. Sensors of this kind were originally developed for the seismic activity monitoring and are well-known for very good noise performance and high sensitivity. This approach, combined with use of special signal processing algorithms, allowed for reaching the accuracy of 0.07° for a measurement time of 200 seconds.

  3. Werken met taalportfolio's in het talenonderwijs aan volwassenen

    NARCIS (Netherlands)

    Broeder, P.; Sorce, M.R.

    2008-01-01

    Werken met portfolio’s is in het talenonderwijs (nog) een veelbelovend nieuw instrument om met leerlingen te werken aan taal. Met een taalportfolio kan de gebruiker de eigen taalkennis inschatten en bewijzen van zijn talenkennis verzamelen. Ook kan door het werken met een taalportfolio het verdere l

  4. Activation of the Met kinase confers acquired drug resistance in FGFR-targeted lung cancer therapy.

    Science.gov (United States)

    Kim, S-M; Kim, H; Yun, M R; Kang, H N; Pyo, K-H; Park, H J; Lee, J M; Choi, H M; Ellinghaus, P; Ocker, M; Paik, S; Kim, H R; Cho, B C

    2016-07-18

    Aberrant fibroblast growth factor receptor (FGFR) activation/expression is a common feature in lung cancer (LC). In this study, we evaluated the antitumor activity of and the mechanisms underlying acquired resistance to two potent selective FGFR inhibitors, AZD4547 and BAY116387, in LC cell lines. The antitumor activity of AZD4547 and BAY1163877 was screened in 24 LC cell lines, including 5 with FGFR1 amplification. Two cell lines containing FGFR1 amplifications, H1581 and DMS114, were sensitive to FGFR inhibitors (IC50FGFR1-amplified H1581 cells resistant to AZD4547 or BAY116387 (H1581AR and H1581BR cells, respectively) were established. Receptor tyrosine kinase (RTK) array and immunoblotting analyses showed strong overexpression and activation of Met in H1581AR/BR cells, compared with that in the parental cells. Gene set enrichment analysis against the Kyoto Encyclopedia of Genes and Genomes (KEGG) database showed that cytokine-cytokine receptor interaction pathways were significantly enriched in H1581AR/BR cells, with Met contributing significantly to the core enrichment. Genomic DNA quantitative PCR and fluorescent in situ hybridization analyses showed MET amplification in H1581AR, but not in H1581BR, cells. Met amplification drives acquired resistance to AZD4547 in H1581AR cells by activating ErbB3. Combination treatment with FGFR inhibitors and an anaplastic lymphoma kinase (ALK)/Met inhibitor, crizotinib, or Met-specific short interfering RNA (siRNA) synergistically inhibited cell proliferation in both H1581AR and H1581BR cells. Conversely, ectopic expression of Met in H1581 cells conferred resistance to AZD4547 and BAY1163877. Acquired resistance to FGFR inhibitors not only altered cellular morphology, but also promoted migration and invasion of resistant clones, in part by inducing epithelial-to-mesenchymal transition. Taken together, our data suggest that Met activation is sufficient to bypass dependency on FGFR signaling. Concurrent inhibition of the Met

  5. Metáfora y novedad

    OpenAIRE

    Edeline, Francis

    2012-01-01

    Antes que nada, quisiera definirme como un semiótico cognoscitivo. Mi formación científica, por una parte, y mi pasado retórico en el sentido del Grupo μ, por otra, constituyen los puntos de partida de mi acercamiento al problema de la metáfora, que no podrá dejar de tocar, de paso, lo relazionado con el conocimiento, la cognición, el sentido.

  6. MET Standards for Electro-Technical Officers

    OpenAIRE

    Janusz Mindykowski

    2014-01-01

    The paper deals with one of the most important changes in the STCW 1978 as amended in 2010 Convention, from the point of view of the watchkeeping officers responsible for control, maintenance, diagnostic and repair of electrical and electronic installations on board of ships. Some reasons, why the MET Standards for Electro-Technical had to be developed and implemented are shortly analyzed and described. A legislative way towards and a short description of the minimum standards competence for ...

  7. Vice President Shen Wenqing Met JST Delegation

    Institute of Scientific and Technical Information of China (English)

    Zhang Yinglan

    2008-01-01

    @@ On May 19,2008,Prof.Shen Weqing,Vice President of NSFC,met with the delegation headed by Prof.Akira Fujishima,Director-General of China Research Center,Japan Science and Technology (JST).Prof.Fujishima is also the Chairman of Kanagawa Academy of Science and Technology,Japan and Foreign Member of the Chinese Academy of Sciences elected in 2003.

  8. Chronic arsenic trioxide exposure leads to enhanced aggressiveness via Met oncogene addiction in cancer cells

    Science.gov (United States)

    Kryeziu, Kushtrim; Pirker, Christine; Englinger, Bernhard; van Schoonhoven, Sushilla; Spitzwieser, Melanie; Mohr, Thomas; Körner, Wilfried; Weinmüllner, Regina; Tav, Koray; Grillari, Johannes; Cichna-Markl, Margit; Berger, Walter; Heffeter, Petra

    2016-01-01

    As an environmental poison, arsenic is responsible for many cancer deaths. Paradoxically, arsenic trioxide (ATO) presents also a powerful therapy used to treat refractory acute promyelocytic leukemia (APL) and is intensively investigated for treatment of other cancer types. Noteworthy, cancer therapy is frequently hampered by drug resistance, which is also often associated with enhancement of tumor aggressiveness. In this study, we analyzed ATO-selected cancer cells (A2780ATO) for the mechanisms underlying their enhanced tumorigenicity and aggressiveness. These cells were characterized by enhanced proliferation and spheroid growth as well as increased tumorigenicity of xenografts in SCID mice. Noteworthy, subsequent studies revealed that overexpression of Met receptor was the underlying oncogenic driver of these effects, as A2780ATO cells were characterized by collateral sensitivity against Met inhibitors. This finding was also confirmed by array comparative genomic hybridization (array CGH) and whole genome gene expression arrays, which revealed that Met overexpression by chronic ATO exposure was based on the transcriptional regulation via activation of AP-1. Finally, it was shown that treatment with the Met inhibitor crizotinib was also effective against A2780ATO cell xenografts in vivo, indicating that targeting of Met presents a promising strategy for the treatment of Met-overexpressing tumors after either arsenic exposure or failure to ATO treatment. PMID:27036042

  9. HGF-transgenic MSCs can improve the effects of tissue self-repair in a rabbit model of traumatic osteonecrosis of the femoral head.

    Directory of Open Access Journals (Sweden)

    Qian Wen

    Full Text Available BACKGROUND: Osteonecrosis of the femoral head (ONFH is generally characterized as an irreversible disease and tends to cause permanent disability. Therefore, understanding the pathogenesis and molecular mechanisms of ONFH and developing effective therapeutic methods is critical for slowing the progress of the disease. METHODOLOGY/PRINCIPAL FINDINGS: In this study, an experimental rabbit model of early stage traumatic ONFH was established, validated, and used for an evaluation of therapy. Computed tomography (CT and magnetic resonance (MR imaging confirmed that this model represents clinical Association Research Circulation Osseous (ARCO phase I or II ONFH, which was also confirmed by the presence of significant tissue damage in osseous tissue and vasculature. Pathological examination detected obvious self-repair of bone tissue up to 2 weeks after trauma, as indicated by revascularization (marked by CD105 and expression of collagen type I (Col I, osteocalcin, and proliferating cell nuclear antigen. Transplantation of hepatocyte growth factor (HGF-transgenic mesenchymal stem cells (MSCs 1 week after trauma promoted recovery from ONFH, as evidenced by a reversed pattern of Col I expression compared with animals receiving no therapeutic treatment, as well as increased expression of vascular endothelial growth factor. CONCLUSIONS/SIGNIFICANCE: These results indicate that the transplantation of HGF-transgenic MSCs is a promising method for the treatment for ONFH and suggest that appropriate interference therapy during the tissue self-repair stage contributes to the positive outcomes. This study also provides a model for the further study of the ONFH etiology and therapeutic interventions.

  10. Leptin receptor polymorphisms interact with polyunsaturated fatty acids to augment risk of insulin resistance and metabolic syndrome in adults

    Science.gov (United States)

    The leptin receptor (LEPR) is associated with insulin resistance, a key feature of metabolic syndrome (MetS). Gene-fatty acid interactions may affect MetS risk. The objective was to investigate the relationship among LEPR polymorphisms, insulin resistance, andMetSrisk and whether plasma fatty acids,...

  11. Metáfora y estructura conceptual

    Directory of Open Access Journals (Sweden)

    Emilia Castaño

    2012-01-01

    Full Text Available La lingüística cognitiva siempre ha argumentado que la metáfora no pertenece exclusivamente al lenguaje, sino que es una competencia que se basa en la habilidad humana de concebir un dominio de experiencia en términos de otro. Entendida así, la metáfora no puede ser otra cosa que un fenómeno conceptual. No obstante, pocos adeptos de la lingüística cognitiva han concentrados sus esfuerzos en catalogar manifestaciones metafóricas en ámbitos no lingüísticos. En este trabajo, sugerimos que es factible encontrar pruebas de que la metáfora es un proceso conceptual y, como tal, se manifiesta en esferas que no son estrictamente lingüísticas. Para ello, aportamos un seguido de evidencias muy diversas, como por ejemplo su papel en el razonamiento lógico-matemático de los niños en la fase preoperacional del desarrollo cognitivo, la programación de interfaces para aplicaciones informáticas y los resultados de tres estudios empíricos realizados recientemente en el campo  de la psicología cognitiva que analizan los efectos whorfianos en la conceptualización del tiempo y los efectos del espacio en la memoria emocional.

  12. Mart Mets : "Mida rohkem ajaloolisi kihistusi, seda põnevam on aed" / Mart Mets

    Index Scriptorium Estoniae

    Mets, Mart

    2006-01-01

    Eesti elukutselisi aialoojaid tutvustavas sarjas vastab küsimustele maastikuarhitekt Mart Mets. M. Metsast, tema tähtsamad tööd. M. Mets endast, oma õpetajatest, lemmikstiilist, oma tulevasest aiast ja töödest, koostööst klientidega, uuselamurajoonide kruntide probleemidest, vana aia ümberkujundamisest, ilutaimedest, Eesti aiast jpm. Ill.: M. Metsa portreefoto, 6 ill. tema töödest

  13. Hepatocyte growth factor, a determinant of airspace homeostasis in the murine lung.

    Directory of Open Access Journals (Sweden)

    Carla Calvi

    Full Text Available The alveolar compartment, the fundamental gas exchange unit in the lung, is critical for tissue oxygenation and viability. We explored hepatocyte growth factor (HGF, a pleiotrophic cytokine that promotes epithelial proliferation, morphogenesis, migration, and resistance to apoptosis, as a candidate mediator of alveolar formation and regeneration. Mice deficient in the expression of the HGF receptor Met in lung epithelial cells demonstrated impaired airspace formation marked by a reduction in alveolar epithelial cell abundance and survival, truncation of the pulmonary vascular bed, and enhanced oxidative stress. Administration of recombinant HGF to tight-skin mice, an established genetic emphysema model, attenuated airspace enlargement and reduced oxidative stress. Repair in the TSK/+ mouse was punctuated by enhanced akt and stat3 activation. HGF treatment of an alveolar epithelial cell line not only induced proliferation and scattering of the cells but also conferred protection against staurosporine-induced apoptosis, properties critical for alveolar septation. HGF promoted cell survival was attenuated by akt inhibition. Primary alveolar epithelial cells treated with HGF showed improved survival and enhanced antioxidant production. In conclusion, using both loss-of-function and gain-of-function maneuvers, we show that HGF signaling is necessary for alveolar homeostasis in the developing lung and that augmentation of HGF signaling can improve airspace morphology in murine emphysema. Our studies converge on prosurvival signaling and antioxidant protection as critical pathways in HGF-mediated airspace maintenance or repair. These findings support the exploration of HGF signaling enhancement for diseases of the airspace.

  14. Fc-mediated activity of EGFR x c-Met bispecific antibody JNJ-61186372 enhanced killing of lung cancer cells.

    Science.gov (United States)

    Grugan, Katharine D; Dorn, Keri; Jarantow, Stephen W; Bushey, Barbara S; Pardinas, Jose R; Laquerre, Sylvie; Moores, Sheri L; Chiu, Mark L

    2017-01-01

    Epidermal growth factor receptor (EGFR) mutant non-small cell lung cancers acquire resistance to EGFR tyrosine kinase inhibitors through multiple mechanisms including c-Met receptor pathway activation. We generated a bispecific antibody targeting EGFR and c-Met (JNJ-61186372) demonstrating anti-tumor activity in wild-type and mutant EGFR settings with c-Met pathway activation. JNJ-61186372 was engineered with low fucosylation (<10 %), resulting in enhanced antibody-dependent cell-mediated cytotoxicity and FcγRIIIa binding. In vitro and in vivo studies with the single-arm EGFR or c-Met versions of JNJ-61186372 identified that the Fc-activity of JNJ-61186372 is mediated by binding of the anti-EGFR arm and required for inhibition of EGFR-driven tumor cells. In a tumor model driven by both EGFR and c-Met, treatment with Fc-silent JNJ-61186372 or with c-Met single-arm antibody reduced tumor growth inhibition compared to treatment with JNJ-61186372, suggesting that the Fc function of JNJ-61186372 is essential for maximal tumor inhibition. Moreover in this same model, downregulation of both EGFR and c-Met receptors was observed upon treatment with Fc-competent JNJ-61186372, suggesting that the Fc interactions are necessary for down-modulation of the receptors in vivo and for efficacy. These Fc-mediated activities, in combination with inhibition of both the EGFR and c-Met signaling pathways, highlight the multiple mechanisms by which JNJ-61186372 combats therapeutic resistance in EGFR mutant patients.

  15. Synthetic lethal screening reveals FGFR as one of the combinatorial targets to overcome resistance to Met-targeted therapy.

    Science.gov (United States)

    Kim, B; Wang, S; Lee, J M; Jeong, Y; Ahn, T; Son, D-S; Park, H W; Yoo, H-s; Song, Y-J; Lee, E; Oh, Y M; Lee, S B; Choi, J; Murray, J C; Zhou, Y; Song, P H; Kim, K-A; Weiner, L M

    2015-02-26

    Met is a receptor tyrosine kinase that promotes cancer progression. In addition, Met has been implicated in resistance of tumors to various targeted therapies such as epidermal growth factor receptor inhibitors in lung cancers, and has been prioritized as a key molecular target for cancer therapy. However, the underlying mechanism of resistance to Met-targeting drugs is poorly understood. Here, we describe screening of 1310 genes to search for key regulators related to drug resistance to an anti-Met therapeutic antibody (SAIT301) by using a small interfering RNA-based synthetic lethal screening method. We found that knockdown of 69 genes in Met-amplified MKN45 cells sensitized the antitumor activity of SAIT301. Pathway analysis of these 69 genes implicated fibroblast growth factor receptor (FGFR) as a key regulator for antiproliferative effects of Met-targeting drugs. Inhibition of FGFR3 increased target cell apoptosis through the suppression of Bcl-xL expression, followed by reduced cancer cell growth in the presence of Met-targeting drugs. Treatment of cells with the FGFR inhibitors substantially restored the efficacy of SAIT301 in SAIT301-resistant cells and enhanced the efficacy in SAIT301-sensitive cells. In addition to FGFR3, integrin β3 is another potential target for combination treatment with SAIT301. Suppression of integrin β3 decreased AKT phosphorylation in SAIT301-resistant cells and restored SAIT301 responsiveness in HCC1954 cells, which are resistant to SAIT301. Gene expression analysis using CCLE database shows that cancer cells with high levels of FGFR and integrin β3 are resistant to crizotinib treatment, suggesting that FGFR and integrin β3 could be used as predictive markers for Met-targeted therapy and provide a potential therapeutic option to overcome acquired and innate resistance for the Met-targeting drugs.

  16. Cross-arm binding efficiency of an EGFR x c-Met bispecific antibody.

    Science.gov (United States)

    Zheng, Songmao; Moores, Sheri; Jarantow, Stephen; Pardinas, Jose; Chiu, Mark; Zhou, Honghui; Wang, Weirong

    2016-01-01

    Multispecific proteins, such as bispecific antibodies (BsAbs), that bind to two different ligands are becoming increasingly important therapeutic agents. Such BsAbs can exhibit markedly increased target binding and target residence time when both pharmacophores bind simultaneously to their targets. The cross-arm binding efficiency (χ) describes an increase in apparent affinity when a BsAb binds to the second target or receptor (R2) following its binding to the first target or receptor (R1) on the same cell. χ is an intrinsic characteristic of a BsAb mostly related to the binding epitopes on R1 and R2. χ can have significant impacts on the binding to R2 for BsAbs targeting two receptors on the same cell. JNJ-61186372, a BsAb that targets epidermal growth factor receptor (EGFR) and c-Met, was used as the model compound for establishing a method to characterize χ. The χ for JNJ-61186372 was successfully determined via fitting of in vitro cell binding data to a ligand binding model that incorporated χ. The model-derived χ value was used to predict the binding of JNJ-61186372 to individual EGFR and c-Met receptors on tumor cell lines, and the results agreed well with the observed IC50 for EGFR and c-Met phosphorylation inhibition by JNJ-61186372. Consistent with the model, JNJ-61186372 was shown to be more effective than the combination therapy of anti-EGFR and anti-c-Met monovalent antibodies at the same dose level in a mouse xenograft model. Our results showed that χ is an important characteristic of BsAbs, and should be considered for rationale design of BsAbs targeting two membrane bound targets on the same cell.

  17. Nucleoporin Nup358 facilitates nuclear import of Methoprene-tolerant (Met) in an importin β- and Hsp83-dependent manner.

    Science.gov (United States)

    He, Qianyu; Zhang, Yuanxi; Zhang, Xu; Xu, DanDan; Dong, Wentao; Li, Sheng; Wu, Rui

    2017-02-01

    The bHLH-PAS transcription factor, Methoprene-tolerant (Met)(1), functions as a juvenile hormone (JH) receptor and transduces JH signals by directly binding to E-box like motifs in the regulatory regions of JH response genes. Nuclear localization of Met is crucial for its transcriptional activity. Our previous studies have shown that the chaperone protein Hsp83 facilitates JH-induced Met nuclear import in Drosophila melanogaster. However, the exact molecular mechanisms of Met nuclear transport are not fully elucidated. Using DNA affinity chromatography, we have previously detected binding of the nucleoporin Nup358, in the presence of JH, to the JH response region (JHRR) sequences isolated from the Krüppel-homolog 1 (Kr-h1) promoter. Here, we have demonstrated that Nup358 regulates JH-Hsp83-induced Met nuclear localization. RNAi-mediated knockdown of Nup358 expression in Drosophila fat body perturbs Met nuclear transport during the 3 h after initiation of wandering, when the JH titer is high. The accompanying reduced expression of the transport receptor importin β in Nup358 RNAi flies could be one of the reasons accounting for Met mislocalization. Furthermore, a tetratricopeptide repeat (TPR) domain at the N-terminal end of Nup358 interacts with Hsp83 and is indispensable for Met nuclear localization. Overexpression of the TPR domain in Drosophila fat body prevents Met nuclear localization resulting in a decrease in JHRR-driven reporter activity and Kr-h1 expression. These data show that Nup358 facilitates JH-induced Met nuclear transport in a manner dependent on importin β and Hsp83.

  18. The Met-allele of the BDNF Val66Met polymorphism enhances task switching in elderly.

    Science.gov (United States)

    Gajewski, Patrick D; Hengstler, Jan G; Golka, Klaus; Falkenstein, Michael; Beste, Christian

    2011-12-01

    In this study we examined the relevance of the functional brain-derived neurotrophic factor (BDNF) Val66Met polymorphism as a modulator of task-switching performance in healthy elderly by using behavioral and event-related potential (ERP) measures. Task switching was examined in a cue-based and a memory-based paradigm. Val/Val carriers were generally slower, showed enhanced reaction time variability and higher error rates, particularly during memory-based task switching than the Met-allele individuals. On a neurophysiological level these dissociative effects were reflected by variations in the N2 and P3 ERP components. The task switch-related N2 was increased while the P3 was decreased in Met-allele carriers, while the Val/Val genotype group revealed the opposite pattern of results. In cue-based task-switching no behavioral and ERP differences were seen between the genotypes. These data suggest that superior memory-based task-switching performance in elderly Met-allele carriers may emerge due to more efficient response selection processes. The results implicate that under special circumstances the Met-allele renders cognitive processes more efficient than the Val/Val genotype in healthy elderly, corroborating recent findings in young subjects.

  19. Hepatocyte Growth Factor Effects on Mesenchymal Stem Cells Derived from Human Arteries: A Novel Strategy to Accelerate Vascular Ulcer Wound Healing

    Directory of Open Access Journals (Sweden)

    Sabrina Valente

    2016-01-01

    Full Text Available Vascular ulcers are a serious complication of peripheral vascular disease, especially in diabetics. Several approaches to treat the wounds are proposed but they show poor outcomes and require long healing times. Hepatocyte Growth Factor/Scatter Factor (HGF/SF is a pleiotropic cytokine exerting many biological activities through the c-Met receptor. This study was aimed at verifying whether HGF/SF influences proliferation, migration, and angiogenesis on mesenchymal stem cells isolated from human arteries (hVW-MSCs. hVW-MSCs were exposed to NIBSC HGF/SF (2.5, 5, 10, and 70 ng/mL from 6 hrs to 7 days. HGF and c-MET mRNA and protein expression, cell proliferation (Alamar Blue and Ki–67 assay, migration (scratch and transwell assays, and angiogenesis (Matrigel were investigated. hVW-MSCs displayed stemness features and expressed HGF and c-MET. HGF/SF did not increase hVW-MSC proliferation, whereas it enhanced the cell migration, the formation of capillary-like structures, and the expression of angiogenic markers (vWF, CD31, and KDR. The HGF/SF effects on hVW-MSC migration and angiogenic potential are of great interest to accelerate wound healing process. Local delivery of HGF/SF could therefore improve the healing of unresponsive vascular ulcers.

  20. Hepatocyte Growth Factor Effects on Mesenchymal Stem Cells Derived from Human Arteries: A Novel Strategy to Accelerate Vascular Ulcer Wound Healing.

    Science.gov (United States)

    Valente, Sabrina; Ciavarella, Carmen; Pasanisi, Emanuela; Ricci, Francesca; Stella, Andrea; Pasquinelli, Gianandrea

    2016-01-01

    Vascular ulcers are a serious complication of peripheral vascular disease, especially in diabetics. Several approaches to treat the wounds are proposed but they show poor outcomes and require long healing times. Hepatocyte Growth Factor/Scatter Factor (HGF/SF) is a pleiotropic cytokine exerting many biological activities through the c-Met receptor. This study was aimed at verifying whether HGF/SF influences proliferation, migration, and angiogenesis on mesenchymal stem cells isolated from human arteries (hVW-MSCs). hVW-MSCs were exposed to NIBSC HGF/SF (2.5, 5, 10, and 70 ng/mL) from 6 hrs to 7 days. HGF and c-MET mRNA and protein expression, cell proliferation (Alamar Blue and Ki-67 assay), migration (scratch and transwell assays), and angiogenesis (Matrigel) were investigated. hVW-MSCs displayed stemness features and expressed HGF and c-MET. HGF/SF did not increase hVW-MSC proliferation, whereas it enhanced the cell migration, the formation of capillary-like structures, and the expression of angiogenic markers (vWF, CD31, and KDR). The HGF/SF effects on hVW-MSC migration and angiogenic potential are of great interest to accelerate wound healing process. Local delivery of HGF/SF could therefore improve the healing of unresponsive vascular ulcers.

  1. Activation of c-Met and upregulation of CD44 expression are associated with the metastatic phenotype in the colorectal cancer liver metastasis model.

    Directory of Open Access Journals (Sweden)

    Victoria A Elliott

    Full Text Available BACKGROUND: Liver metastasis is the most common cause of death in patients with colorectal cancer. Despite extensive research into the biology of cancer progression, the molecular mechanisms that drive colorectal cancer metastasis are not well characterized. METHODS: HT29 LM1, HT29 LM2, HT29 LM3 cell lines were derived from the human colorectal cancer cell line HT29 following multiple rounds of in vivo selection in immunodeficient mice. RESULTS: CD44 expression, a transmembrane glycoprotein involved in cell-cell and cell-matrix adhesions, and cancer cells adhesion to endothelial cells was increased in all in vivo selected cell lines, with maximum CD44 expression and cancer cells adhesion to endothelial cells in the highly metastatic HT29 LM3 cell line. Activation of c-Met upon hepatocyte growth factor (HGF stimulation in the in vivo selected cell lines is CD44 independent. In vitro separation of CD44 high and low expression cells from HT29 LM3 cell line with FACS sorting confirmed that c-Met activation is CD44 independent upon hepatocyte growth factor stimulation. Furthermore, in vivo evaluation of CD44 low and high expressing HT29 LM3 cells demonstrated no difference in liver metastasis penetrance. CONCLUSIONS: Taken together, our findings indicate that the aggressive metastatic phenotype of in vivo selected cell lines is associated with overexpression of CD44 and activation of c-MET. We demonstrate that c-Met activation is CD44 independent upon hepatocyte growth factor stimulation and confirm that CD44 expression in HT29 LM3 cell line is not responsible for the increase in metastatic penetrance in HT29 LM3 cell line.

  2. The Serum Levels and Clinical Significance of HGF and KL-6 in Patients of Interstitial Lung Disease with Reumatoid Arthritis%HGF 与 KL-6在 RA-ILD 患者血清中的表达水平及意义

    Institute of Scientific and Technical Information of China (English)

    王树刚; 王晓东; 慈春增; 于杰; 李向东

    2015-01-01

    目的:通过检测肝细胞生长因子( HGF)和人Ⅱ型肺泡细胞表面抗原( KL-6)在类风湿关节炎合并肺间质病变( RA-ILD)患者血清中的表达水平,探讨其在RA-ILD中的意义。方法采用ELISA法检测60例RA(包括28例RA-ILD)和20例健康体检者血清HGF,KL-6的表达水平。结果 RA-ILD组中HGF的含量明显低于单纯RA组及对照组,差异有统计学意义(P<0.05);RA-ILD组中KL-6的含量明显高于单纯RA组及对照组,差异有统计学意义(P<0.05);且HGF与KL-6呈负相关关系;在RA-ILD组,HGF与疾病活动性指标DAS28评分呈负相关关系,KL-6与疾病活动性指标DAS28评分呈正相关关系。结论 HGF和KL-6可能参与RA-ILD的发生发展过程,HGF和KL-6可作为判断RA-ILD活动的指标。%Objective To analyze the hepatocyte growth factor( HGF) and human typeⅡalveolar cell sur-face antigen( KL-6 ) serum levels and their clinical significance in the patients of interstitial lung disease with rheumatoid arthritis( RA-ILD) .Methods The serum levels of HGF and KL-6 were detected in 60 patients with rheumatoid arthritis ( including 28 patients with interstitial lung disease) and 20 healthy individuals by means of enzyme linked immunosor-bent assay( ELISA) .Results In patients of RA-ILD,the serum levels of HGF was lower than simple RA group and the control group,and the serum levels of KL-6 was higher than simple RA group and the control group,there were signifi-cantly statistical difference(P<0.05).The levels of HGF and KL-6 were negatively related;In group RA-ILD,HGF was negatively correlated with disease activity index DAS28 score,KL-6 was positively correlated with disease activity index DAS28 score.Conclusion The cytokines of HGF and KL-6 may play important roles in the development of RA-ILD;perhaps they can be seen as indexes of RA-ILD activities.

  3. c-Met in chromophobe renal cell carcinoma.

    Science.gov (United States)

    Erlmeier, Franziska; Ivanyi, Philipp; Hartmann, Arndt; Autenrieth, Michael; Wiedemann, Max; Weichert, Wilko; Steffens, Sandra

    2017-02-01

    c-Met plays a role as a prognostic marker in clear cell renal cell carcinoma. In addition, recently the tyrosine kinase inhibitor cabozantinib targeting c-Met was approved for the treatment of advanced renal cell carcinoma (RCC). In contrast to clear cell RCC, little is known about c-Met expression patterns in rarer RCC subtypes. The aim of this study was to evaluate the prevalence, distribution and prognostic impact of c-Met expression on chromophobe (ch)RCC. Patients who underwent renal surgery due to chRCC were retrospectively evaluated. Tumor specimens were analyzed for c-Met expression by immunohistochemistry. Expression data were associated with clinicopathological parameters including patient survival. Eighty-one chRCC patients were eligible for analysis. Twenty-four (29.6%) patients showed a high c-Met expression (c-Met(high), staining intensity higher than median). Our results showed an association between c-Met(high) expression and the existence of lymph node metastasis (p = 0.007). No further significant clinicopathological associations with c-Met were identified, also regarding c-Met expression and overall survival. In conclusion, to our knowledge this is the first study evaluating the prognostic impact of c-Met in a considerably large cohort of chRCC. High c-Met expression is associated with the occurrence of lymph node metastasis. This indicates that c-Met might be implicated into metastatic progression in chRCC.

  4. MetR and CRP bind to the Vibrio harveyi lux promoters and regulate luminescence.

    Science.gov (United States)

    Chatterjee, Jaidip; Miyamoto, Carol M; Zouzoulas, Athina; Lang, B Franz; Skouris, Nicolas; Meighen, Edward A

    2002-10-01

    The induction of luminescence in Vibrio harveyi at the later stages of growth is controlled by a quorum-sensing mechanism in addition to nutritional signals. However, the mechanism of transmission of these signals directly to the lux promoters is unknown and only one regulatory protein, LuxR, has been shown to bind directly to lux promoter DNA. In this report, we have cloned and sequenced two genes, crp and metR, coding for the nutritional regulators, CRP (cAMP receptor protein) and MetR (a LysR homologue), involved in catabolite repression and methionine biosynthesis respectively. The metR gene was cloned based on a general strategy to detect lux DNA-binding proteins expressed from a genomic library, whereas the crp gene was cloned based on its complementation of an Escherichia coli crp mutant. Both CRP and MetR were shown to bind to lux promoter DNA, with CRP being dependent on the presence of cAMP. Expression studies indicated that the two regulators had opposite effects on luminescence: CRP was an activator and MetR a repressor. Disruption of crp decreased luminescence by about 1,000-fold showing that CRP is a major activator of luminescence the same as LuxR, whereas disruption of MetR resulted in activation of luminescence over 10-fold, confirming its function as a repressor. Comparison of the levels of the autoinducers involved in quorum sensing excreted by V. harveyi, and the crp and metR mutants, showed that autoinducer production was not significantly different, thus indicating that the nutritional signals do not affect luminescence by changing the levels of the signals required for quorum sensing. Indeed, the large effects of these nutritional sensors show that luminescence is controlled by multiple signals related to the environment and the cell density which must be integrated at the molecular level to control expression at the lux promoters.

  5. Targeting the MET gene for the treatment of non-small-cell lung cancer.

    Science.gov (United States)

    Gelsomino, F; Facchinetti, F; Haspinger, E R; Garassino, M C; Trusolino, L; De Braud, F; Tiseo, M

    2014-02-01

    Recently, a better understanding of the specific mechanisms of oncogene addiction has led to the development of antitumor strategies aimed at blocking these abnormalities in different malignancies, including lung cancer. These abnormalities trigger constitutive activation of tyrosine kinase receptors (RTKs) involved in fundamental cell mechanisms such as proliferation, survival, differentiation and migration, and consequently the aberrant signaling of RTKs leads to cancer growth and survival. The inhibition of aberrant RTKs and downstream signaling pathways has opened the door to the targeted therapy era. In non-small-cell lung cancer (NSCLC), molecular research has allowed the discrimination of different aberrant RTKs in lung cancer tumorigenesis and progression, and thus the identification of several targetable oncogenic drivers. Following the development of small molecules (gefitinib/erlotinib and crizotinib) able to reversibly inhibit the epidermal growth factor receptor (EGFR) and signaling pathways mediated by anaplastic lymphoma kinase (ALK), respectively, the MET signaling pathway has also been recognized as a potential target. Moreover, according to current knowledge, MET could be considered both as a secondary oncogenic mechanism and as a prognostic factor. Several therapeutic strategies for inhibiting activated hepatocyte growth factor receptor (HGFR) and the subsequent downstream signaling transduction have been improved in order to block tumor growth. This review will focus on the MET pathway and its role in resistance to EGFR TK (tyrosine kinase) inhibitors, the different strategies of its inhibition, and the potential approaches to overcoming acquired resistance.

  6. Volwassenen met overgewicht in beweging: de rol van de gezondheidsattitude

    NARCIS (Netherlands)

    Wouters, Eveline

    2008-01-01

    Factoren die mensen met overgewicht belemmeren om met een fysiek trainingsprogramma te beginnen Achtergrond: Bij overgewicht heeft lichaamsbeweging (bijvoorbeeld sportbeoefening) gunstige effecten op het behoud van gewicht(svermindering) en op verschillende aan overgewicht gerelateerde aandoeningen

  7. Samenwerking Wageningen UR met: Faculteit Diergeneeskunde Universiteit Utrecht

    NARCIS (Netherlands)

    Noorduyn, L.

    2008-01-01

    Wageningen UR werkt in haar onderzoeksprogramma’s samen met andere kennis - instellingen. Zo werkt Wageningen UR samen met de Universiteit van Utrecht bij het ontwikkelen van het welzijnsprogramma op het gebied van gezelschapsdieren

  8. NK4 with Anti-tumor Activity: A Competitive Antagonist against HGF%肝细胞生长因子抑制剂——NK4的抗肿瘤作用

    Institute of Scientific and Technical Information of China (English)

    蔡超; 侯玲玲; 胡红刚

    2014-01-01

    肝细胞生长因子(hepatocyte growth factor,HGF)是一种多功能的细胞因子,其生物学活性由c-Met蛋白所介导.HGF/c-Met信号通路在肿瘤生成、侵袭、转移以及肿瘤新生血管生成方面起重要促进作用.因此,HGF/c-Met信号转导通路可以作为抗肿瘤药物设计的靶点.其中,HGF α链N端447个氨基酸组成的NK4蛋白是HGF的特异性拮抗剂,它不仅通过抑制HGF/c-Met系统的信号转导发挥抗肿瘤效应;而且可以通过拮抗HGF和其它血管生成因子如成纤维细胞生长因子(fibroblast growth factors,FGF)、血管内皮生长因子(vascular endothelial growth factor,VEGF)的活性,进而抑制肿瘤新生血管生成,最终导致肿瘤细胞的凋亡.NK4的这种双重抗肿瘤功能使其成为一类很有前景的新型抗肿瘤药物.本文就NK4对肿瘤的抑制作用及其机制的研究进展进行综述.

  9. Onderzoek naar de mutagene werking van methylacrylaat met microorganismen

    NARCIS (Netherlands)

    Voogd CE; van der Stel JJ; Verharen HW

    1984-01-01

    Met methylacrylaat is geen mutagene werking gevonden in de fluctuatietest met Klebsiella pneumoniae bij 0,02 mol/l (0,172% w/v) of minder in de vloeistoffase of bij 0,0002 mol/l (17,2 mg/l) of minder in de lucht. Met de Salmonella typhimurium stammen TA 98, TA 100 en TA 1535 is met methylacrylaat g

  10. MET Standards for Electro-Technical Officers

    Directory of Open Access Journals (Sweden)

    Janusz Mindykowski

    2014-12-01

    Full Text Available The paper deals with one of the most important changes in the STCW 1978 as amended in 2010 Convention, from the point of view of the watchkeeping officers responsible for control, maintenance, diagnostic and repair of electrical and electronic installations on board of ships. Some reasons, why the MET Standards for Electro-Technical had to be developed and implemented are shortly analyzed and described. A legislative way towards and a short description of the minimum standards competence for ETO are presented. Next, new tools supporting ETO’s standards implementation are appointed. Finally, the future works as well as the concluding remarks concerning discussed issue are formulated and commented on.

  11. Installing met towers in marine environments

    Energy Technology Data Exchange (ETDEWEB)

    Hanberg, Jackie [DNV Canada (Canada)

    2011-07-01

    Onshore measurements are taken to supplement offshore wind resource measurement campaigns. To maximize the quality of the measured data, the conditions presented by marine environments must be well understood and mitigated. This paper discusses the several factors that need attention prior to installation of the met towers. The towers experience high corrosion from their exposure to moist, salt-laden, marine air. Careful instrumentation and material selection can prevent or decrease corrosion. Stainless or galvanized hardware and coating sensor terminals with petroleum jelly are both helpful. Soil in the marine environment has variable moisture levels and is extremely wet, which makes grounding systems and backfill enhancers necessary. Weather conditions in these environments also tend to be unpredictable; hence, towers should be strong enough to handle typical marine weather. In conclusion, successful marine wind resource assessment campaigns require environmental research, careful planning, and awareness of the specific issues.

  12. Gevolgen nieuwe mineralen beleid : met aanvoernormen voor Telen met toekomst en BIOM bedrijven 6 bedrijven doorgerekend

    NARCIS (Netherlands)

    Wolf, de M.

    2004-01-01

    In 2006 gaat het nieuwe mestbeleid op basis van gebruiksnormen van start. In veel gevallen zullen de gebruiksnormen de totale aanvoer van mineralen sterker begrenzen dan Minas. PPO heeft voor een aantal Telen met Toekomst (TmT) en BIOM bedrijvendoorgerekend wat de gevolgen kunnen zijn.

  13. 'Gezond met haver' rapportage van het haverketenproject 'Gezond met haver' 2006-2008

    NARCIS (Netherlands)

    Gilissen, L.J.W.J.; Pinxterhuis, E.K.; Gremmen, H.G.J.

    2009-01-01

    In dit rapport wordt ingegaan op de resultaten en ervaringen van het project ‘Gezond met haver’. Het project betreft een innovatief Praktijkproject van TransForum. Het project is gestart in 2006 en afgerond in 2008. Het project heeft beoogd om een relevante bijdrage te leveren aan de maatschappelijk

  14. De eerste ervaringen van mensen met lichamelijke beperkingen met de Wmo.

    NARCIS (Netherlands)

    Klerk, M. de; Marangos, A.M.; Cardol, M.

    2009-01-01

    Op verzoek van het ministerie van Volksgezondheid, Welzijn en Sport (VWS) deed het SCP onderzoek naar de Wmo. Dit onderzoek bestaat uit twee sporen: onderzoek naar de effecten van de Wmo voor mensen met beperkingen en onderzoek naar gemeentelijk beleid. Onlangs verscheen een tussenrapport.

  15. Groei sturen en meer ruimte benutten met LED's in tulpenbroei (interview met Jeroen Wildschut)

    NARCIS (Netherlands)

    Bouwman-van Velden, P.; Wildschut, J.

    2010-01-01

    Bij blauw licht groeien tulpen omhoog en blijven langer dicht. Bij rood licht gaan ze hun blad juist spreiden. Lelies reageren heel anders. Het eerste oriënterende onderzoek met LED-belichting heeft aangetoond dat de kleuren van het licht straks mogelijk zijn in te zetten om de groei echt te sturen.

  16. Houtcomposities met glas, beton en kunststof. Onderzoeken TNO Bouw

    NARCIS (Netherlands)

    Kuilen, J.W.G. van de; Robson, D.J.

    1999-01-01

    TNO Bouw in Rijswijk probeert hout een meerwaarde te geven door het te combineren met andere materialen. De studies richten zich onder meer op de versterking van balken met vezels en van vloeren met een laag beton. Bovendien kijken de onderzoekers naar moge-lijkheden om afvalhout in kunststof te

  17. Gastrointestinal malignancies harbor actionable MET exon 14 deletions

    Science.gov (United States)

    Hong, Mineui; Kim, Sun Young; Jang, Jiryeon; Ahn, Soomin; Kang, So Young; Lee, Sujin; Kim, Seung Tae; Kim, Bogyou; Choi, Jaehyun; Kim, Kyung-Ah; Lee, Jiyun; Park, Charny; Park, Se Hoon; Park, Joon Oh; Lim, Ho Yeong; Kang, Won Ki; Park, Keunchil; Park, Young Suk; Kim, Kyoung-Mee

    2015-01-01

    Recently, MET exon 14 deletion (METex14del) has been postulated to be one potential mechanism for MET protein overexpression. We screened for the presence of METex14del transcript by multiplexed fusion transcript analysis using nCounter assay followed by confirmation with quantitative reverse transcription PCR with correlation to MET protein expression by immunohistochemistry (IHC) and MET amplification by fluorescence in situ hybridization (FISH). We extracted RNAs from 230 patients enrolled onto the prospective molecular profiling clinical trial (NEXT-1) (NCT02141152) between November 2013 and August 2014. Thirteen METex14del cases were identified including 3 gastric cancer, 4 colon cancer, 5 non-small cell lung cancer, and one adenocarcinoma of unknown primary. Of these 13 METex14del cases, 11 were MET IHC 3+ and 2 were 2+. Only one out of the 13 METex14del cases was MET amplified (MET/CEP ratio > 2.0). Growths of two (gastric, colon) METex14del+ patient tumor derived cell lines were profoundly inhibited by both MET tyrosine kinase inhibitors and a monoclonal antibody targeting MET. In conclusion, METex14del is a unique molecular aberration present in gastrointestinal (GI) malignancies corresponding with overexpression of MET protein but rarely with MET amplification. Substantial growth inhibition of METex14del+ patient tumor derived cell lines by several MET targeting drugs strongly suggests METex14del is a potential actionable driver mutation in GI malignancies. PMID:26375439

  18. Innoveren met serious games : Wat is serious gaming?

    NARCIS (Netherlands)

    Werkhoven, P.J.

    2008-01-01

    Het begrip serious gaming is inmiddels gekaapt door vele aanbieders van wat vroeger simulatie en virtual reality technologie genoemd werd. Met die technologie kunnen we mensen laten rondlopen in virtuele gebouwen en landschappen, al dan niet met grote projectieschermen of met brillen op. Maar dat is

  19. Theanine from tea and its semi-synthetic derivative TBrC suppress human cervical cancer growth and migration by inhibiting EGFR/Met-Akt/NF-κB signaling.

    Science.gov (United States)

    Liu, Jiannan; Sun, Yuping; Zhang, Huarong; Ji, Dexin; Wu, Fei; Tian, Huihui; Liu, Kun; Zhang, Ying; Wu, Benhao; Zhang, Guoying

    2016-11-15

    Cervical cancer is the third most prevalent cancer among women worldwide. Theanine from tea and its derivatives show some anticancer activities. However, the role of theanine and its derivatives against human cervical cancer and the molecular mechanisms of action remain unclear. Thus, in this study, we aim to investigate the anticancer activities and underlying mechanisms of theanine and a theanine derivative, ethyl 6-bromocoumarin-3- carboxylyl L-theanine (TBrC), against human cervical cancer. In vitro and in vivo assays for cancer cell growth and migration have confirmed the inhibition of the cell growth and migration by TBrC and theanine in highly-metastatic human cervical cancer. TBrC displays much stronger activity than theanine on inhibition of the cell growth and migration as well as induction of apoptosis and regulation of related protein expressions in the human cervical cancer cells. TBrC and theanine greatly reduced endogenous and exogenous factors-stimulated cell migration and completely repressed HGF- and EGF+HGF-activated EGFR/Met-Akt/NF-κB signaling by reducing the phosphorylation and expressions of EGFR, Met, Akt, and NF-κB in cervical cancer cells. The enhancer of zeste homolog 2 (EZH2) knockdown decreased the cancer cell migration and NF-κB expression. The NF-κB knockdown reduced the cancer cell migration. TBrC and theanine reduced the EZH2 expression by more than 80%. In addition, TBrC and theanine significantly suppressed human cervical tumor growth in tumor-bearing nude mice without toxicity to the mice. Our results suggest that TBrC and theanine may have the potentials of the therapeutic and/or adjuvant therapeutic application in the treatment of human cervical cancer.

  20. Development of antibody-based c-Met inhibitors for targeted cancer therapy

    Directory of Open Access Journals (Sweden)

    Lee D

    2015-02-01

    Full Text Available Dongheon Lee, Eun-Sil Sung, Jin-Hyung Ahn, Sungwon An, Jiwon Huh, Weon-Kyoo You Hanwha Chemical R&D Center, Biologics Business Unit, Daejeon, Republic of Korea Abstract: Signaling pathways mediated by receptor tyrosine kinases (RTKs and their ligands play important roles in the development and progression of human cancers, which makes RTK-mediated signaling pathways promising therapeutic targets in the treatment of cancer. Compared with small-molecule compounds, antibody-based therapeutics can more specifically recognize and bind to ligands and RTKs. Several antibody inhibitors of RTK-mediated signaling pathways, such as human epidermal growth factor receptor 2, vascular endothelial growth factor, epidermal growth factor receptor or vascular endothelial growth factor receptor 2, have been developed and are widely used to treat cancer patients. However, since the therapeutic options are still limited in terms of therapeutic efficacy and types of cancers that can be treated, efforts are being made to identify and evaluate novel RTK-mediated signaling pathways as targets for more efficacious cancer treatment. The hepatocyte growth factor/c-Met signaling pathway has come into the spotlight as a promising target for development of potent cancer therapeutic agents. Multiple antibody-based therapeutics targeting hepatocyte growth factor or c-Met are currently in preclinical or clinical development. This review focuses on the development of inhibitors of the hepatocyte growth factor/c-Met signaling pathway for cancer treatment, including critical issues in clinical development and future perspectives for antibody-based therapeutics. Keywords: hepatocyte growth factor, ligands, receptor tyrosine kinase, signaling pathway, therapeutic agent

  1. MET: roles in epithelial-mesenchymal transition and cancer stemness

    Science.gov (United States)

    Jeon, Hye-Min

    2017-01-01

    In a number of cancers, deregulated MET pathway leads to aberrantly activated proliferative and invasive signaling programs that promote malignant transformation, cell motility and migration, angiogenesis, survival in hypoxia, and invasion. A better understanding of oncogenic MET signaling will help us to discover effective therapeutic approaches and to identify which tumors are likely to respond to MET-targeted cancer therapy. In this review, we will summarize the roles of MET signaling in cancer, with particular focus on epithelial-mesenchymal transition (EMT) and cancer stemness. Then, we will provide update on MET targeting agents and discuss the challenges that should be overcome for the development of an effective therapy. PMID:28164090

  2. The c-Met tyrosine kinase inhibitor JNJ-38877605 causes renal toxicity through species-specific insoluble metabolite formation

    NARCIS (Netherlands)

    M.P. Lolkema (Martijn); H.H. Bohets (Hilde H.); H.-T. Arkenau (H.); A. Lampo (Ann); E. Barale (Erio); M.J.A. de Jonge (Maja); L. van Doorn (Leni); P. Hellemans (Peter); J.S. de Bono (Johann); F.A.L.M. Eskens (Ferry)

    2015-01-01

    textabstractPurpose: The receptor tyrosine kinase c-Met plays an important role in tumorigenesis and is a novel target for anticancer treatment. This phase I, first-in-human trial, explored safety, pharmacokinetics, pharmacodynamics, and initial antitumor activity of JNJ-38877605, a potent and

  3. Effect of cerebral ventricles perfusion with morphiceptin and Met-enkephalin on trigemino-hypoglossal reflex in rats.

    Science.gov (United States)

    Zubrzycka, M; Fichna, J; Janecka, A

    2002-12-01

    Opioids administered by intracerebroventricular injections produce analgesic responses in rats. The present study was undertaken to investigate the effects of a highly selective mu-opioid receptor ligand morphiceptin on trigemino-hypoglossal reflex in rats. The analgesic effect of morphiceptin was compared with another opioid peptide, Met-enkephalin. With the experimental settings used in this study, we have demonstrated that both morphiceptin and Met-enkephalin show significant dose-dependent analgesic effects after i.c.v. administration in rats as assayed by trigemino-hypoglossal reflex test. The antinociceptive response to Met-enkephalin was short lasting and was observed 10 to 15 min after i.c.v. perfusion. Morphiceptin had a relatively longer duration of antinociceptive action, the effect was observed 20-50 min after i.c.v. perfusion. Neither morphiceptin nor Met-enkephalin produced antinociception after peripheral injections. The results of the present study indicate that both tested peptides act at mu-opioid receptors situated in the central nervous system. They also suggest that mu-opioid receptors present in the central nervous system are an important element of the trigemino-hypoglossal reflex arc. For that reason selective mu-opioid receptor ligands, like morphiceptin, inhibit the reflex more significantly.

  4. Lys63/Met1-hybrid ubiquitin chains are commonly formed during the activation of innate immune signalling.

    Science.gov (United States)

    Emmerich, Christoph H; Bakshi, Siddharth; Kelsall, Ian R; Ortiz-Guerrero, Juanma; Shpiro, Natalia; Cohen, Philip

    2016-06-03

    We have reported previously that activation of the MyD88-signaling network rapidly induces the formation of hybrid ubiquitin chains containing both Lys63-linked and Met1-linked ubiquitin (Ub) oligomers, some of which are attached covalently to Interleukin Receptor Associated kinase 1. Here we show that Lys63/Met1-Ub hybrids are also formed rapidly when the TNFR1/TRADD, TLR3/TRIF- and NOD1/RIP2-signaling networks are activated, some of which are attached covalently to Receptor-Interacting Protein 1 (TNFR1 pathway) or Receptor-Interacting Protein 2 (NOD1 pathway). These observations suggest that the formation of Lys63/Met1-Ub hybrids are of general significance for the regulation of innate immune signaling systems, and their potential roles in vivo are discussed. We also report that TNFα induces the attachment of Met1-linked Ub chains directly to TNF receptor 1, which do not seem to be attached covalently to Lys63-linked or other types of ubiquitin chain. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

  5. Mammalian neuronal actions of FMRFamide and the structurally related opioid Met-enkephalin-Arg6-Phe7.

    Science.gov (United States)

    Gayton, R J

    1982-07-15

    Since the enkephalins were first isolated a number of opioid peptides have been discovered, including a heptapeptide with the sequence Tyr-Gly-Gly-Phe-Met-Arg-Phe (Met-enkephalin-Arg6-Phe7). The heptapeptide was first isolated from chromaffin granules in bovine adrenal medulla, but using immunochemical techniques it has now been identified in human, rat and bovine brains. The C-terminal tetrapeptide of this molecule (Phe-Met-Arg-Phe) occurs in amidated form as the molluscan peptide FMRFamide. Antisera raised against FMRFamide have revealed immunoreactive material in the brains of several vertebrate species, including the rat where it occurs in nerve cell bodies and terminals. I now report that ionophoretically applied FMRFamide has an excitatory effect on rat medullary neurones which is unaffected by the opiate antagonist naloxone. In contrast, Met-enkephalin-Arg6-Phe7 and leucine-enkephalin (Leu-enkephalin) have predominantly depressant effects, which suggests that FMRFamide acts at a separate receptor.

  6. I. Estructuras metálicas ligeras

    Directory of Open Access Journals (Sweden)

    Beer, Hermann

    1967-09-01

    Full Text Available The first part of this paper is being published in the present issue of «Informes de la Construcción», and will be followed by two further parts in the next two numbers of this magazine. It corresponds to the manuscript utilised for the two lecturers given at Costillares by professor Hermann Beer. These lectures were given on March 8 and 9th last. Professor Beer, professor of the High Technical School of Graz, Austria, is President of the Committee II of A.I.P.C. and of the Committee VIII of the European Convention on Metallic Construction, and has worldwide reputation in the field of metallic structures. The up to date nature of the subject and the abundant graphical documentation which illustrates it has led this Institute to believe that it will be of great interest to professionals to publish the text of these lectures. It should be emphasized that professor Beer knows Spanish very well. He learnt this language during the years he was professor at the University of Tucumán, in Argentina. In the following text the Institute has only introduced some slight adjustments of syntax and spelling.Este trabajo, cuya primera parte se publica en este número y continuará y terminará en los dos próximos de INFORMES DE LA CONSTRUCCIÓN, corresponde al texto escrito por el propio conferenciante de las dos conferencias pronunciadas, en el aula de Costillares, por el profesor Hermann Beer, los días 8 y 9 de marzo pasado. El profesor Beer, Catedrático de la Escuela Técnica Superior de Graz (Austria, Presidente de la Comisión II de la A.I.P.C. y de la Comisión VIII de la Convención Europea de la Construcción Metálica, goza de una reputación universal en el campo de las estructuras metálicas. La actualidad del tema elegido para sus conferencias y la abundante documentación gráfica con que las ilustró, han hecho pensar al Instituto en el gran interés que, para los profesionales, pueda tener su publicación. Es de destacar que el profesor

  7. 3D RoboMET Characterization

    Energy Technology Data Exchange (ETDEWEB)

    Madison, Jonathan D. [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States); Susan, Donald F. [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States); Kilgo, Alice C. [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States)

    2015-10-01

    The goal of this project is to generate 3D microstructural data by destructive and non-destructive means and provide accompanying characterization and quantitative analysis of such data. This work is a continuing part of a larger effort to relate material performance variability to microstructural variability. That larger effort is called “Predicting Performance Margins” or PPM. In conjunction with that overarching initiative, the RoboMET.3D™ is a specific asset of Center 1800 and is an automated serialsectioning system for destructive analysis of microstructure, which is called upon to provide direct customer support to 1800 and non-1800 customers. To that end, data collection, 3d reconstruction and analysis of typical and atypical microstructures have been pursued for the purposes of qualitative and quantitative characterization with a goal toward linking microstructural defects and/or microstructural features with mechanical response. Material systems examined in FY15 include precipitation hardened 17-4 steel, laser-welds of 304L stainless steel, thermal spray coatings of 304L and geological samples of sandstone.

  8. Phase II study evaluating 2 dosing schedules of oral foretinib (GSK1363089, cMET/VEGFR2 inhibitor, in patients with metastatic gastric cancer.

    Directory of Open Access Journals (Sweden)

    Manish A Shah

    Full Text Available PURPOSE: The receptors for hepatocyte and vascular endothelial cell growth factors (MET and VEGFR2, respectively are critical oncogenic mediators in gastric adenocarcinoma. The purpose is to examine the safety and efficacy of foretinib, an oral multikinase inhibitor targeting MET, RON, AXL, TIE-2, and VEGFR2 receptors, for the treatment of metastatic gastric adenocarcinoma. PATIENTS AND METHODS: Foretinib safety and tolerability, and objective response rate (ORR were evaluated in patients using intermittent (240 mg/day, for 5 days every 2 weeks or daily (80 mg/day dosing schedules. Thirty evaluable patients were required to achieve alpha = 0.10 and beta = 0.2 to test the alternative hypothesis that single-agent foretinib would result in an ORR of ≥ 25%. Up to 10 additional patients could be enrolled to ensure at least eight with MET amplification. Correlative studies included tumor MET amplification, MET signaling, pharmacokinetics and plasma biomarkers of foretinib activity. RESULTS: From March 2007 until October 2009, 74 patients were enrolled; 74% male; median age, 61 years (range, 25-88; 93% had received prior therapy. Best response was stable disease (SD in 10 (23% patients receiving intermittent dosing and five (20% receiving daily dosing; SD duration was 1.9-7.2 months (median 3.2 months. Of 67 patients with tumor samples, 3 had MET amplification, one of whom had SD. Treatment-related adverse events occurred in 91% of patients. Rates of hypertension (35% vs. 15% and elevated aspartate aminotransferase (23% vs. 8% were higher with intermittent dosing. In both patients with high baseline tumor phospho-MET (pMET, the pMET:total MET protein ratio decreased with foretinib treatment. CONCLUSION: These results indicate that few gastric carcinomas are driven solely by MET and VEGFR2, and underscore the diverse molecular oncogenesis of this disease. Despite evidence of MET inhibition by foretinib, single-agent foretinib lacked efficacy in

  9. Methoprene-tolerant (Met knockdown in the adult female cockroach, Diploptera punctata completely inhibits ovarian development.

    Directory of Open Access Journals (Sweden)

    Elisabeth Marchal

    Full Text Available Independent of the design of the life cycle of any insect, their growth and reproduction are highly choreographed through the action of two versatile hormones: ecdysteroids and juvenile hormones (JH. However, the means by which JH can target tissues and exert its pleiotropic physiological effects is currently still not completely elucidated. Although the identity of the one JH receptor is currently still elusive, recent evidence seems to point to the product of the Methoprene-tolerant gene (Met as the most likely contender in transducing the action of JH. Studies on the role of this transcription factor have mostly been focused on immature insect stages. In this study we used the viviparous cockroach Diploptera punctata, a favorite model in studying JH endocrinology, to examine the role of Met during reproduction. A tissue distribution and developmental profile of transcript levels was determined for Met and its downstream partners during the first gonadotropic cycle of this cockroach. Using RNA interference, our study shows that silencing Met results in an arrest of basal oocyte development; vitellogenin is no longer transcribed in the fat body and no longer taken up by the ovary. Patency is not induced in these animals which fail to produce the characteristic profile of JH biosynthesis typical of the first gonadotropic cycle. Moreover, the ultrastructure of the follicle cells showed conspicuous whorls of rough endoplasmic reticulum and a failure to form chorion. Our study describes the role of Met on a cellular and physiological level during insect reproduction, and confirms the role of Met as a key factor in the JH signaling pathway.

  10. Prognostic Value of MACC1 and c-met Expressions in Non-small Cell Lung Cancer

    Directory of Open Access Journals (Sweden)

    Xingsheng HU

    2012-07-01

    Full Text Available Background and objective It has been proven that metastasis-associated in colon cancer 1 (MACC1 is a new gene that is related to the invasion and metastasis of tumors. MACC1 also regulates c-met expression. The aim of this study is to explore the expressions of MACC1 and hepatocyte growth factor receptor (c-met, and its relationship with invasion, metastasis, and prognosis of non-small cell lung cancer (NSCLC. Methods MACC1 and c-met expressions were detected in 103 cases of NSCLC and 40 cases of neighboring normal lung cancer tissue using immunohistochemistry. Results MACC1 and c-met expressions were significantly higher in lung cancer tissues than that in neighboring normal tissue (P<0.001. MACC1 and c-met expressions were associated with poor differentiation, advanced T stages, lymph node metastasis, and advanced TNM stages (P<0.05 of NSCLC, but not with sex, age, smoking, and histological classification (P>0.05. In addition, a positive correlation between MACC1 and c-met expressions was observed (r=0.403, P<0.001. The result from the Kaplan-Meier survival analysis showed that the five-year survival rate in patients with positive MACC1 and c-met expressions was remarkanly lower than that in patients with negative expressions (P<0.05. The result from the Cox regression analysis showed that MACC1 expression was an independent prognostic factor for NSCLC (P=0.026. Conclusion MACC1 and c-met have an important function in the differentiation, invasion, and metastasis of NSCLC. MACC1 and c-met have poor prognosis in patients with NSCLC. Moreover, MACC1 expression is an independent prognostic factor for NSCLC.

  11. Mars MetNet Mission Pressure and Humidity Devices

    Science.gov (United States)

    Haukka, H.; Harri, A.-M.; Schmidt, W.; Genzer, M.; Polkko, J.; Kemppinen, O.; Leinonen, J.

    2012-09-01

    A new kind of planetary exploration mission for Mars is being developed in collaboration between the Finnish Meteorological Institute (FMI), Lavochkin Association (LA), Space Research Institute (IKI) and Institutio Nacional de Tecnica Aerospacial (INTA). The Mars MetNet mission [1] is based on a new semi-hard landing vehicle called MetNet Lander (MNL). MetBaro and MetHumi are part of the scientific payload of the MNL. Main scientific goal of both devices is to measure the meteorological phenomena (pressure and humidity) of the Martian atmosphere and complement the previous Mars mission atmospheric measurements (Viking and Phoenix) for better understanding of the Martian atmospheric conditions.

  12. In vivo modulation of gastrointestinal motor activity by Met-enkephalin, morphine and enkephalin analogs in chickens.

    Science.gov (United States)

    Jiménez, M; Martínez, V; Goñalons, E; Vergara, P

    1993-03-05

    The main objectives of this work have been to study (1) whether or not opioid effects on gastrointestinal motility in chicken are mediated through central or peripheral pathways; (2) the receptors involved; (3) the correlation of the motor response to the distribution of Met-enkephalin in the gastrointestinal tract and (4) to evaluate the physiological role of endogenous opioids in spontaneous MMCs. Intravenous infusion of Met-enkephalin and morphine (5 x 10(-7) mol/kg) induced gastric inhibition and a migrating intestinal hyperactivity. Induced intestinal activity was faster in vagotomized chickens. In the stomach there was a correlation between the duration of the inhibitory response and the affinity of the agonists for mu-receptors ([D-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin (DAGO) > morphine > Met-enkephalin > Tyr-D-Pen-Gly-Phe-D-Pen (DPDPE)). DPDPE induced duodenal hyperactivity which was not propagated. Immunohistochemistry showed that Met-ENK like material is mainly located at the myenteric plexus and the outer circular muscle in stomach. In the intestine, it was found in the myenteric and the deep muscular plexuses. When endogenous MMCs were studied, i.v. infusion of naloxone lengthened significantly their duration. In conclusion, the fact that Met-enkephalin and their analogs induced a migrating activity in the intestine and the lengthening of MMC by naloxone, suggest a physiological role for opioids on induction of MMC in birds, acting at peripheral level.

  13. Efficacy of HGF carried by ultrasound microbubble-cationic nano-liposomes complex for treating hepatic fibrosis in a bile duct ligation rat model, and its relationship with the diffusion-weighted MRI parameters.

    Science.gov (United States)

    Zhang, Shou-hong; Wen, Kun-ming; Wu, Wei; Li, Wen-yan; Zhao, Jian-nong

    2013-12-01

    Hepatic fibrosis is a major consequence of liver aggression. Finding novel ways for counteracting this damaging process, and for evaluating fibrosis with a non-invasive imaging approach, represent important therapeutic and diagnostic challenges. Hepatocyte growth factor (HGF) is an anti-fibrosis cell growth factor that induces apoptosis in activated hepatic stellate cells, reduces excessive collagen deposition, and stimulates hepatocyte regeneration. Thus, using HGF in gene therapy against liver fibrosis is an attractive approach. The aims of the present study were: (i) to explore the efficacy of treating liver fibrosis using HGF expression vector carried by a novel ultrasound microbubble delivery system; (ii) to explore the diagnostic interest of diffusion-weighted MRI (DWI-MRI) in evaluating liver fibrosis. We established a rat model of hepatic fibrosis. The rats were administered HGF linked to novel ultrasound micro-bubbles. Progression of hepatic fibrosis was evaluated by histopathology, hydroxyproline content, and DWI-MRI to determine the apparent diffusion coefficient (ADC). Our targeted gene therapy produced a significant anti-fibrosis effect, as shown by liver histology and significant reduction of hydroxyproline content. Moreover, using DWI-MRI, the b value (diffusion gradient factor) was equal to 300s/mm(2), and the ADC values significantly decreased as the severity of hepatic fibrosis increased. Using this methodology, F0-F2 could be distinguished from F3 and F4 (Pmicrobubble-cationic nano-liposome complex for gene delivery. The data indicate that, this approach is efficient to counteract the fibrosis process. DWI-MRI appears a promising imaging technique for evaluating liver fibrosis.

  14. miR-1 suppresses the growth of esophageal squamous cell carcinoma in vivo and in vitro through the downregulation of MET, cyclin D1 and CDK4 expression

    Science.gov (United States)

    JIANG, SEN; ZHAO, CHAO; YANG, XIAODI; LI, XIANGYANG; PAN, QING; HUANG, HAIJIN; WEN, XUYANG; SHAN, HUSHENG; LI, QIANWEN; DU, YUNXIANG; ZHAO, YAPING

    2016-01-01

    Several aberrant microRNAs (miRNAs or miRs) have been implicated in esophageal cancer (EC), which is widely prevalent in China. However, their role in EC tumorigenesis has not yet been fully elucidated. In the present study, we determined that miR-1 was downregulated in esophageal squamous cell carcinoma (ESCC) tissues compared with adjacent non-neoplastic tissues using RT-qPCR, and confirmed this using an ESCC cell line. Using a nude mouse xenograft model, we confirmed that the re-expression of miR-1 significantly inhibited ESCC tumor growth. A tetrazolium assay and a trypan blue exclusion assay revealed that miR-1 suppressed ESCC cell proliferation and increased apoptosis, whereas the silencing of miR-1 promoted cell proliferation and decreased apoptosis, suggesting that miR-1 is a novel tumor suppressor. To elucidate the molecular mechanisms of action of miR-1 in ESCC, we investigated putative targets using bioinformatics tools. MET, cyclin D1 and cyclin-dependent kinase 4 (CDK4), which are involved in the hepatocyte growth factor (HGF)/MET signaling pathway, were found to be targets of miR-1. miR-1 expression inversely correlated with MET, cyclin D1 and CDK4 expression in ESCC cells. miR-1 directly targeted MET, cyclin D1 and CDK4, suppressing ESCC cell growth. The newly identified miR-1/MET/cyclin D1/CDK4 axis provides new insight into the molecular mechanisms of ESCC pathogenesis and indicates a novel strategy for the diagnosis and treatment of ESCC. PMID:27247259

  15. Hepatic stellate cells secreted hepatocyte growth factor contributes to the chemoresistance of hepatocellular carcinoma.

    Directory of Open Access Journals (Sweden)

    Guofeng Yu

    Full Text Available As the main source of extracellular matrix proteins in tumor stroma, hepatic stellate cells (HSCs have a great impact on biological behaviors of hepatocellular carcinoma (HCC. In the present study, we have investigated a mechanism whereby HSCs modulate the chemoresistance of hepatoma cells. We used human HSC line lx-2 and chemotherapeutic agent cisplatin to investigate their effects on human HCC cell line Hep3B. The results showed that cisplatin resistance in Hep3B cells was enhanced with LX-2 CM (cultured medium exposure in vitro as well as co-injection with LX-2 cells in null mice. Meanwhile, in presence of LX-2 CM, Hep3B cells underwent epithelial to mesenchymal transition (EMT and upregulation of cancer stem cell (CSC -like properties. Besides, LX-2 cells synthesized and secreted hepatic growth factor (HGF into the CM. HGF receptor tyrosine kinase mesenchymal-epithelial transition factor (Met was activated in Hep3B cells after LX-2 CM exposure. The HGF level of LX-2 CM could be effectively reduced by using HGF neutralizing antibody. Furthermore, depletion of HGF in LX-2 CM abolished its effects on activation of Met as well as promotion of the EMT, CSC-like features and cisplatin resistance in Hep3B cells. Collectively, secreting HGF into tumor milieu, HSCs may decrease hepatoma cells sensitization to chemotherapeutic agents by promoting EMT and CSC-like features via HGF/Met signaling.

  16. Effects of the BDNF Val66Met Polymorphism and Met Allele Load on Declarative Memory Related Neural Networks

    DEFF Research Database (Denmark)

    Dodds, Chris M; Henson, Richard N; Suckling, John;

    2013-01-01

    It has been suggested that the BDNF Val66Met polymorphism modulates episodic memory performance via effects on hippocampal neural circuitry. However, fMRI studies have yielded inconsistent results in this respect. Moreover, very few studies have examined the effect of met allele load on activation...... of memory circuitry. In the present study, we carried out a comprehensive analysis of the effects of the BDNF polymorphism on brain responses during episodic memory encoding and retrieval, including an investigation of the effect of met allele load on memory related activation in the medial temporal lobe....... In contrast to previous studies, we found no evidence for an effect of BDNF genotype or met load during episodic memory encoding. Met allele carriers showed increased activation during successful retrieval in right hippocampus but this was contrast-specific and unaffected by met allele load. These results...

  17. The progesterone and estrogen modify the uterine prolactin and prolactin receptor expression of hyperprolactinemic mice.

    Science.gov (United States)

    do Amaral, Vinícius Cestari; Carvalho, Kátia Candido; Maciel, Gustavo Arantes Rosa; Simoncini, Tommaso; da Silva, Priscilla Ludovico; Marcondes, Rodrigo Rodrigues; Soares, José Maria; Baracat, Edmund Chada

    2015-02-01

    The aim of this study was to evaluate the effects of metoclopramide-induced hyperprolactinemia on the prolactin (PRL) and PRL receptor's expression in the uterus of mice. For this purpose, 49 Swiss mice were divided into the following groups: GrSS (non-ovariectomized mice given vehicle); GrMET (non-ovariectomized mice treated with metoclopramide); OvSS (ovariectomized mice given vehicle); OvMET (ovariectomized mice treated with metoclopramide); OvMET+17βE (ovariectomized mice treated with metoclopramide and 17β estradiol); OvMET+MP (ovariectomized mice treated with metoclopramide and micronized progesterone); OvMET+17βE+MP (ovariectomized mice treated with metoclopramide and a solution of 17β estradiol and micronized progesterone). Immunohistochemical analyzes were evaluated semi-quantitatively. Our results showed that GrMET, OvMET+MP, and OvMET+17βE+MP presented strong PRL expression. OvMET and OvMET+17βE presented mild reaction, while GrSS and OvSS presented weak reaction. Concerning PRL receptor, OvMET+MP and OvMET+17βE+MP showed strong reaction; GrMET, OvSS, and OvMET+17βE showed mild reaction; and GrSS and OvMET showed weak reaction. These findings suggest that progesterone alone or in combination with estrogen may increase the expression of uterine PRL and PRL receptor.

  18. MET Expression in Primary and Metastatic Clear Cell Renal Cell Carcinoma: Implications of Correlative Biomarker Assessment to MET Pathway Inhibitors

    Directory of Open Access Journals (Sweden)

    Brian Shuch

    2015-01-01

    Full Text Available Aims. Inhibitors of the MET pathway hold promise in the treatment for metastatic kidney cancer. Assessment of predictive biomarkers may be necessary for appropriate patient selection. Understanding MET expression in metastases and the correlation to the primary site is important, as distant tissue is not always available. Methods and Results. MET immunofluorescence was performed using automated quantitative analysis and a tissue microarray containing matched nephrectomy and distant metastatic sites from 34 patients with clear cell renal cell carcinoma. Correlations between MET expressions in matched primary and metastatic sites and the extent of heterogeneity were calculated. The mean expression of MET was not significantly different between primary tumors when compared to metastases (P=0.1. MET expression weakly correlated between primary and matched metastatic sites (R=0.5 and a number of cases exhibited very high levels of discordance between these tumors. Heterogeneity within nephrectomy specimens compared to the paired metastatic tissues was not significantly different (P=0.39. Conclusions. We found that MET expression is not significantly different in primary tumors than metastatic sites and only weakly correlates between matched sites. Moderate concordance of MET expression and significant expression heterogeneity may be a barrier to the development of predictive biomarkers using MET targeting agents.

  19. Dual Constant Domain-Fab: A novel strategy to improve half-life and potency of a Met therapeutic antibody.

    Science.gov (United States)

    Cignetto, Simona; Modica, Chiara; Chiriaco, Cristina; Fontani, Lara; Milla, Paola; Michieli, Paolo; Comoglio, Paolo M; Vigna, Elisa

    2016-06-01

    The kinase receptor encoded by the Met oncogene is a sensible target for cancer therapy. The chimeric monovalent Fab fragment of the DN30 monoclonal antibody (MvDN30) has an odd mechanism of action, based on cell surface removal of Met via activation of specific plasma membrane proteases. However, the short half-life of the Fab, due to its low molecular weight, is a severe limitation for the deployment in therapy. This issue was addressed by increasing the Fab molecular weight above the glomerular filtration threshold through the duplication of the constant domains, in tandem (DCD-1) or reciprocally swapped (DCD-2). The two newly engineered molecules showed biochemical properties comparable to the original MvDN30 in vitro, acting as full Met antagonists, impairing Met phosphorylation and activation of downstream signaling pathways. As a consequence, Met-mediated biological responses were inhibited, including anchorage-dependent and -independent cell growth. In vivo DCD-1 and DCD-2 showed a pharmacokinetic profile significantly improved over the original MvDN30, doubling the circulating half-life and reducing the clearance. In pre-clinical models of cancer, generated by injection of tumor cells or implant of patient-derived samples, systemic administration of the engineered molecules inhibited the growth of Met-addicted tumors.

  20. Metástasis coroideas Choroidal metastases

    Directory of Open Access Journals (Sweden)

    C. Camarillo

    2008-01-01

    Full Text Available Las metástasis uveales son el tumor intraocular maligno más frecuente y de ellas, más del 80% se localizan en la coroides. Esto, unido al progresivo aumento de la incidencia, hace necesario su estudio y revisión para un correcto diagnóstico y tratamiento en la práctica clínica actual. La etiología varía según el sexo del paciente, siendo el carcinoma de pulmón el que con más frecuencia metastatiza en el varón y el de mama en la mujer. Tienden a la multifocalidad y generalmente se localizan en el polo posterior. En el 50% de los casos cursan de forma asintomática, pero pueden producir pérdida de visión, escotomas, metamorfopsias, y fotopsias. La exploración oftalmoscópica característica muestra una lesión coroidea placoide, homogénea y de aspecto cremoso. En el diagnóstico diferencial se debe considerar el nevus amelanótico, el melanoma amelanótico de coroides, el hemangioma coroideo, la escleritis posterior, el osteoma de coroides, las coriorretinitis, la enfermedad de Harada, el desprendimiento de retina rhegmatógeno, el síndrome de efusión uveal, y la coriorretinopatía serosa central. Una exhaustiva anamnesis y exploración oftalmológica completa son imprescindibles para el diagnóstico, a lo que se pueden añadir como pruebas complementarias la angiografía con fluoresceína, la ecografía ocular, la punción-aspiración con aguja fina (PAAF, la tomografía computarizada y la resonancia magnética. El tratamiento de estos tumores suele ser el tratamiento sistémico del tumor primario; las posibilidades de tratamiento local son la observación, la radioterapia externa, la braquiterapia, la termoterapia transpupilar y la enucleación.Uveal metastases are the most frequent malign intraocular tumour, of which more than 80% are localized in the choroids. This, together with the progressive increase in its incidence, makes its study and review necessary for a correct diagnosis and treatment in current clinical practice

  1. C. elegans as a model organism for in vivo screening in cancer: effects of human c-Met in lung cancer affect C. elegans vulva phenotypes.

    Science.gov (United States)

    Siddiqui, Shahid S; Loganathan, Sivakumar; Krishnaswamy, Soundararajan; Faoro, Leonardo; Jagadeeswaran, Ramasamy; Salgia, Ravi

    2008-06-01

    Cancers typically harbour several mutant forms of key cellular genes that contribute to its complex phenotype. Our lab has previously identified gain-of-function mutations in some of the receptor tyrosine kinases such as c-Met in lung cancer. In order to investigate the mutant gene in the context of a whole organism, the current choice of in vivo model is limited to the mouse. To rapidly screen the functional aspects of mutant forms of c-Met detected in lung cancer, we used the nematode C. elegans as the model organism. Transgenic worms were generated that harbour wild type or the frequently seen mutant forms of c-Met in lung cancer (c-MetR988C and c-MetT1010I). Expression of the mutant human c-Met forms in C. elegans consistently resulted in significantly low fecundity and abnormal vulval development characterized by hyperplasia. Interestingly, exposure of c-Met mutant transgenic worms to nicotine resulted in enhanced abnormal vulval development, fecundity and locomotion. Our studies provide first evidence that human c-Met mutations can be studied in C. elegans, and that carcinogens can enhance mutant c-Met function expressed in C. elegans transgenic animals. We therefore propose the use of C. elegans as a model to rapidly assess the role of cancer specific gene mutations in the context of a whole organism.

  2. Downsyndroom-kansbepaling met de eerstetrimestercombinatietest 2006-2008

    NARCIS (Netherlands)

    Schielen PCJI; Koster MPH; Elvers LH; Loeber JG; LIS

    2010-01-01

    Tussen 2006 en 2008 is 70 % van de zwangerschappen van een kind met downsyndroom correct voorspeld met de eerstetrimester-combinatietest. De test presteert daarmee iets minder dan in de vorige onderzochte periode, tussen 2004 en 2006. Het aantal aanvragen voor de test is in de onderzochte periode li

  3. Ringonderzoek : bepaling van coccidiostaticagehalte in diervoeders, met behulp van turbidimetrie

    NARCIS (Netherlands)

    Broex, N.J.G.; Huf, F.

    1988-01-01

    Voor de gehalte bepaling van monensin, salinomycine en narasin in diervoeders is de zg. turbidimetrische methode geringtest door 12 laboratoria. Ieder laboratorium heeft 9 monsters ontvangen, resp. 3 voormengsels en 6 diervoeders met monensin, salinomycine of narasin. De monsters zijn onderzocht met

  4. Wankel succes met druppelfertigatie in Franse prei : Op Proefboerderij Vredepeel

    NARCIS (Netherlands)

    Verstegen, S.; PPO Akkerbouw, Groene Ruimte en Vollegrondsgroente

    2007-01-01

    Bij PPO Vredepeel wordt in proeven prei geteeld met behulp van druppelfertigatie, met minder kunstmest en minder uitspoeling als doelen. In Frankrijk werken al sinds 2005 vijf preitelers in de streek Loire-Atlantique er mee op hun hele areaal. Eén van hen gebruikt 20 tot 40 procent minder kunst mest

  5. Massage bij verpleeghuisbewoners met ernstige dementie: een waardevolle interventie.

    NARCIS (Netherlands)

    Inhulsen, M.B.; Verkaik, R.; Busch, M.; Francke, A.

    2016-01-01

    Zorgverleners vinden dat massage een waardevolle bijdrage levert aan de zorg voor verpleeghuisbewoners met ernstige dementie. Met name in het maken van contact en het verminderen van onrust. Dit blijkt uit een pilot uitgevoerd door zorgorganisatie Laurens, het Van Praag Instituut en

  6. Alternatieve voedergewassen : ervaringen met erwten/graan, amarinth en snijsorghum

    NARCIS (Netherlands)

    Schooten, van H.A.

    2003-01-01

    In 2002 zijn door Praktijkonderzoek Veehouderij, in samenwerking met Stimuland Overijssel, drie demo's aangelegd met alternatieve voedergewassen voor de biologische melkveehouderij. De opbrengsten en voederwaarde-gegevens voor mengteelten gerst/erwten, gerst/rode klaver en triticale/erwten, en voor

  7. Milde voedselverwerkingstechnologie II : milde conservering met hoge druk : nieuwe ontwikkelingen

    NARCIS (Netherlands)

    Matser, A.M.; Ven, van der C.; Berg, van den R.

    2004-01-01

    Met behulp van hogedruktechnologie kunnen producten langer houdbaar worden gemaakt. Deze bekende techniek kent de laatste tijd nieuwe ontwikkelingen en toepassingen . Naast pasteuriseren door een hogedrukbehandeling bij kamertemperatuur is het nu ook mogelijk om te steriliseren met hoge druk. Ook zi

  8. Massage bij verpleeghuisbewoners met ernstige dementie: een waardevolle interventie.

    NARCIS (Netherlands)

    Inhulsen, M.B.; Verkaik, R.; Busch, M.; Francke, A.

    2016-01-01

    Zorgverleners vinden dat massage een waardevolle bijdrage levert aan de zorg voor verpleeghuisbewoners met ernstige dementie. Met name in het maken van contact en het verminderen van onrust. Dit blijkt uit een pilot uitgevoerd door zorgorganisatie Laurens, het Van Praag Instituut en onderzoeksinstit

  9. Success, but Slowly, as Met School Redefines Learning

    Science.gov (United States)

    Pearson, George

    2012-01-01

    Seven Oaks Met School, the only high school in Canada that is part of the U.S.-based Big Picture Learning network of innovative schools, graduated its first class this spring. Internships with businesses and institutions in the community are a core element of the Met School experience. Students report on their internship experience, as well as on…

  10. Isolaatvorming en confessie in verband met de genetische bevolkingsstructuur

    NARCIS (Netherlands)

    1958-01-01

    In dit proefschrift is een onderzoek ingesteld bij een roomskatholieke enclave, gelegen in een gebied met een overwegend protestantse bevolking, in het noorden van de provincie Groningen in het noordelijkste deel van Nederland (Gemeente Leens). Door de beide bevolkingsgroepen met elkaar te vergelijk

  11. MET gene copy number predicts worse overall survival in patients with non-small cell lung cancer (NSCLC; a systematic review and meta-analysis.

    Directory of Open Access Journals (Sweden)

    Anastasios Dimou

    Full Text Available OBJECTIVES: MET is a receptor present in the membrane of NSCLC cells and is known to promote cell proliferation, survival and migration. MET gene copy number is a common genetic alteration and inhibition o MET emerges as a promising targeted therapy in NSCLC. Here we aim to combine in a meta-analysis, data on the effect of high MET gene copy number on the overall survival of patients with resected NSCLC. METHODS: Two independent investigators applied parallel search strategies with the terms "MET AND lung cancer", "MET AND NSCLC", "MET gene copy number AND prognosis" in PubMed through January 2014. We selected the studies that investigated the association of MET gene copy number with survival, in patients who received surgery. RESULTS: Among 1096 titles that were identified in the initial search, we retrieved 9 studies on retrospective cohorts with adequate retrievable data regarding the prognostic impact of MET gene copy number on the survival of patients with NSCLC. Out of those, 6 used FISH and the remaining 3 used RT PCR to assess the MET gene copy number in the primary tumor. We calculated the I2 statistic to assess heterogeneity (I2 = 72%. MET gene copy number predicted worse overall survival when all studies were combined in a random effects model (HR = 1.78, 95% CI 1.22-2.60. When only the studies that had at least 50% of adenocarcinoma patients in their populations were included, the effect was significant (five studies, HR 1.55, 95% CI 1.23-1.94. This was not true when we included only the studies with no more than 50% of the patients having adenocarcinoma histology (four studies HR 2.18, 95% CI 0.97-4.90. CONCLUSIONS: Higher MET gene copy number in the primary tumor at the time of diagnosis predicts worse outcome in patients with NSCLC. This prognostic impact may be adenocarcinoma histology specific.

  12. Analysis of receptor tyrosine kinase internalization using flow cytometry.

    Science.gov (United States)

    Li, Ning; Hill, Kristen S; Elferink, Lisa A

    2008-01-01

    The internalization of activated receptor tyrosine kinases (RTKs) by endocytosis and their subsequent down regulation in lysosomes plays a critical role in regulating the duration and intensity of downstream signaling events. Uncoupling of the RTK cMet from ligand-induced degradation was recently shown to correlate with sustained receptor signaling and increased cell tumorigenicity, suggesting that the corruption of these endocytic mechanisms could contribute to increased cMet signaling in metastatic cancers. To understand how cMet signaling for normal cell growth is controlled by endocytosis and how these mechanisms are dysregulated in metastatic cancers, we developed flow cytometry-based assays to examine cMet internalization.

  13. A Novel SND1-BRAF Fusion Confers Resistance to c-Met Inhibitor PF-04217903 in GTL16 Cells though MAPK Activation

    Science.gov (United States)

    Lee, Nathan V.; Lira, Maruja E.; Pavlicek, Adam; Ye, Jingjing; Buckman, Dana; Bagrodia, Shubha; Srinivasa, Sreesha P.; Zhao, Yongjun; Aparicio, Samuel; Rejto, Paul A.; Christensen, James G.; Ching, Keith A.

    2012-01-01

    Targeting cancers with amplified or abnormally activated c-Met (hepatocyte growth factor receptor) may have therapeutic benefit based on nonclinical and emerging clinical findings. However, the eventual emergence of drug resistant tumors motivates the pre-emptive identification of potential mechanisms of clinical resistance. We rendered a MET amplified gastric cancer cell line, GTL16, resistant to c-Met inhibition with prolonged exposure to a c-Met inhibitor, PF-04217903 (METi). Characterization of surviving cells identified an amplified chromosomal rearrangement between 7q32 and 7q34 which overexpresses a constitutively active SND1-BRAF fusion protein. In the resistant clones, hyperactivation of the downstream MAPK pathway via SND1-BRAF conferred resistance to c-Met receptor tyrosine kinase inhibition. Combination treatment with METi and a RAF inhibitor, PF-04880594 (RAFi) inhibited ERK activation and circumvented resistance to either single agent. Alternatively, treatment with a MEK inhibitor, PD-0325901 (MEKi) alone effectively blocked ERK phosphorylation and inhibited cell growth. Our results suggest that combination of a c-Met tyrosine kinase inhibitor with a BRAF or a MEK inhibitor may be effective in treating resistant tumors that use activated BRAF to escape suppression of c-Met signaling. PMID:22745804

  14. A comparison of metabolic syndrome (MetS) risk factors in Filipino women and Filipino American women: a pilot study.

    Science.gov (United States)

    Ancheta, Irma B; Battie, Cynthia A; Tuason, Teresa; Ancheta, Christine V

    2012-01-01

    Cardiovascular disease (CVD) is a significant cause of morbidity and mortality in women of Filipino ethnicity. The objective of our work was to determine if metabolic syndrome (MetS), a modifiable CVD risk factor, differs in women as a function of country of residency and to determine if, CVD prevention strategies need to differ for these groups of Filipino women. Data were collected in community-based health screenings for this cross-sectional study. PARTICIPANTS were recruited at places of worship in southeast United States (n=60) and Central Visayas, Philippines (n=56). Prevalence of MetS and its component factors as defined by the International Diabetes Federation criteria. The prevalence of MetS in Filipino women (FW) and Filipino American women (FAW) groups was similar (52% vs 55%, P=.08) although the prevalence of elevated waist circumference was greater for FAW (78% vs 59%, P=.03). Conversely, the percentage of FW women with risk-associated high-density lipoprotein (HDL) levels was higher than the FAW group (84% vs 42%, P<.001). Other MetS component factors (blood pressure, glucose and triglycerides) did not significantly differ between groups. Similar high rates of MetS were observed in Filipino women regardless of the country of residency although the FAW tended to have higher rates of central obesity while the FW tended to have higher rates of risk-associated HDL levels. Further research should examine the cause of these differences in order to develop better cardiovascular screening and intervention strategies.

  15. Combinatie van walnoten met grasproductie en reactie : verslag van resultaten en ervaringen van de eerste jaren met 'Multifunctionele beplantingen', als bouwsteen voor meervoudig duurzaam landgebruik

    NARCIS (Netherlands)

    Oosterbaan, A.; Berg, van den C.A.; Valk, H.

    2003-01-01

    In de omgeving van Winterswijk is vanaf 1999 10 ha multifunctionele beplantingen aangelegd, hoofdzakelijk van walnoot met gras. Overhoeken zijn ingeplant met vruchtstruiken. De eerste ervaringen met aanplant, grasbeheer, bijdrage aan recreatie en dergelijke zijn in dit rapport weergegeven.

  16. MET and AKT genetic influence on facial emotion perception.

    Directory of Open Access Journals (Sweden)

    Ming-Teng Lin

    Full Text Available BACKGROUND: Facial emotion perception is a major social skill, but its molecular signal pathway remains unclear. The MET/AKT cascade affects neurodevelopment in general populations and face recognition in patients with autism. This study explores the possible role of MET/AKT cascade in facial emotion perception. METHODS: One hundred and eighty two unrelated healthy volunteers (82 men and 100 women were recruited. Four single nucleotide polymorphisms (SNP of MET (rs2237717, rs41735, rs42336, and rs1858830 and AKT rs1130233 were genotyped and tested for their effects on facial emotion perception. Facial emotion perception was assessed by the face task of Mayer-Salovey-Caruso Emotional Intelligence Test (MSCEIT. Thorough neurocognitive functions were also assessed. RESULTS: Regarding MET rs2237717, individuals with the CT genotype performed better in facial emotion perception than those with TT (p = 0.016 by ANOVA, 0.018 by general linear regression model [GLM] to control for age, gender, and education duration, and showed no difference with those with CC. Carriers with the most common MET CGA haplotype (frequency = 50.5% performed better than non-carriers of CGA in facial emotion perception (p = 0.018, df = 1, F = 5.69, p = 0.009 by GLM. In MET rs2237717/AKT rs1130233 interaction, the C carrier/G carrier group showed better facial emotion perception than those with the TT/AA genotype (p = 0.035 by ANOVA, 0.015 by GLM, even when neurocognitive functions were controlled (p = 0.046 by GLM. CONCLUSIONS: To our knowledge, this is the first study to suggest that genetic factors can affect performance of facial emotion perception. The findings indicate that MET variances and MET/AKT interaction may affect facial emotion perception, implicating that the MET/AKT cascade plays a significant role in facial emotion perception. Further replication studies are needed.

  17. Effects of prenatal ethanol exposure on central dopamine and Met-enkephalin system ontogeny

    Energy Technology Data Exchange (ETDEWEB)

    Hand, D.E.

    1987-01-01

    The effect of utero ethanol exposure on the development of central neurotransmitter systems was examined in rat offspring of dams that consumed liquid diets containing 35% ethanol derived calories either before and during pregnancy (E-P and P), or exclusively during gestation (E-Preg). Autoradiography of tritiated ligand receptor binding was used to rapidly screen neurotransmitter receptors in cholinergic, dopaminergic, serotonergic, noradrenergic, GABAergic, and opiatergic systems. The results led to a more comprehensive study of (1) the dopaminergic D-2 receptor binding using (/sup 3/H)spiroperidol, and (2) the opiatergic mu and delta receptor binding defined by (/sup 3/H)Met-enkephalin. Significant reductions in (/sup 3/H)spiroperidol binding were found in the 15 day old E-Preg caudate-putamen, which may be related to reductions in neurotransmission and increased locomotor activity. This provides a link between the hyperactivity reported in animal models and children with fetal alcohol syndrome (FAS) and its attenuation by drugs that facilitate dopaminergic transmission. Significant reductions were also seen in D-2 receptor binding in the inferior colliculus, which may be related to the functional deficits in the auditory processing of information by hyperactive children and the changes in the auditory evoked potentials of FAS children found at the level of that structure. The hyperactivity and auditory dysfunction improve with age, consistent with the trend in binding of (/sup 3/H)spiroperidol to D-2 receptors. The D-2 receptor binding in the E-P and P group was normal in nearly all brain regions which suggests that ethanol exposure begun during pregnancy may be more harmful than when initiated before pregnancy.

  18. Discovery and Pharmacokinetic and Pharmacological Properties of the Potent and Selective MET Kinase Inhibitor 1-{6-[6-(4-Fluorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-ylsulfanyl]benzothiazol-2-yl}-3-(2-morpholin-4-ylethyl)urea (SAR125844).

    Science.gov (United States)

    Ugolini, Antonio; Kenigsberg, Mireille; Rak, Alexey; Vallée, Francois; Houtmann, Jacques; Lowinski, Maryse; Capdevila, Cécile; Khider, Jean; Albert, Eva; Martinet, Nathalie; Nemecek, Conception; Grapinet, Sandrine; Bacqué, Eric; Roesner, Manfred; Delaisi, Christine; Calvet, Loreley; Bonche, Fabrice; Semiond, Dorothée; Egile, Coumaran; Goulaouic, Hélène; Schio, Laurent

    2016-08-11

    The HGF/MET pathway is frequently activated in a variety of cancer types. Several selective small molecule inhibitors of the MET kinase are currently in clinical evaluation, in particular for NSCLC, liver, and gastric cancer patients. We report herein the discovery of a series of triazolopyridazines that are selective inhibitors of wild-type (WT) MET kinase and several clinically relevant mutants. We provide insight into their mode of binding and report unprecedented crystal structures of the Y1230H variant. A multiparametric chemical optimization approach allowed the identification of compound 12 (SAR125844) as a development candidate. In this chemical series, absence of CYP3A4 inhibition was obtained at the expense of satisfactory oral absorption. Compound 12, a promising parenteral agent for the treatment of MET-dependent cancers, promoted sustained target engagement at tolerated doses in a human xenograft tumor model. Preclinical pharmacokinetics conducted in several species were predictive for the observed pharmacokinetic behavior of 12 in cancer patients.

  19. MetNet Precursor - Network Mission to Mars

    Science.gov (United States)

    Harri, Arri-Matti

    2010-05-01

    We are developing a new kind of planetary exploration mission for Mars - MetNet in situ observation network based on a new semi-hard landing vehicle called the Met-Net Lander (MNL). The first MetNet vehicle, MetNet Precursor, slated for launch in 2011. The MetNet development work started already in 2001. The actual practical Precursor Mission development work started in January 2009 with participation from various space research institutes and agencies. The scientific rationale and goals as well as key mission solutions will be discussed. The eventual scope of the MetNet Mission is to deploy some 20 MNLs on the Martian surface using inflatable descent system structures, which will be supported by observations from the orbit around Mars. Currently we are working on the MetNet Mars Precursor Mission (MMPM) to deploy one MetNet Lander to Mars in the 2011 launch window as a technology and science demonstration mission. The MNL will have a versatile science payload focused on the atmospheric science of Mars. Time-resolved in situ Martian meteorological measurements acquired by the Viking, Mars Pathfinder and Phoenix landers and remote sensing observations by the Mariner 9, Viking, Mars Global Surveyor, Mars Odyssey and the Mars Express orbiters have provided the basis for our current understanding of the behavior of weather and climate on Mars. However, the available amount of data is still scarce and a wealth of additional in situ observations are needed on varying types of Martian orography, terrain and altitude spanning all latitudes and longitudes to address microscale and mesoscale atmospheric phenomena. Detailed characterization of the Martian atmospheric circulation patterns and climatological cycles requires simultaneous in situ atmospheric observations. The scientific payload of the MetNet Mission encompasses separate instrument packages for the atmospheric entry and descent phase and for the surface operation phase. The MetNet mission concept and key probe

  20. Metáfora e transferência

    OpenAIRE

    2007-01-01

    O presente artigo tem como fito apontar em que sentido a transferência, no processo analítico, pode ser compreendida como metáfora. Utilizando o esquema gráfico construído por Searle (1995) para explicitar o processo que ocorre nas metáforas mortas, construímos uma analogia para compreender a transferência como uma metáfora morta (ainda que viva, no sentido de Lakoff e Johnson), que pode ser trazida para o plano da fala no campo analítico, ali onde o analista deve manter-se na ressonância de ...

  1. Hepatocyte Growth Factor Suppresses Transforming Growth Factor-Beta-1 and Type III Collagen in Human Primary Renal Fibroblasts

    Directory of Open Access Journals (Sweden)

    Shan Mou

    2009-11-01

    Full Text Available Tubulointerstitial changes in the diabetic kidney correlate closely with renal fibrosis, and transforming growth factor-beta-1 (TGF-β1 is thought to play a key role in this process. In contrast, hepatocyte growth factor (HGF has shown therapeutic effects on injured renal tubules in animal models. This study was undertaken to test the hypothesis that the preventive effects of HGF may result from interventions in TGF-β1-mediated signaling and collagen III secretion. We examined the expression of HGF/HGF receptor (c-Met and TGF-β1 in renal fibroblasts at multiple time points. The effects of recombinant human HGF on TGF-β1 expression were studied by RT-PCR and Western blotting, and the levels of collagen III were measured by ELISA. In the high-glucose condition, the expression of HGF and c-Met in renal fibroblasts was detected as early as 6 hours following cell culture while the level of TGF-β1 peaked at 96 hours. The addition of recombinant human HGF to the culture media dose-dependently inhibited TGF-β1 mRNA expression and reduced collagen III secretion by 34%. These results indicate that, during hyperglycemia, HGF inhibits TGF-β1 signaling and type III collagen activation in interstitial fibroblasts. Furthermore, we should recognize that changes in the balance between HGF and TGF-β1 might be decisive in the pathogenesis of chronic renal fibrosis. Therefore, administration of HGF to restore this balance may offer a novel therapeutic intervention in managing renal fibrogenesis in diabetic nephropathy.

  2. JH modulates a cellular immunity of Tribolium castaneum in a Met-independent manner.

    Science.gov (United States)

    Hepat, Rahul; Kim, Yonggyun

    2014-04-01

    Juvenile hormone (JH) regulates diverse physiological processes in insects during entire developmental stages. Especially, the identification of Methoprene-tolerant (Met), a JH nuclear receptor, allows us to better understand molecular actions of JH to control gene expressions related with metamorphosis. However, several physiological processes including cellular immune response and some molecular actions of JH have been suspected to be mediated via its non-genomic actions. To prove its non-genomic action, JH nuclear signals were suppressed by RNA interference (RNAi) of Met or its downstream gene, Krüppel homolog 1 (Kr-h1), in the red flour beetle, Tribolium castaneum. These RNAi-treated larvae failed to undergo a normal development and suffered precocious metamorphosis. Hemocytes of T. castaneum exhibited their spreading behavior on extracellular matrix and nodule formation in response to bacterial challenge. When the larvae were treated with either RNAi of Met or Kr-h1, the hemocytes of the treated larvae were responsive to JH without any significant difference with those of control larvae. These results suggest that the response of hemocytes to JH is not mediated by its nuclear signal. On the other hand, the JH modulation of hemocyte behaviors of T. castaneum was significantly influenced by membrane and cytosolic protein activities, in which ethoxyzolamide (a specific inhibitor of carbonic anhydrase), calphostin C (a specific inhibitor of protein kinase C) or ouabain (a specific inhibitor of Na(+)-K(+) ATPase) significantly suppressed the responsiveness of hemocytes to JH.

  3. Opiate receptors: an introduction.

    Science.gov (United States)

    Carmody, J J

    1987-02-01

    Current status of opiate receptors and their agonists is reviewed--basic aspects of receptor theory, the importance of stereospecificity in drug-receptor interactions and the role of 'second messengers' in drug action. The three classes of endogenous opioids, originating from three distinct genes, are discussed: pro-opiomelanocortin, giving rise to beta-endorphin, ACTH and various MSHs; pro-enkephalin, giving methionine enkephalin and leucine enkephalin; and prodynorphin; their anatomical distribution and the main classes of receptors with which they interact, the mu-receptor, with a high affinity for met-enkephalin and beta-endorphin (as well as morphine and dynorphin A); the delta-receptor for which the primary ligand is leu-enkephalin; and the kappa-receptor which is the main target for the dynorphins. Functional roles for endogenous opioids are considered. Essentially they are inhibitory to target neurones, depressing motor reflexes, baroreflexes and nociception. They also have roles in the response to physical and psychological stress.

  4. Phase II and Biomarker Study of the Dual MET/VEGFR2 Inhibitor Foretinib in Patients With Papillary Renal Cell Carcinoma

    Science.gov (United States)

    Choueiri, Toni K.; Vaishampayan, Ulka; Rosenberg, Jonathan E.; Logan, Theodore F.; Harzstark, Andrea L.; Bukowski, Ronald M.; Rini, Brian I.; Srinivas, Sandy; Stein, Mark N.; Adams, Laurel M.; Ottesen, Lone H.; Laubscher, Kevin H.; Sherman, Laurie; McDermott, David F.; Haas, Naomi B.; Flaherty, Keith T.; Ross, Robert; Eisenberg, Peter; Meltzer, Paul S.; Merino, Maria J.; Bottaro, Donald P.; Linehan, W. Marston; Srinivasan, Ramaprasad

    2013-01-01

    Purpose Foretinib is an oral multikinase inhibitor targeting MET, VEGF, RON, AXL, and TIE-2 receptors. Activating mutations or amplifications in MET have been described in patients with papillary renal cell carcinoma (PRCC). We aimed to evaluate the efficacy and safety of foretinib in patients with PRCC. Patients and Methods Patients were enrolled onto the study in two cohorts with different dosing schedules of foretinib: cohort A, 240 mg once per day on days 1 through 5 every 14 days (intermittent arm); cohort B, 80 mg daily (daily dosing arm). Patients were stratified on the basis of MET pathway activation (germline or somatic MET mutation, MET [7q31] amplification, or gain of chromosome 7). The primary end point was overall response rate (ORR). Results Overall, 74 patients were enrolled, with 37 in each dosing cohort. ORR by Response Evaluation Criteria in Solid Tumors (RECIST) 1.0 was 13.5%, median progression-free survival was 9.3 months, and median overall survival was not reached. The presence of a germline MET mutation was highly predictive of a response (five of 10 v five of 57 patients with and without germline MET mutations, respectively). The most frequent adverse events of any grade associated with foretinib were fatigue, hypertension, gastrointestinal toxicities, and nonfatal pulmonary emboli. Conclusion Foretinib demonstrated activity in patients with advanced PRCC with a manageable toxicity profile and a high response rate in patients with germline MET mutations. PMID:23213094

  5. Leren met behulp van strategieën

    NARCIS (Netherlands)

    Reijners, Pauline; Kester, Liesbeth; Wetzels, Sandra; Kirschner, Paul A.

    2012-01-01

    Reijners, P. B. G., Kester, L., Wetzels, S. A. J., & Kirschner, P. A. (2012, 9 March). Leren met behulp van strategieën. Presentation at mini conference 'The Testing Effect' from the master programme Learning Sciences, Eindhoven, The Netherlands.

  6. Skills Labs: Hoogwaardige e-practica Water Management met EMERGO

    NARCIS (Netherlands)

    Nadolski, Rob; Hummel, Hans; Slootmaker, Aad; Kurvers, Hub

    2010-01-01

    Nadolski, R. J., Hummel, H. G. K., Slootmaker, A., & Kurvers, H. (2010, 27 May). Skills Labs: Hoogwaardige e-practica Water Management met EMERGO. Presentatie tijdens de bijeenkomst: Surfen door Zeeland: e-learning delta innovaties, Vlissingen, Nederland. SURFFoundation.

  7. c-Met in pancreatic cancer stem cells: Therapeutic implications

    Institute of Scientific and Technical Information of China (English)

    Marta Herreros-Villanueva; Aizpea Zubia-Olascoaga; Luis Bujanda

    2012-01-01

    Pancreatic cancer is the deadliest solid cancer and currently the fourth most frequent cause of cancer-related deaths.Emerging evidence suggests that cancer stem cells (CSCs) play a crucial role in the development and progression of this disease.The identification of CSC markers could lead to the development of new therapeutic targets.In this study,the authors explore the functional role of c-Met in pancreatic CSCs,by analyzing self-renewal with sphere assays and tumorigenicity capacity in NOD SCID mice.They concluded that c-Met is a novel marker for identifying pancreatic CSCs and c-Methigh in a higher tumorigenic cancer cell population.Inhibition of c-Met with XL184 blocks self-renewal capacity in pancreatic CSCs.In pancreatic tumors established in NOD SCID mice,c-Met inhibition slowed tumor growth and reduced the population of CSCs,along with preventing the development of metastases.

  8. Onderzoek leert ook van praktijk : telen met toekomst

    NARCIS (Netherlands)

    Kool, de S.A.M.; Dwarswaard, A.

    2002-01-01

    Het project 'Telen met toekomst' is een leerproces van zowel de onderzoeker als de teler. In zes jaar gaan deelnemers na wat technisch en economisch mogelijk is om het gebruik van mineralen, gewasbeschermingmiddelen en energie terug te dringen

  9. Met flora meer fauna de stad in trekken

    NARCIS (Netherlands)

    Hoffman, M.H.A.

    2010-01-01

    Meer flora en fauna in de stedelijke omgeving begint met de aanplant van gevarieerd groen. Plant Publicity Holland geeft in een overzicht aan welke bomen, heesters en vaste planten daarvoor geschikt zijn.

  10. Samenwerking Wageningen UR met BayerCropScience

    NARCIS (Netherlands)

    Wijsmuller, J.

    2010-01-01

    Wageningen UR werkt in haar onderzoeksprogramma’s samen met andere kennisinstellingen. In dit artikel een nadere kennismaking meteen van deze partners: Bayer CropsScience. Bayer CropScience ontwikkelt bestrijdingsmiddelen voor de Nederlandse markt.

  11. Mars MetNet Mission - Martian Atmospheric Observational Post Network

    Science.gov (United States)

    Hari, Ari-Matti; Haukka, Harri; Aleksashkin, Sergey; Arruego, Ignacio; Schmidt, Walter; Genzer, Maria; Vazquez, Luis; Siikonen, Timo; Palin, Matti

    2017-04-01

    A new kind of planetary exploration mission for Mars is under development in collaboration between the Finnish Meteorological Institute (FMI), Lavochkin Association (LA), Space Research Institute (IKI) and Institutio Nacional de Tecnica Aerospacial (INTA). The Mars MetNet mission is based on a new semi-hard landing vehicle called MetNet Lander (MNL). The scientific payload of the Mars MetNet Precursor [1] mission is divided into three categories: Atmospheric instruments, Optical devices and Composition and structure devices. Each of the payload instruments will provide significant insights in to the Martian atmospheric behavior. The key technologies of the MetNet Lander have been qualified and the electrical qualification model (EQM) of the payload bay has been built and successfully tested. 1. MetNet Lander The MetNet landing vehicles are using an inflatable entry and descent system instead of rigid heat shields and parachutes as earlier semi-hard landing devices have used. This way the ratio of the payload mass to the overall mass is optimized. The landing impact will burrow the payload container into the Martian soil providing a more favorable thermal environment for the electronics and a suitable orientation of the telescopic boom with external sensors and the radio link antenna. It is planned to deploy several tens of MNLs on the Martian surface operating at least partly at the same time to allow meteorological network science. 2. Strawman Scientific Payload The strawman payload of the two MNL precursor models includes the following instruments: Atmospheric instruments: - MetBaro Pressure device - MetHumi Humidity device - MetTemp Temperature sensors Optical devices: - PanCam Panoramic - MetSIS Solar irradiance sensor with OWLS optical wireless system for data transfer - DS Dust sensor Composition and Structure Devices: Tri-axial magnetometer MOURA Tri-axial System Accelerometer The descent processes dynamic properties are monitored by a special 3-axis

  12. Nieuw Zorgaanbod: Gesloten jeugdzorg voor adolescenten met ernstige gedragsproblemen

    NARCIS (Netherlands)

    Nijhof, K.S.; Dam, C. van; Veerman, J.W.; Engels, R.C.M.E.; Scholte, R.H.J.

    2010-01-01

    Tot voor kort werd een toenemend aantal jongeren met ernstige gedragsproblemen in jeugdgevangenissen geplaatst. Deze jongeren, ook wel ‘civielrechtelijke’ jongeren genoemd, werden niet geplaatst vanwege veroordelingen voor criminele activiteiten, maar omdat zij beschermd dienden te worden tegen zich

  13. Genetic Nrf2 Overactivation Inhibits the Deleterious Effects Induced by Hepatocyte-Specific c-met Deletion during the Progression of NASH

    Directory of Open Access Journals (Sweden)

    Pierluigi Ramadori

    2017-01-01

    Full Text Available We have recently shown that hepatocyte-specific c-met deficiency accelerates the progression of nonalcoholic steatohepatitis in experimental murine models resulting in augmented production of reactive oxygen species and accelerated development of fibrosis. The aim of this study focuses on the elucidation of the underlying cellular mechanisms driven by Nrf2 overactivation in hepatocytes lacking c-met receptor characterized by a severe unbalance between pro-oxidant and antioxidant functions. Control mice (c-metfx/fx, single c-met knockouts (c-metΔhepa, and double c-met/Keap1 knockouts (met/Keap1Δhepa were then fed a chow or a methionine-choline-deficient (MCD diet, respectively, for 4 weeks to reproduce the features of nonalcoholic steatohepatitis. Upon MCD feeding, met/Keap1Δhepa mice displayed increased liver mass albeit decreased triglyceride accumulation. The marked increase of oxidative stress observed in c-metΔhepa was restored in the double mutants as assessed by 4-HNE immunostaining and by the expression of genes responsible for the generation of free radicals. Moreover, double knockout mice presented a reduced amount of liver-infiltrating cells and the exacerbation of fibrosis progression observed in c-metΔhepa livers was significantly inhibited in met/Keap1Δhepa. Therefore, genetic activation of the antioxidant transcription factor Nrf2 improves liver damage and repair in hepatocyte-specific c-met-deficient mice mainly through restoring a balance in the cellular redox homeostasis.

  14. Methoprene-tolerant (Met) and Krüpple-homologue 1 (Kr-h1) are required for ovariole development and egg maturation in the brown plant hopper.

    Science.gov (United States)

    Lin, Xinda; Yao, Yun; Wang, Bo

    2015-12-14

    The brown plant hopper is one of the most destructive known pests of rice. We studied the roles of the JH receptor Met and the downstream transcription factor Kr-h1 in ovariole development and egg maturation. The predicted Met protein in N. lugens (NlMet) contained 517 amino acids. qRT-PCR showed that NlMet was expressed in all tissues and that the highest expression occurred in the embryonic stage. In NlMet- or NlKr-h1-silenced female adults, ovarian development varied significantly, whereas the numbers of ovarioles were less variable in those injected with dsRNA targeting NlMet, NlKrh-1 or both NlMet and NlKr-h1. In females injected with dsNlKr-h1 or with dsNlMet in combination with dsNlKr-h1 dsRNA, the preoviposition period was prolonged, whereas the females injected with NlMet dsRNA showed no significant changes. Moreover, we found no differences in the length of the preoviposition period between macropterous and brachypterous females. The disruption of Nlmet or NlKr-h1 or the dual knockdown of NlMet and NlKr-h1 significantly reduced the number of eggs laid. Moreover, significant differences were also found between the macropterous and the brachypterous brown plant hoppers. These results indicated that Met and Kr-h1 are required for ovariole development and egg maturation in the brown plant hopper.

  15. MMPM - Mission implementation of Mars MetNet Precursor

    Science.gov (United States)

    Harri, A.-M.

    2009-04-01

    We are developing a new kind of planetary exploration mission for Mars - MetNet in situ observation network based on a new semi-hard landing vehicle called the Met-Net Lander (MNL). The key technical aspects and solutions of the mission will be discussed. The eventual scope of the MetNet Mission is to deploy some 20 MNLs on the Martian surface using inflatable descent system structures, which will be supported by observations from the orbit around Mars. Currently we are working on the MetNet Mars Precursor Mission (MMPM) to deploy one MetNet Lander to Mars in the 2009/2011 launch window as a technology and science demonstration mission. The MNL will have a versatile science payload focused on the atmospheric science of Mars. Detailed characterization of the Martian atmospheric circulation patterns, boundary layer phenomena, and climatology cycles, require simultaneous in-situ measurements by a network of observation posts on the Martian surface. The scientific payload of the MetNet Mission encompasses separate instrument packages for the atmospheric entry and descent phase and for the surface operation phase. The MetNet mission concept and key probe technologies have been developed and the critical subsystems have been qualified to meet the Martian environmental and functional conditions. This development effort has been fulfilled in collaboration between the Finnish Meteorological Institute (FMI), the Russian Lavoschkin Association (LA) and the Russian Space Research Institute (IKI) since August 2001. Currently the INTA (Instituto Nacional de Técnica Aeroespacial) from Spain is also participating in the MetNet payload development.

  16. Metsänomistajien suhtautuminen suometsien hoidon kokonaispalveluun Pirkanmaan alueella

    OpenAIRE

    Viitanen, Matti

    2012-01-01

    Metsäojituksia on Suomen maaperällä tehty jo toistasataa vuotta. Tänä aikana uudisojittamisesta on siirrytty jo ojitettujen suometsien kunnostuksiin. Vaikka monille metsistään huolehtiminen on sydämen asia, toisaalla hakkuukypsiä metsiköitä lahoaa hiljalleen luonnontilaiseksi ennallistuviin suometsiin. Kunnostamattomien tai mahdollisesti vuosikymmeniä sitten edellisen kerran käsiteltyjen ojitusalueiden kartoittaminen ja kunnostaminen tarjoavat metsänomistajalle hyvän tilaisuuden reali...

  17. Erythropoietin, ferritin, haptoglobin, hemoglobin and transferrin receptor in metabolic syndrome: a case control study

    Directory of Open Access Journals (Sweden)

    Hämäläinen Päivi

    2012-09-01

    Full Text Available Abstract Background Increased ferritin concentrations are associated with metabolic syndrome (MetS. The association between ferritin as well as hemoglobin level and individual MetS components is unclear. Erythropoietin levels in subjects with MetS have not been determined previously. The aim of this study was to compare serum erythropoietin, ferritin, haptoglobin, hemoglobin, and transferrin receptor (sTFR levels between subjects with and without MetS and subjects with individual MetS components. Methods A population based cross-sectional study of 766 Caucasian, middle-aged subjects (341 men and 425 women from five age groups born in Pieksämäki, Finland who were invited to a health check-up in 2004 with no exclusion criteria. Laboratory analyzes of blood samples collected in 2004 were done during year 2010. MetS was defined by National Cholesterol Education Program criteria. Results 159 (53% men and 170 (40% women of study population met MetS criteria. Hemoglobin and ferritin levels as well as erythropoietin and haptoglobin levels were higher in subjects with MetS (p  Conclusion Subjects with MetS have elevated hemoglobin, ferritin, erythropoietin and haptoglobin concentrations. Higher hemoglobin levels are related to all components of MetS. Higher ferritin levels associate with TG, abdominal obesity, elevated glucose or low high density cholesterol. Haptoglobin levels associate with blood pressure or elevated glucose. However, erythropoietin levels are related only with abdominal obesity. Higher serum erythropoietin concentrations may suggest underlying adipose tissue hypoxemia in MetS.

  18. Daytime sleepiness and the COMT val158met polymorphism in patients with Parkinson disease.

    Science.gov (United States)

    Rissling, Ida; Frauscher, Birgit; Kronenberg, Florian; Tafti, Mehdi; Stiasny-Kolster, Karin; Robyr, Anne-Catherine; Körner, Yvonne; Oertel, Wolfgang Hermann; Poewe, Werner; Högl, Birgit; Möller, Jens Carsten

    2006-01-01

    A preliminary study by our group suggested an association between daytime sleepiness and the catechol-O-methyltransferase (COMT) val158met polymorphism (rs4680) in patients with Parkinson disease (PD). We sought to confirm this association in a large group of patients with PD. Genetic association study in patients with PD. Movement disorder sections at 2 university hospitals. PD patients with and without episodes of suddenly falling asleep matched for antiparkinsonian medication, disease duration, sex, and age, who participated in a previous genetic study on dopamine-receptor polymorphisms. Not applicable. In this study, 240 patients with PD (154 men; age 65.1 +/- 6.1 years; disease duration 9.4 +/- 6.0 years) were included. Seventy had the met-met (LL), 116 the met-val (LH), and 54 the val-val (HH) genotype. In the combined LL+LH group (featuring reduced COMT activity), the mean Epworth Sleepiness Scale (ESS) score was 9.0 +/- 5.9 versus 11.0 +/- 6.1 in the HH (high COMT activity) group (P = .047). Forty-seven percent of the LL and LH patients had sudden sleep onset compared with 61% of the HH patients (P = .07). Logistic regression, however, showed that both pathologic ESS scores (i.e., > 10) and sudden sleep onset were predicted by subjective disease severity (P < .001 each) but not by the COMT genotype. Our previous finding that the L-allele may be associated with daytime sleepiness could not be confirmed in the present study. Altogether, our data do not support a clinically relevant effect of the COMT genotype on daytime sleepiness in PD.

  19. Mars MetNet Mission - Martian Atmospheric Observational Post Network

    Science.gov (United States)

    Harri, Ari-Matti; Aleksashkin, Sergey; Arruego, Ignacio; Schmidt, Walter; Ponomarenko, Andrey; Apestigue, Victor; Genzer, Maria; Vazquez, Luis; Uspensky, Mikhail; Haukka, Harri

    2016-04-01

    A new kind of planetary exploration mission for Mars is under development in collaboration between the Finnish Meteorological Institute (FMI), Lavochkin Association (LA), Space Research Institute (IKI) and Institutio Nacional de Tecnica Aerospacial (INTA). The Mars MetNet mission is based on a new semi-hard landing vehicle called MetNet Lander (MNL). The scientific payload of the Mars MetNet Precursor [1] mission is divided into three categories: Atmospheric instruments, Optical devices and Composition and structure devices. Each of the payload instruments will provide significant insights in to the Martian atmospheric behavior. The key technologies of the MetNet Lander have been qualified and the electrical qualification model (EQM) of the payload bay has been built and successfully tested. MetNet Lander The MetNet landing vehicles are using an inflatable entry and descent system instead of rigid heat shields and parachutes as earlier semi-hard landing devices have used. This way the ratio of the payload mass to the overall mass is optimized. The landing impact will burrow the payload container into the Martian soil providing a more favorable thermal environment for the electronics and a suitable orientation of the telescopic boom with external sensors and the radio link antenna. It is planned to deploy several tens of MNLs on the Martian surface operating at least partly at the same time to allow meteorological network science. Strawman Scientific Payload The strawman payload of the two MNL precursor models includes the following instruments: Atmospheric instruments: • MetBaro Pressure device • MetHumi Humidity device • MetTemp Temperature sensors Optical devices: • PanCam Panoramic • MetSIS Solar irradiance sensor with OWLS optical wireless system for data transfer • DS Dust sensor Composition and Structure Devices: • Tri-axial magnetometer MOURA • Tri-axial System Accelerometer The descent processes dynamic properties are monitored by a special

  20. Intersectorale samenwerking in de biologische landbouw : mengvoergrondstoffen met binnen- of buitenlandse oorsprong: effect op energieverbruik met mengvoerproductie

    NARCIS (Netherlands)

    Bos, J.F.F.P.

    2006-01-01

    Plant Research International (PRI) gaat in het rapport 'Mengvoergrondstoffen met binnen- of buitenlandse oorsprong: effect op energieverbruik van mengvoerproductie' in op het energieverbruik van de productie van enkele mengvoeders voor biologisch gehouden vleesvarkens. De onderzochte mengvoeders ver

  1. Greguerías - da metáfora literária à metáfora visual

    OpenAIRE

    Amador, Constança Araújo

    2014-01-01

    A presente investigação visa a passagem da metáfora literária para a metáfora visual, através do resultado de um trabalho de ilustração, tendo como ponto de partida, as Greguerías de Ramón Gómez de la Serna (1888 - 1963). Reflectindo sobre a interpretação da metáfora, o objectivo passa por criar uma nova selecção de Greguerías ilustradas que também estabeleçam novas metáforas visuais, a partir da sua interacção com a palavra. Mas uma vez independentes, cada ilustração ou cada conjunto d...

  2. c-Met Expression Is a Marker of Poor Prognosis in Patients With Locally Advanced Head and Neck Squamous Cell Carcinoma Treated With Chemoradiation

    Energy Technology Data Exchange (ETDEWEB)

    Baschnagel, Andrew M. [Department of Radiation Oncology, William Beaumont Hospital, Royal Oak, Michigan (United States); Williams, Lindsay [Department of Pathology, William Beaumont Hospital, Royal Oak, Michigan (United States); Hanna, Alaa; Chen, Peter Y.; Krauss, Daniel J. [Department of Radiation Oncology, William Beaumont Hospital, Royal Oak, Michigan (United States); Pruetz, Barbara L. [Beaumont BioBank, William Beaumont Hospital, Royal Oak, Michigan (United States); Akervall, Jan [Beaumont BioBank, William Beaumont Hospital, Royal Oak, Michigan (United States); Department of Otolaryngology, William Beaumont Hospital, Royal Oak, Michigan (United States); Wilson, George D., E-mail: George.Wilson@Beaumont.edu [Department of Radiation Oncology, William Beaumont Hospital, Royal Oak, Michigan (United States); Beaumont BioBank, William Beaumont Hospital, Royal Oak, Michigan (United States)

    2014-03-01

    Purpose: To examine the prognostic significance of c-Met expression in relation to p16 and epidermal growth factor receptor (EGFR) in patients with locally advanced head and neck squamous cell carcinoma (HNSCC) treated with definitive concurrent chemoradiation. Methods and Materials: Archival tissue from 107 HNSCC patients treated with chemoradiation was retrieved, and a tissue microarray was assembled. Immunohistochemical staining of c-Met, p16, and EGFR was performed. c-Met expression was correlated with p16, EGFR, clinical characteristics, and clinical endpoints including locoregional control (LRC), distant metastasis (DM), disease-free survival (DFS), and overall survival (OS). Results: Fifty-one percent of patients were positive for p16, and 53% were positive for EGFR. Both p16-negative (P≤.001) and EGFR-positive (P=.019) status predicted for worse DFS. Ninety-three percent of patients stained positive for c-Met. Patients were divided into low (0, 1, or 2+ intensity) or high (3+ intensity) c-Met expression. On univariate analysis, high c-Met expression predicted for worse LRC (hazard ratio [HR] 2.27; 95% CI, 1.08-4.77; P=.031), DM (HR 4.41; 95% CI, 1.56-12.45; P=.005), DFS (HR 3.00; 95% CI, 1.68-5.38; P<.001), and OS (HR 4.35; 95% CI, 2.13-8.88; P<.001). On multivariate analysis, after adjustment for site, T stage, smoking history, and EGFR status, only high c-Met expression (P=.011) and negative p16 status (P=.003) predicted for worse DFS. High c-Met expression was predictive of worse DFS in both EGFR-positive (P=.032) and -negative (P=.008) patients. In the p16-negative patients, those with high c-Met expression had worse DFS (P=.036) than did those with low c-Met expression. c-Met expression was not associated with any outcome in the p16-positive patients. Conclusions: c-Met is expressed in the majority of locally advanced HNSCC cases, and high c-Met expression predicts for worse clinical outcomes. High c-Met expression predicted for worse DFS in p16

  3. Mars MetNet Mission - Martian Atmospheric Observational Post Network

    Science.gov (United States)

    Haukka, Harri; Harri, Ari-Matti; Aleksashkin, Sergey; Arruego, Ignacio; Schmidt, Walter; Genzer, Maria; Vazquez, Luis; Siikonen, Timo; Palin, Matti

    2016-10-01

    A new kind of planetary exploration mission for Mars is under development in collaboration between the Finnish Meteorological Institute (FMI), Lavochkin Association (LA), Space Research Institute (IKI) and Institutio Nacional de Tecnica Aerospacial (INTA). The Mars MetNet mission is based on a new semi-hard landing vehicle called MetNet Lander (MNL).The scientific payload of the Mars MetNet Precursor mission is divided into three categories: Atmospheric instruments, Optical devices and Composition and structure devices. Each of the payload instruments will provide significant insights in to the Martian atmospheric behavior.The key technologies of the MetNet Lander have been qualified and the electrical qualification model (EQM) of the payload bay has been built and successfully tested.Full Qualification Model (QM) of the MetNet landing unit with the Precursor Mission payload is currently under functional tests. In the near future the QM unit will be exposed to environmental tests with qualification levels including vibrations, thermal balance, thermal cycling and mechanical impact shock. One complete flight unit of the entry, descent and landing systems (EDLS) has been manufactured and tested with acceptance levels. Another flight-like EDLS has been exposed to most of the qualification tests, and hence it may be used for flight after refurbishments. Accordingly two flight-capable EDLS systems exist. The eventual goal is to create a network of atmospheric observational posts around the Martian surface. The next step in the MetNet Precursor Mission is the demonstration of the technical robustness and scientific capabilities of the MetNet type of landing vehicle. Definition of the Precursor Mission and discussions on launch opportunities are currently under way. The baseline program development funding exists for the next five years. Flight unit manufacture of the payload bay takes about 18 months, and it will be commenced after the Precursor Mission has been defined.

  4. Sequential EMT-MET induces neuronal conversion through Sox2.

    Science.gov (United States)

    He, Songwei; Chen, Jinlong; Zhang, Yixin; Zhang, Mengdan; Yang, Xiao; Li, Yuan; Sun, Hao; Lin, Lilong; Fan, Ke; Liang, Lining; Feng, Chengqian; Wang, Fuhui; Zhang, Xiao; Guo, Yiping; Pei, Duanqing; Zheng, Hui

    2017-01-01

    Direct neuronal conversion can be achieved with combinations of small-molecule compounds and growth factors. Here, by studying the first or induction phase of the neuronal conversion induced by defined 5C medium, we show that the Sox2-mediated switch from early epithelial-mesenchymal transition (EMT) to late mesenchymal-epithelial transition (MET) within a high proliferation context is essential and sufficient for the conversion from mouse embryonic fibroblasts (MEFs) to TuJ(+) cells. At the early stage, insulin and basic fibroblast growth factor (bFGF)-induced cell proliferation, early EMT, the up-regulation of Stat3 and Sox2, and the subsequent activation of neuron projection. Up-regulated Sox2 then induced MET and directed cells towards a neuronal fate at the late stage. Inhibiting either stage of this sequential EMT-MET impaired the conversion. In addition, Sox2 could replace sequential EMT-MET to induce a similar conversion within a high proliferation context, and its functions were confirmed with other neuronal conversion protocols and MEFs reprogramming. Therefore, the critical roles of the sequential EMT-MET were implicated in direct cell fate conversion in addition to reprogramming, embryonic development and cancer progression.

  5. 外源性HGF基因转染对肺动脉高压兔肺血流灌注及肺动脉压力的影响%Effect of exogenous HGF gene transfection on pulmonary perfusion and pressure in pulmonary artery hypertension in rabbits

    Institute of Scientific and Technical Information of China (English)

    王伟; 张芳; 谢悦; 张宜乾; 吴树明

    2011-01-01

    AIM: To investigate the feasibility of exogenous hepatocyte growth factor (HGF) gene transfection to promote pulmonary collateral angiogenesis, improve pulmonary perfusion and reduce pulmonary artery pressure in the rabbit model of pulmonary artery hypertension (PAH). METHODS: The model rabbits of PAH were randomly divided into control group, empty vector group and HGF gene transfection group. The rabbits in HGF gene transfection group were transfected with Ad - HGF via intratracheal instillation. Pulmonary hemodynamic indicators were monitored in the 4th week after HGF gene transfection. Density of pulmonary vessels was examined with double - labeling immunofluorescence (endo-thelial cells were labeled with anti - FVK and vascular smooth muscle cells were marked with anti - a - SMA). Double - labeling immunofluorescence of FTTC - lectin and anti - a - SMA was also performed to evaluate the pulmonary blood perfusion. RESULTS: Four weeks after transfection, the density of pulmonary arterioles of the rabbits in HGF gene transfection group was higher than that in control group and empty vector group ( P < 0.05 ) , which was confirmed by double - labeling immunofluorescence. Pulmonary blood perfusion in HGF group was significantly increased compared with that in the other two groups, in which pulmonary arterial stenosis and occlusion were observed. The mean pulmonary artery pressure in HGF transfection group was much lower than that in control group and empty vector group (P <0.05). CONCLUSION: Four weeks after intratracheal adenoviral - mediated HGF gene transfection, pulmonary collateral vessels and pulmonary perfusion increase, and the pulmonary artery pressure is effectively reduced.%目的:探讨外源性肝细胞生长因子(HGF)基因转染高动力性肺动脉高压家兔后促进侧支肺血管生成、改善肺血流灌注、降低肺动脉压力的可行性.方法:将肺动脉高压兔随机分为对照组、空病毒组和HGF基因转染组;HGF基因转染

  6. Targeted MET Inhibition in Castration-Resistant Prostate Cancer: A Randomized Phase II Study and Biomarker Analysis with Rilotumumab plus Mitoxantrone and Prednisone

    NARCIS (Netherlands)

    Ryan, C.J.; Rosenthal, M.; Ng, S.; Alumkal, J.; Picus, J.; Gravis, G.; Fizazi, K.; Forget, F.; Machiels, J.P.; Srinivas, S.; Zhu, M.; Tang, R.; Oliner, K.S.; Jiang, Y.; Loh, E.; Dubey, S.; Gerritsen, W.R.

    2013-01-01

    PURPOSE: To evaluate the efficacy, safety, biomarkers, and pharmacokinetics of rilotumumab, a fully human, monoclonal antibody against hepatocyte growth factor (HGF)/scatter factor, combined with mitoxantrone and prednisone (MP) in patients with castration-resistant prostate cancer (CRPC).

  7. An Improved Image Segmentation Algorithm Based on MET Method

    Directory of Open Access Journals (Sweden)

    Z. A. Abo-Eleneen

    2012-09-01

    Full Text Available Image segmentation is a basic component of many computer vision systems and pattern recognition. Thresholding is a simple but effective method to separate objects from the background. A commonly used method, Kittler and Illingworth's minimum error thresholding (MET, improves the image segmentation effect obviously. Its simpler and easier to implement. However, it fails in the presence of skew and heavy-tailed class-conditional distributions or if the histogram is unimodal or close to unimodal. The Fisher information (FI measure is an important concept in statistical estimation theory and information theory. Employing the FI measure, an improved threshold image segmentation algorithm FI-based extension of MET is developed. Comparing with the MET method, the improved method in general can achieve more robust performance when the data for either class is skew and heavy-tailed.

  8. Making The Most Of MET: Mass Reconstruction From Collimated Decays

    CERN Document Server

    Spannowsky, Michael

    2013-01-01

    At hadron colliders invisible particles $\\chi$ can be inferred only through observation of the transverse component of the vectorial sum of their momenta -- missing $E_T$ or MET -- preventing reconstruction of the masses of their mother particles. Here we outline situations where prior prejudice about the event kinematics allows one to make the most of MET by decomposing it into its expected sum of transverse contributions, each of which may be promoted to a full four-momentum approximating the associated $\\chi$. Such prejudice arises when all $\\chi$ in the event are expected to be light and (anti-)parallel to a visible object, due to spin-correlations, back-to-back decays or boosted decays. We focus on the last of these, with boosted semi-invisibly decaying neutralinos widely motivated in supersymmetry (in the presence of light gravitinos, singlinos, photini or pseudo-goldstini), and demonstrate our simple method's ability to reconstruct sharp mass peaks from the MET decomposition.

  9. Metáforas rígidas

    Directory of Open Access Journals (Sweden)

    González-Marín, Carmen

    1997-04-01

    Full Text Available No disponible.Las metáforas del tipo «Julieta es el sol» se interpretan normalmente como enunciados predicativos, y en consecuencia, como usos defectivos del lenguaje. Como tratamiento alternativo, analizamos el citado tipo de metáforas como enunciados que instauran una identidad entre dos objetos y no como enunciados que predican una semejanza o una defectiva pertenencia de un objeto a una clase dada. Las metáforas que responden a un esquema «a es (un b» son consideradas como parte de un enunciado que da cuenta de un estado intencional, o en otras palabras, como el alcance de un operador epistémico M, con la fuerza ilocucionaria de una declaración. Un trasfondo platónico justifica nuestra propuesta.

  10. EMT and MET as paradigms for cell fate switching

    Institute of Scientific and Technical Information of China (English)

    Jiekai Chen; Qingkai Han; Duanqing Pei

    2012-01-01

    Cell fate determination is a major unsolved problem in cell and developmental biology,The discovery of reprogramming by pluripotent factors offers a rational system to investigate the molecular mechanisms associated with cell fate decisions.The idea that reprogramming of fibroblasts starts with a mesenchymal-epithelial transition (MET) suggests that the process is perhaps a reversal of epithelial to mesenchymal transition (EMT) found frequently during early embryogenesis,As such,we believe that investigations into MET-EMT may yield detailed molecular insights into cell fate decisions,not only for the switching between epithelial and mesenchymal cells,but also other cell types.

  11. Transcriptional activation of the Axl and PDGFR-α by c-Met through a ras- and Src-independent mechanism in human bladder cancer

    Directory of Open Access Journals (Sweden)

    Tseng Vincent S

    2011-04-01

    Full Text Available Abstract Background A cross-talk between different receptor tyrosine kinases (RTKs plays an important role in the pathogenesis of human cancers. Methods Both NIH-Met5 and T24-Met3 cell lines harboring an inducible human c-Met gene were established. C-Met-related RTKs were screened by RTK microarray analysis. The cross-talk of RTKs was demonstrated by Western blotting and confirmed by small interfering RNA (siRNA silencing, followed by elucidation of the underlying mechanism. The impact of this cross-talk on biological function was demonstrated by Trans-well migration assay. Finally, the potential clinical importance was examined in a cohort of 65 cases of locally advanced and metastatic bladder cancer patients. Results A positive association of Axl or platelet-derived growth factor receptor-alpha (PDGFR-α with c-Met expression was demonstrated at translational level, and confirmed by specific siRNA knock-down. The transactivation of c-Met on Axl or PDGFR-α in vitro was through a ras- and Src-independent activation of mitogen-activated protein kinase/extracellular signal-regulated kinase (MEK/ERK pathway. In human bladder cancer, co-expression of these RTKs was associated with poor patient survival (p p Conclusions In addition to c-Met, the cross-talk with Axl and/or PDGFR-α also contributes to the progression of human bladder cancer. Evaluation of Axl and PDGFR-α expression status may identify a subset of c-Met-positive bladder cancer patients who may require co-targeting therapy.

  12. Affect-modulated startle: interactive influence of catechol-O-methyltransferase Val158Met genotype and childhood trauma.

    Science.gov (United States)

    Klauke, Benedikt; Winter, Bernward; Gajewska, Agnes; Zwanzger, Peter; Reif, Andreas; Herrmann, Martin J; Dlugos, Andrea; Warrings, Bodo; Jacob, Christian; Mühlberger, Andreas; Arolt, Volker; Pauli, Paul; Deckert, Jürgen; Domschke, Katharina

    2012-01-01

    The etiology of emotion-related disorders such as anxiety or affective disorders is considered to be complex with an interaction of biological and environmental factors. Particular evidence has accumulated for alterations in the dopaminergic and noradrenergic system--partly conferred by catechol-O-methyltransferase (COMT) gene variation--for the adenosinergic system as well as for early life trauma to constitute risk factors for those conditions. Applying a multi-level approach, in a sample of 95 healthy adults, we investigated effects of the functional COMT Val158Met polymorphism, caffeine as an adenosine A2A receptor antagonist (300 mg in a placebo-controlled intervention design) and childhood maltreatment (CTQ) as well as their interaction on the affect-modulated startle response as a neurobiologically founded defensive reflex potentially related to fear- and distress-related disorders. COMT val/val genotype significantly increased startle magnitude in response to unpleasant stimuli, while met/met homozygotes showed a blunted startle response to aversive pictures. Furthermore, significant gene-environment interaction of COMT Val158Met genotype with CTQ was discerned with more maltreatment being associated with higher startle potentiation in val/val subjects but not in met carriers. No main effect of or interaction effects with caffeine were observed. Results indicate a main as well as a GxE effect of the COMT Val158Met variant and childhood maltreatment on the affect-modulated startle reflex, supporting a complex pathogenetic model of the affect-modulated startle reflex as a basic neurobiological defensive reflex potentially related to anxiety and affective disorders.

  13. Affect-modulated startle: interactive influence of catechol-O-methyltransferase Val158Met genotype and childhood trauma.

    Directory of Open Access Journals (Sweden)

    Benedikt Klauke

    Full Text Available The etiology of emotion-related disorders such as anxiety or affective disorders is considered to be complex with an interaction of biological and environmental factors. Particular evidence has accumulated for alterations in the dopaminergic and noradrenergic system--partly conferred by catechol-O-methyltransferase (COMT gene variation--for the adenosinergic system as well as for early life trauma to constitute risk factors for those conditions. Applying a multi-level approach, in a sample of 95 healthy adults, we investigated effects of the functional COMT Val158Met polymorphism, caffeine as an adenosine A2A receptor antagonist (300 mg in a placebo-controlled intervention design and childhood maltreatment (CTQ as well as their interaction on the affect-modulated startle response as a neurobiologically founded defensive reflex potentially related to fear- and distress-related disorders. COMT val/val genotype significantly increased startle magnitude in response to unpleasant stimuli, while met/met homozygotes showed a blunted startle response to aversive pictures. Furthermore, significant gene-environment interaction of COMT Val158Met genotype with CTQ was discerned with more maltreatment being associated with higher startle potentiation in val/val subjects but not in met carriers. No main effect of or interaction effects with caffeine were observed. Results indicate a main as well as a GxE effect of the COMT Val158Met variant and childhood maltreatment on the affect-modulated startle reflex, supporting a complex pathogenetic model of the affect-modulated startle reflex as a basic neurobiological defensive reflex potentially related to anxiety and affective disorders.

  14. Metingen aan varkenskarkassen met classificatie-apparatuur in combinatie met lichtreflectie-metingen met de fibre optic probe = Measurements on swine carcases with carcase grading equipment together with the fibre optic probe

    NARCIS (Netherlands)

    Wal, van der P.G.; Nijeboer, H.

    1985-01-01

    Het voorkomen van de afwijkende vleeskwaliteit PSE (pale, soft, exudative = bleek, losvezelig, nat) kan met een lichtreflectiemeter aangetoond worden. Met apparatuur voor de classificatie van varkenskarkassen zijn deze metingen ook mogelijk. In dit onderzoek is de bruikbaarheid van dergelijke meters

  15. Las metáforas de comunicación como metáforas que cobran realidad

    OpenAIRE

    Meunier, Jean Pierrer; Université catholique de Louvain

    1997-01-01

    En el paisaje teórico relativo a la comunicación, la noción de metáfora parece manifestarse y producir efectos en todas las dimensiones de la comunicación que sucesivamente se dan en el campo de la investigación: la significación, la relación, la cognición. La metáfora se presenta a la vez como un concepto iluminador y un concepto apra iluminar, como un concepto capaz de esclarecer toda clase de relaciones concretas de comunicación.

  16. Residues Met76 and Gln79 in HLA-G α1 domain involved in KIR2DL4 recognition

    Institute of Scientific and Technical Information of China (English)

    Wei Hua YAN; Li An FAN

    2005-01-01

    Human leukocyte antigen-G (HLA-G) has long been speculated as a beneficial factor for a successful pregnancy for its restricted expression on fetal-maternal extravillous cytotrophoblasts and its capability of modulating uterine natural killer cell (uNK) function such as cytotoxicity and cytokine production through NK cell receptors. HLA class I α1domain is an important killer cell Ig-like receptor (KIR) recognition site and the Met76 and Gln79 are unique to HLA-G in this region. NK cell receptor KIR2DL4 is a specific receptor for HLA-G, yet the recognition site on HLA-G remains unknown. In this study, retroviral transduction was applied to express the wild type HLA-G (HLA-wtG), mutant HLA-G (HLA-mG) on the chronic myelogenous leukemia cell line K562 cells and KIR2DL4 molecule on NK-92 cells,respectively. KIR2DL4-IgG Fc fusion protein was generated to determine the binding specificity between KIR2DL4and HLA-G. Our results showed that residue Met76, Gln79 mutated to Ala76,79 in the α1 domain of HLA-G protein could affect the binding affinity between KIR2DL4 and HLA-G, meanwhile, the KIR2DL4 transfected NK-92 cells (NK-92-2DL4) showed a considerably different cytolysis ability against the HLA-wtG and HLA-mG transfected K562 targets.Taken together, our data indicated that residue Met76 and Gln79 in HLA-G α1 domain plays a critical role in the recognition of KIR2DL4, which could be an explanation for the isoforms of HLA-G, all containing the α1 domain, with the potential to regulate NK functions.

  17. Automatisering bij de vervaardiging van montageplaten met gedrukte bedrading

    NARCIS (Netherlands)

    Leenhouts, A.J.

    1966-01-01

    MontagepIaten met gedrukte bedrading voor het monteren van geïntegreerde schakelingen bevatten in het algemeen een gecompliceerd geleiderpatroon. Bij de vervaardiging van dergelijke montagepIaten wordt veelal gebruik gemaakt van een fotografisch negatief. Het maken van het negatief is tamelijk tijdr

  18. Huisartsen motiveren om samen te werken met bedrijfsartsen

    NARCIS (Netherlands)

    Heuvel, F.M.M. van den; Buijs, P.C.; Putten, D.J. van

    2003-01-01

    De stuurgroep van het ZonMw-Deskundigheidsbevorderingsproject ‘Leren samenwerken bij Sociaal Medische Begeleiding’ heeft TNO Arbeid gevraagd om een beknopt, kwalitatief onderzoek uit te voeren naar wat huisartsen kan motiveren om aandacht te besteden aan samenwerking met bedrijfsartsen. In dit kader

  19. Vice President He Minghong Met with NSF Inspector General

    Institute of Scientific and Technical Information of China (English)

    Liu Xiuping

    2008-01-01

    @@ NSFC Vice President,Prof.He Minghong met with Dr.Tina Boesz,Inspector General of the US National Science Foundation on 29 October,2008.In-depth discussions were carried out on new progresses in both organizations on financial auditing and countermeasures on scientific misconducts.

  20. Vice President Shen Yan Met with CSIR Director General

    Institute of Scientific and Technical Information of China (English)

    Lei Rong

    2008-01-01

    @@ On November 11,2008,Professor Shen Yan,Vice President of NSFC met with a CSIR delegation headed by its Director General,Professor S K Brahmachari,who came to China to participate in "Academic,Research institution & National Innovation systems symposium".They discussed issues of cooperation between two organizations.

  1. Scoren met interim-management : De weg naar tevreden opdrachtgevers

    NARCIS (Netherlands)

    Schaveling, J.

    2010-01-01

    Tegenwoordig kijkt niemand in organisaties meer op van de aanwezigheid van interim-managers. Interim-management biedt dé flexibiliteit om het management van organisaties aan te vullen. Maar wat maakt interim-managementopdrachten succesvol? Daarover gaat 'Scoren met interim-management: de weg naar te

  2. Gazons duurder dan borders met rozen of vaste planten?

    NARCIS (Netherlands)

    Hop, M.E.C.M.

    2013-01-01

    In de eerste uitgave van Vitale Stad stond een artikel over gazons die duurder zouden zijn dan borders met vaste planten of sierheesters. Volgens dit artikel zouden vaste planten dus goedkoper zijn dan gazons. Als wij die vraag stellen aan de gemiddelde groenbeheerder, krijgt je een compleet ander a

  3. Kostenberekening van een uitbraak met Afrikaanse paardenpest in Nederland

    OpenAIRE

    Mourits, M.C.M.; Saatkamp, H.W.

    2010-01-01

    Met de introductie in 2006 van Blauwtong in Nederland is het bewustzijn betreffende het voorkomen van vectorgebonden ziekten toegenomen. Een bedreigende vectorziekte die vooral paarden en pony’s treft, is Afrikaanse Paardenpest (APP). De mortaliteit bij APP is hoog. Gezien de plaats die het paard in de Nederlandse maatschappij inneemt, zal een uitbraak van een dergelijke bedreigende ziekte een grote maatschappelijke impact hebben.

  4. Imidacloprid of niet? (interview met Sjef van der Steen)

    NARCIS (Netherlands)

    Kleis, R.; Steen, van der J.J.M.

    2014-01-01

    Is bijensterfte het werk van neonicotinoïden? Ja, zeggen en denken velen. Volgens hen zijn de neo’s rechtstreeks verantwoordelijk voor de hoge sterfte onder bijen. Nee, toont Wagenings onderzoek aan. Intussen lijkt het met de sterfte voorzichtig de goede kant op te gaan.

  5. Efficiënte softwaretraining met taakgerichte e-learning

    NARCIS (Netherlands)

    Wopereis, Iwan; Van der Baaren, John

    2013-01-01

    Wopereis, I., & Van der Baaren, J. (2013, May). Efficiënte softwaretraining met taakgerichte e-learning [Efficient software training with task-based e-learning]. Presentation at the Onderwijs Research Dagen [Educational Research Days], Brussels, Belgium. Please see also:

  6. Efficiënte softwaretraining met taakgerichte e-learning

    NARCIS (Netherlands)

    Wopereis, Iwan; Van der Baaren, John

    2013-01-01

    Wopereis, I., & Van der Baaren, J. (2013, May). Efficiënte softwaretraining met taakgerichte e-learning [Efficient software training with task-based e-learning]. Paper presented at the Onderwijs Research Dagen [Educational Research Days], Brussels, Belgium. Please see also:

  7. State of the art met betrekking tot het intellectueel eigendomsrecht

    NARCIS (Netherlands)

    Mossink, Wilma

    2005-01-01

    Mossink, W. (2004). State of the art met betrekking tot het intellectueel eigendomsrecht. In: Van Geloven, M., Koper, R. & Van der Veen, J., E-learning trends (pp. 13-15). Utrecht, Stichting Digitale Universiteit.
    Ook beschikbaar in dspace: http://hdl.hand

  8. Beoordeling gezondheidsrisico's door sporten op kunstgrasvelden met rubbergranulaat

    NARCIS (Netherlands)

    Oomen AG; de Groot GM; CPV; M&V

    2016-01-01

    Uit nieuw onderzoek van het RIVM blijkt dat het risico voor de gezondheid van sporten op kunstgrasvelden die zijn ingestrooid met rubbergranulaat, praktisch verwaarloosbaar is. Dat betekent dat het verantwoord is om op deze velden te sporten. Aanleiding voor het onderzoek is de maatschappelijke

  9. Huisartsen motiveren om samen te werken met bedrijfsartsen

    NARCIS (Netherlands)

    Heuvel, F.M.M. van den; Buijs, P.C.; Putten, D.J. van

    2003-01-01

    De stuurgroep van het ZonMw-Deskundigheidsbevorderingsproject ‘Leren samenwerken bij Sociaal Medische Begeleiding’ heeft TNO Arbeid gevraagd om een beknopt, kwalitatief onderzoek uit te voeren naar wat huisartsen kan motiveren om aandacht te besteden aan samenwerking met bedrijfsartsen. In dit kader

  10. EFFECTS OF GONADAL HORMONES ON MET-ENKEPHALIN IN BRAIN

    Institute of Scientific and Technical Information of China (English)

    PENGYing-Xiu; LIUGuo

    1989-01-01

    The relationship between gonadal hormones and Met-enkephalin ( MEK ) in the brain was investigated to explore the role of gonadal hormones in regulating the contents of MEK, Experiments were performed on rats of both sexes. The animals were divided into

  11. Broei- en brandkoppen gevolg van problemen met de verdamping

    NARCIS (Netherlands)

    Heuvelink, E.; Kierkels, T.; Janse, J.

    2009-01-01

    Als de plant de verdamping niet bij kan houden of juist te weinig kan verdampen, onstaan fysiogene problemen met praktijknamen als broeikoppen, brandkoppen, bolrand, bladrand. Brandkoppen ontstaan als de top van de plant te warm wordt. De top kan afsterven, wat productiedaling en verlies van

  12. Imidacloprid of niet? (interview met Sjef van der Steen)

    NARCIS (Netherlands)

    Kleis, R.; Steen, van der J.J.M.

    2014-01-01

    Is bijensterfte het werk van neonicotinoïden? Ja, zeggen en denken velen. Volgens hen zijn de neo’s rechtstreeks verantwoordelijk voor de hoge sterfte onder bijen. Nee, toont Wagenings onderzoek aan. Intussen lijkt het met de sterfte voorzichtig de goede kant op te gaan.

  13. Professor Wang Jie Met with NSF Assistant Director

    Institute of Scientific and Technical Information of China (English)

    Chen Huai

    2008-01-01

    @@ Prof.Wang Jie,NSFC Vice President,cordially met with Dr.David Lightfoot,Assistant Director of USA National Science Foundation (NSF) responsible for the Directorate for Social,Behavioral and Economic Sciences,on April 21,2008.

  14. Mondgezondheid van patiënten met een bipolaire stoornis

    NARCIS (Netherlands)

    Brand, H.S.; Bots, C.P.; Schulte, P.F.J.

    2012-01-01

    Patiënten met een bipolaire stoornis hebben vaak mondgezondheidsproblemen. Deze problemen kunnen het gevolg zijn van het ziektebeeld, maar kunnen ook veroorzaakt worden door de toegepaste farmacotherapie. Zo veroorzaken lithium, anti-epileptica, antipsychotica en antidepressiva een droge mond

  15. State of the art met betrekking tot het intellectueel eigendomsrecht

    NARCIS (Netherlands)

    Mossink, Wilma

    2005-01-01

    Mossink, W. (2004). State of the art met betrekking tot het intellectueel eigendomsrecht. In: Van Geloven, M., Koper, R. & Van der Veen, J., E-learning trends (pp. 13-15). Utrecht, Stichting Digitale Universiteit.
    Ook beschikbaar in dspace: http://hdl.hand

  16. Prof. Zhu Zuoyan Met with Director General of ANR

    Institute of Scientific and Technical Information of China (English)

    Fan Yingjie; Lu Rongkai

    2007-01-01

    @@ On Feb. 2, 2007, Prof. Zhu Zuoyan, Vice President of NSFC met with Ms. Jacqueline Lecourtier, Director General of the French National Research Agency (Agence Nationale de la Recherche, ANR) and Mr.Bernard Belloc, the Science and Technology Counselor of the French Embassy in China.

  17. Aanvullend radiumonderzoek op twee met woningen bebouwde havenspeciepolders

    NARCIS (Netherlands)

    Stoop P; Hiemstra YS; Lembrechts JFMM; LSO

    1995-01-01

    Dit rapport beschrijft een onderzoek naar radiumgehalten dat uitgevoerd is voor de locaties Steendijkpolder-zuid, Maassluis (STPZ) en Woudhoek-noord, Schiedam (WH). Het doel van het onderzoek is, voor een met havenspecie opgespoten polder zonder afdeklaag (STPZ), te bepalen of de variatie in het

  18. Tweetalig onderwijs met vervroegd Engels in het basisonderwijs

    NARCIS (Netherlands)

    Aarts, R.; Ronde, S.

    2006-01-01

    In dit artikel wordt verslag gedaan van een explortief onderzoek naar het functioneren van een tweetalig onderwijsprogramma waarin (naast het Nederlands) Engels aangeboden wordt in de onderbouw van het basisonderwijs. De resultaten laten zien dat de betrokkenen positieve ervaringen met en hoge

  19. MET-RODOS: A comprehensive atmospheric dispersion module

    DEFF Research Database (Denmark)

    Mikkelsen, T.; Thykier-Nielsen, S.; Astrup, P.;

    1997-01-01

    air concentrations, and ground level gamma dose rates from up to 15 simultaneous released nuclides are calculated using a nested system of local and long range atmospheric dispersion models, driven by real-time available on-line meteorological information. The MET-PODOS module uses concurrently...

  20. Hyacintentelers stemmen in met aanpak Erwinia en fonds onderzoek

    NARCIS (Netherlands)

    Dwarswaard, A.; Vreeburg, P.J.M.

    2013-01-01

    Twee stevige onderwerpen telde de agenda van de jaarvergadering van de KAVB-productgroep Hyacint. Het voorstel om werkbollen te gaan toetsen op Erwinia kreeg bijval, en ook het plan om een fonds te vormen waaruit hyacintenonderzoek wordt betaald werd met instemming begroet.

  1. Klaverbank Survey met de ARCA 17‐21 Nov 2014

    NARCIS (Netherlands)

    Lavaleye, M.

    2014-01-01

    Op Maandag 17 Nov 2014 vertrok de ARCA om 9:00 van uit de haven van Scheveningen richting Klaverbank. Het weer was bijzonder mooi en rustig, uitzonderlijk voor deze tijd van het jaar. Om 19:00 werd de Klaverbank bereikt, en werd gelijk begonnen met de Multibeam en side scan sonar raaien (Fig. 1).

  2. 17 CFR 230.502 - General conditions to be met.

    Science.gov (United States)

    2010-04-01

    ... advertising, including, but not limited to, the following: (1) Any advertisement, article, notice or other... 17 Commodity and Securities Exchanges 2 2010-04-01 2010-04-01 false General conditions to be met. 230.502 Section 230.502 Commodity and Securities Exchanges SECURITIES AND EXCHANGE COMMISSION...

  3. Luchtverontreiniging met CO aan de Amsterdamsestraatweg-Zuilen/Utrecht

    NARCIS (Netherlands)

    Hady MSA

    1989-01-01

    Het rapport beschrijft de resultaten van een modelmatige studie naar de bijdrage van de emissies van een industriegebied aan de westkand van Utrecht aan de CO-concentraties of leefniveau. Deze bijdrage is vergeleken met de bijdrage van het verkeer en die van bronnen binnenshuis. Vervolgens is ee

  4. Hyacintentelers stemmen in met aanpak Erwinia en fonds onderzoek

    NARCIS (Netherlands)

    Dwarswaard, A.; Vreeburg, P.J.M.

    2013-01-01

    Twee stevige onderwerpen telde de agenda van de jaarvergadering van de KAVB-productgroep Hyacint. Het voorstel om werkbollen te gaan toetsen op Erwinia kreeg bijval, en ook het plan om een fonds te vormen waaruit hyacintenonderzoek wordt betaald werd met instemming begroet.

  5. Verdamping van water uit dierlijke mest met zonne-energie

    NARCIS (Netherlands)

    Huijben, J.; Wagenberg, van V.

    1998-01-01

    Uit een praktijkproef blijkt dat in een mestbassin met een gesloten lichtdoorlatende overkapping in één jaar 26 I liter water per m2 mestoppervlak kan worden verdampt. Bij toepassing van een drijfdek op de mest is de verdamping 304 I/m2.

  6. Let's play : ouderen stimuleren tot bewegen met applied games

    NARCIS (Netherlands)

    Heuvelink, A.; Groot, J.; Hofstede-Kleyweg, C.

    2014-01-01

    Op 30 september 2014 presenteerde de coalitie Applied Gaming for Healthy Aging de whitepaper ‘Let’s Play. Ouderen stimuleren tot bewegen met applied games’. De coalitie wil hiermee richting geven aan de verdere (door)ontwikkeling en implementatie van bewegingsgames voor ouderen. De whitepaper geeft

  7. Waardevermindering pluimveevlees besmet met Salmonella enteritidis en Salmonella typhymurium

    NARCIS (Netherlands)

    Horne, van P.L.M.

    2011-01-01

    De doelstelling van het onderzoek is om de waardevermindering van met Salmonella enteritidis (S.e.) en Salmonella typhymurium (S.t.) besmet pluimveevlees van vleeskuikens te bepalen. Hoe hoog is de opbrengstenderving en hoe hoog zijn de extra kosten van maatregelen voor de slachterij of uitsnijderij

  8. Horizontale en verticale samenwerking in distributieketens met cross-docks

    NARCIS (Netherlands)

    Buijs, Paul

    2014-01-01

    Logistiek dienstverleners staan voor grote uitdagingen op het gebied van duurzaamheid, in het bijzonder vanwege de steeds kleiner wordende zendingen die just-in-time bij de klant moeten worden afgeleverd. Samenwerking tussen partners in de distributieketen en met concurrenten daarbuiten biedt kansen

  9. Transport analysis of ozone enhancement in Southern Ontario during BAQS-Met

    Directory of Open Access Journals (Sweden)

    H. He

    2010-06-01

    Full Text Available Twice-daily ozonesondes were launched from Harrow, Ontario (east of Detroit during the BAQS-Met (Border Air Quality and Meteorology Study campaign in the summer of 2007. A co-located radar windprofiler measured tropopause height continuously. Simulation results from the dispersion model FLEXPART, using the output of the Environment Canada Global Environmental Multiscale (GEM weather forecast model, indicate the occurrence of stratospheric ozone intrusion events during the BAQS-Met campaign. This interpretation is supported by the ozonesonde observations, one-minute average surface ozone data measured by the chemistry supersite at Harrow, and geostatistical interpolation results of satellite ozone data that were observed from TES (Tropospheric Emission Spectrometer onboard NASA's Aura satellite and AIRS (Atmospheric Infrared Sounder onboard NASA's Aqua satellite. Source-receptor analysis using the GEM-FLEXPART model shows the stratosphere over the Northwest Territories region close to the Beaufort Sea to be the main source of the enhanced ozone at Harrow on 1 July 2007.

  10. The Met-genotype of the BDNF Val66Met polymorphism is associated with reduced Stroop interference in elderly.

    Science.gov (United States)

    Gajewski, Patrick D; Hengstler, Jan G; Golka, Klaus; Falkenstein, Michael; Beste, Christian

    2012-12-01

    Aging is accompanied by impairments of executive functions that rely on the functional integrity of fronto-striatal networks. This integrity is modulated by the release of neurotrophins like the brain-derived-neurotrophic factor (BDNF). Here, we investigate effects of the functional BDNF Val66Met polymorphism on interference processing in 131 healthy elderly subjects using event-related potentials (ERPs). In a Stroop task, participants had to indicate the name or the colour of colour-words while colour was either compatible or incompatible with the name. We show that susceptibility to Stroop-interference is affected by the BDNF Val66Met polymorphism: the Met-allele carriers showed better performance and enhanced N450 in interference trials. Other processes necessary to prepare and allocate cognitive resources to a particular task were not affected by BDNF Val66Met polymorphism, underlining the specificity of the observed effects. The observed performance and ERP difference is possibly due to dopamine related effects of BDNF in fronto-striatal networks, where it putatively mediates a shift in the balance of the direct and indirect pathway involved in inhibitory functions.

  11. Role of peroxisome proliferator-activated receptors gene polymorphisms in type 2 diabetes and metabolic syndrome.

    Science.gov (United States)

    Dong, Chen; Zhou, Hui; Shen, Chong; Yu, Lu-Gang; Ding, Yi; Zhang, Yong-Hong; Guo, Zhi-Rong

    2015-05-15

    Metabolic syndrome (MetS) and type 2 diabetes mellitus (T2DM) are the serious public health problems worldwide. Moreover, it is estimated that MetS patients have about five-fold greater risk of the T2DM development compared with people without the syndrome. Peroxisome proliferator-activated receptors are a subgroup of the nuclear hormone receptor superfamily of ligand-activated transcription factors which play an important role in the pathogenesis of MetS and T2DM. All three members of the peroxisome proliferator-activated receptor (PPAR) nuclear receptor subfamily, PPARα, PPARβ/δ and PPARγ are critical in regulating insulin sensitivity, adipogenesis, lipid metabolism, and blood pressure. Recently, more and more studies indicated that the gene polymorphism of PPARs, such as Leu(162)Val and Val(227)Ala of PPARα, +294T > C of PPARβ/δ, Pro(12)Ala and C1431T of PPARγ, are significantly associated with the onset and progressing of MetS and T2DM in different population worldwide. Furthermore, a large body of evidence demonstrated that the glucose metabolism and lipid metabolism were influenced by gene-gene interaction among PPARs genes. However, given the complexity pathogenesis of metabolic disease, it is unlikely that genetic variation of a single locus would provide an adequate explanation of inter-individual differences which results in diverse clinical syndromes. Thus, gene-gene interactions and gene-environment interactions associated with T2DM and MetS need future comprehensive studies.

  12. A New Transgenic Mouse Model of Heart Failure and Cardiac Cachexia Raised by Sustained Activation of Met Tyrosine Kinase in the Heart.

    Science.gov (United States)

    Sala, Valentina; Gatti, Stefano; Gallo, Simona; Medico, Enzo; Cantarella, Daniela; Cimino, James; Ponzetto, Antonio; Crepaldi, Tiziana

    2016-01-01

    Among other diseases characterized by the onset of cachexia, congestive heart failure takes a place of relevance, considering the high prevalence of this pathology in most European countries and in the United States, and is undergoing a rapid increase in developing countries. Actually, only few models of cardiac cachexia exist. Difficulties in the recruitment and follow-up of clinical trials implicate that new reproducible and well-characterized animal models are pivotal in developing therapeutic strategies for cachexia. We generated a new model of cardiac cachexia: a transgenic mouse expressing Tpr-Met receptor, the activated form of c-Met receptor of hepatocyte growth factor, specifically in the heart. We showed that the cardiac-specific induction of Tpr-Met raises a cardiac hypertrophic remodelling, which progresses into concentric hypertrophy with concomitant increase in Gdf15 mRNA levels. Hypertrophy progresses to congestive heart failure with preserved ejection fraction, characterized by reduced body weight gain and food intake and skeletal muscle wasting. Prevention trial by suppressing Tpr-Met showed that loss of body weight could be prevented. Skeletal muscle wasting was also associated with altered gene expression profiling. We propose transgenic Tpr-Met mice as a new model of cardiac cachexia, which will constitute a powerful tool to understand such complex pathology and test new drugs/approaches at the preclinical level.

  13. A New Transgenic Mouse Model of Heart Failure and Cardiac Cachexia Raised by Sustained Activation of Met Tyrosine Kinase in the Heart

    Directory of Open Access Journals (Sweden)

    Valentina Sala

    2016-01-01

    Full Text Available Among other diseases characterized by the onset of cachexia, congestive heart failure takes a place of relevance, considering the high prevalence of this pathology in most European countries and in the United States, and is undergoing a rapid increase in developing countries. Actually, only few models of cardiac cachexia exist. Difficulties in the recruitment and follow-up of clinical trials implicate that new reproducible and well-characterized animal models are pivotal in developing therapeutic strategies for cachexia. We generated a new model of cardiac cachexia: a transgenic mouse expressing Tpr-Met receptor, the activated form of c-Met receptor of hepatocyte growth factor, specifically in the heart. We showed that the cardiac-specific induction of Tpr-Met raises a cardiac hypertrophic remodelling, which progresses into concentric hypertrophy with concomitant increase in Gdf15 mRNA levels. Hypertrophy progresses to congestive heart failure with preserved ejection fraction, characterized by reduced body weight gain and food intake and skeletal muscle wasting. Prevention trial by suppressing Tpr-Met showed that loss of body weight could be prevented. Skeletal muscle wasting was also associated with altered gene expression profiling. We propose transgenic Tpr-Met mice as a new model of cardiac cachexia, which will constitute a powerful tool to understand such complex pathology and test new drugs/approaches at the preclinical level.

  14. Activating mutation in MET oncogene in familial colorectal cancer

    Directory of Open Access Journals (Sweden)

    Schildkraut Joellen M

    2011-10-01

    Full Text Available Abstract Background In developed countries, the lifetime risk of developing colorectal cancer (CRC is 5%, and it is the second leading cause of death from cancer. The presence of family history is a well established risk factor with 25-35% of CRCs attributable to inherited and/or familial factors. The highly penetrant inherited colon cancer syndromes account for approximately 5%, leaving greater than 20% without clear genetic definition. Familial colorectal cancer has been linked to chromosome 7q31 by multiple affected relative pair studies. The MET proto-oncogene which resides in this chromosomal region is considered a candidate for genetic susceptibility. Methods MET exons were amplified by PCR from germline DNA of 148 affected sibling pairs with colorectal cancer. Amplicons with altered sequence were detected with high-resolution melt-curve analysis using a LightScanner (Idaho Technologies. Samples demonstrating alternative melt curves were sequenced. A TaqMan assay for the specific c.2975C >T change was used to confirm this mutation in a cohort of 299 colorectal cancer cases and to look for allelic amplification in tumors. Results Here we report a germline non-synonymous change in the MET proto-oncogene at amino acid position T992I (also reported as MET p.T1010I in 5.2% of a cohort of sibling pairs affected with CRC. This genetic variant was then confirmed in a second cohort of individuals diagnosed with CRC and having a first degree relative with CRC at prevalence of 4.1%. This mutation has been reported in cancer cells of multiple origins, including 2.5% of colon cancers, and in Conclusions Although the MET p.T992I genetic mutation is commonly found in somatic colorectal cancer tissues, this is the first report also implicating this MET genetic mutation as a germline inherited risk factor for familial colorectal cancer. Future studies on the cancer risks associated with this mutation and the prevalence in different at-risk populations will

  15. Stimulation of oral fibroblast chemokine receptors identifies CCR3 and CCR4 as potential wound healing targets.

    Science.gov (United States)

    Buskermolen, Jeroen K; Roffel, Sanne; Gibbs, Susan

    2017-11-01

    The focus of this study was to determine which chemokine receptors are present on oral fibroblasts and whether these receptors influence proliferation, migration, and/or the release of wound healing mediators. This information may provide insight into the superior wound healing characteristics of the oral mucosa. The gingiva fibroblasts expressed 12 different chemokine receptors (CCR3, CCR4, CCR6, CCR9, CCR10, CXCR1, CXCR2, CXCR4, CXCR5, CXCR7, CX3CR1, and XCR1), as analyzed by flow cytometry. Fourteen corresponding chemokines (CCL5, CCL15, CCL20, CCL22, CCL25, CCL27, CCL28, CXCL1, CXCL8, CXCL11, CXCL12, CXCL13, CX3CL1, and XCL1) were used to study the activation of these receptors on gingiva fibroblasts. Twelve of these fourteen chemokines stimulated gingiva fibroblast migration (all except for CXCL8 and CXCL12). Five of the chemokines stimulated proliferation (CCL5/CCR3, CCL15/CCR3, CCL22/CCR4, CCL28/CCR3/CCR10, and XCL1/XCR1). Furthermore, CCL28/CCR3/CCR10 and CCL22/CCR4 stimulation increased IL-6 secretion and CCL28/CCR3/CCR10 together with CCL27/CCR10 upregulated HGF secretion. Moreover, TIMP-1 secretion was reduced by CCL15/CCR3. In conclusion, this in-vitro study identifies chemokine receptor-ligand pairs which may be used in future targeted wound healing strategies. In particular, we identified the chemokine receptors CCR3 and CCR4, and the mucosa specific chemokine CCL28, as having an predominant role in oral wound healing by increasing human gingiva fibroblast proliferation, migration, and the secretion of IL-6 and HGF and reducing the secretion of TIMP-1. © 2017 The Authors. Journal of Cellular Physiology Published by wiley periodicals, Inc.

  16. Hepatocyte growth factor modulates interleukin-6 production in bone marrow derived macrophages: implications for inflammatory mediated diseases.

    Directory of Open Access Journals (Sweden)

    Gina M Coudriet

    Full Text Available The generation of the pro-inflammatory cytokines IL-6, TNF-α, and IL-1β fuel the acute phase response (APR. To maintain body homeostasis, the increase of inflammatory proteins is resolved by acute phase proteins via presently unknown mechanisms. Hepatocyte growth factor (HGF is transcribed in response to IL-6. Since IL-6 production promotes the generation of HGF and induces the APR, we posited that accumulating HGF might be a likely candidate for quelling excess inflammation under non-pathological conditions. We sought to assess the role of HGF and how it influences the regulation of inflammation utilizing a well-defined model of inflammatory activation, lipopolysaccharide (LPS-stimulation of bone marrow derived macrophages (BMM. BMM were isolated from C57BL6 mice and were stimulated with LPS in the presence or absence of HGF. When HGF was present, there was a decrease in production of the pro-inflammatory cytokine IL-6, along with an increase in the anti-inflammatory cytokine IL-10. Altered cytokine production correlated with an increase in phosphorylated GSK3β, increased retention of the phosphorylated NFκB p65 subunit in the cytoplasm, and an enhanced interaction between CBP and phospho-CREB. These changes were a direct result of signaling through the HGF receptor, MET, as effects were reversed in the presence of a selective inhibitor of MET (SU11274 or when using BMM from macrophage-specific conditional MET knockout mice. Combined, these data provide compelling evidence that under normal circumstances, HGF acts to suppress the inflammatory response.

  17. Comment on "Effect of transferred NK4 gene on proliferation,migration, invasion, and apoptosis of human prostate cancer DU145 cells" by Dan Yue et al. in Asian Journal of Andrology

    Institute of Scientific and Technical Information of China (English)

    Shahriar Koochekpour

    2010-01-01

    @@ Hepatocyte growth factor/scatter factor (HGF/SF) interacting with its cell surface receptor tyrosine kinase (RTK) c-met proto-oncogene drives downstream signaling pathways which lead to cell proliferation, migration,invasion, apoptotic cell-death protection, angiogenesis during embryogenesis, repair and regeneration, and neoplastic growth and metastatic progression [1-6].

  18. BDNF pro-peptide actions facilitate hippocampal LTD and are altered by the common BDNF polymorphism Val66Met.

    Science.gov (United States)

    Mizui, Toshiyuki; Ishikawa, Yasuyuki; Kumanogoh, Haruko; Lume, Maria; Matsumoto, Tomoya; Hara, Tomoko; Yamawaki, Shigeto; Takahashi, Masami; Shiosaka, Sadao; Itami, Chiaki; Uegaki, Koichi; Saarma, Mart; Kojima, Masami

    2015-06-09

    Most growth factors are initially synthesized as precursor proteins and subsequently processed into their mature form by proteolytic cleavage, resulting in simultaneous removal of a pro-peptide. However, compared with that of mature form, the biological role of the pro-peptide is poorly understood. Here, we investigated the biological role of the pro-peptide of brain-derived neurotrophic factor (BDNF) and first showed that the pro-peptide is expressed and secreted in hippocampal tissues and cultures, respectively. Interestingly, we found that the BDNF pro-peptide directly facilitates hippocampal long-term depression (LTD), requiring the activation of GluN2B-containing NMDA receptors and the pan-neurotrophin receptor p75(NTR). The BDNF pro-peptide also enhances NMDA-induced α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor endocytosis, a mechanism crucial for LTD expression. Thus, the BDNF pro-peptide is involved in synaptic plasticity that regulates a mechanism responsible for promoting LTD. The well-known BDNF polymorphism valine for methionine at amino acid position 66 (Val66Met) affects human memory function. Here, the BDNF pro-peptide with Met mutation completely inhibits hippocampal LTD. These findings demonstrate functional roles for the BDNF pro-peptide and a naturally occurring human BDNF polymorphism in hippocampal synaptic depression.

  19. 猎隼肾脏的组织学观察及HGF在肾脏中的表达%Histological Observation and Expression of HGF of Falco Cherrug Kidney

    Institute of Scientific and Technical Information of China (English)

    王昱

    2015-01-01

    应用组织学方法观察了猎隼肾脏的组织结构,利用免疫组织化学方法检测了肝细胞生长因子(hepatocyte growth factor,HGF)在肾脏中的表达。结果表明:与大多数鸟类的肾脏结构相似,猎隼的肾脏主要由许多肾单位、集合管和少量结缔组织构成,但猎隼的肾脏皮质与髓质分界较明显。肾单位由肾小体和与之相连的上皮样肾小管构成。肾小体由一团蟠曲的毛细血管构成。近曲小管由单层立方上皮细胞组成,上皮细胞游离面有刷状缘。远曲小管和集合管管腔较大,腔面无刷状缘。肾小管和集合管上皮细胞都呈HGF免疫反应阳性。表明HGF可能参与调节正常组织细胞的生命活动。%To provide basic data for the study on zoology, physiology and zootomy, the structural features of the kidney of Falco cherrug were studied by microscopy and expression of HGF was measured by immunohistochem-ical method. The result shows that similar to most birds’ kidney, the kidney of Falco cherrug consisted mainly of nephrons, collecting ducts and a little connective tissue, but the verge of cortex and medulla in kidney was clear. The nephron comprised renal corpuscle and a renal tubule. The structure of glomerular capillary was made from convoluted capillaries. The proximal convoluted tubule was lined with a well-developed brush border. The lumen diameters of both distal convoluted tubule and collecting duct were large, and their cell apex had no a bush border. HGF appeared to be expressed in the epithelial cells of the renal tubular and collecting duct. The evidence indicates that HGF might be involved in the regulation of the normal histiocyte life activities.

  20. BioMet Toolbox: genome-wide analysis of metabolism

    DEFF Research Database (Denmark)

    Cvijovic, M.; Olivares Hernandez, Roberto; Agren, R.

    2010-01-01

    models. Systematic analysis of biological processes by means of modelling and simulations has made the identification of metabolic networks and prediction of metabolic capabilities under different conditions possible. For facilitating such systemic analysis, we have developed the BioMet Toolbox, a web......-based resource for stoichiometric analysis and for integration of transcriptome and interactome data, thereby exploiting the capabilities of genome-scale metabolic models. The BioMet Toolbox provides an effective user-friendly way to perform linear programming simulations towards maximized or minimized growth...... rates, substrate uptake rates and metabolic production rates by detecting relevant fluxes, simulate single and double gene deletions or detect metabolites around which major transcriptional changes are concentrated. These tools can be used for high-throughput in silico screening and allows fully...

  1. Testing ATLAS Z+MET excess with LHC run 2

    Energy Technology Data Exchange (ETDEWEB)

    Lu, Xiaochuan [California Univ., Davis, CA (United States). Dept. of Physics; Shirai, Satoshi [Deutsches Elektronen-Synchrotron (DESY), Hamburg (Germany); Terada, Takahiro [Tokyo Univ. (Japan). Dept. of Physics; Asia Pacific Center for Theoretical Physics (APCTP), Pohang (Korea, Republic of)

    2016-05-15

    The ATLAS collaboration reported a 3σ excess in the search of events containing on-Z dilepton, jets, and large missing momentum (MET) in the 8 TeV LHC run. Motivated by this excess, many models of new physics have been proposed. Recently, the ATLAS and CMS collaborations reported new results for similar Z+MET channels in the 13 TeV run. In this paper, we comprehensively discuss the consistency between the proposed models and the LHC results of Run 1 and Run 2. We find that in models with heavy gluino production, there is generically some tension between the 8 TeV and 13 TeV results. On the other hand, models with light squark production provide relatively better fitting to both results.

  2. Operational Use of OGC Web Services at the Met Office

    Science.gov (United States)

    Wright, Bruce

    2010-05-01

    The Met Office has adopted the Service-Orientated Architecture paradigm to deliver services to a range of customers through Rich Internet Applications (RIAs). The approach uses standard Open Geospatial Consortium (OGC) web services to provide information to web-based applications through a range of generic data services. "Invent", the Met Office beta site, is used to showcase Met Office future plans for presenting web-based weather forecasts, product and information to the public. This currently hosts a freely accessible Weather Map Viewer, written in JavaScript, which accesses a Web Map Service (WMS), to deliver innovative web-based visualizations of weather and its potential impacts to the public. The intention is to engage the public in the development of new web-based services that more accurately meet their needs. As the service is intended for public use within the UK, it has been designed to support a user base of 5 million, the analysed level of UK web traffic reaching the Met Office's public weather information site. The required scalability has been realised through the use of multi-tier tile caching: - WMS requests are made for 256x256 tiles for fixed areas and zoom levels; - a Tile Cache, developed in house, efficiently serves tiles on demand, managing WMS request for the new tiles; - Edge Servers, externally hosted by Akamai, provide a highly scalable (UK-centric) service for pre-cached tiles, passing new requests to the Tile Cache; - the Invent Weather Map Viewer uses the Google Maps API to request tiles from Edge Servers. (We would expect to make use of the Web Map Tiling Service, when it becomes an OGC standard.) The Met Office delivers specialist commercial products to market sectors such as transport, utilities and defence, which exploit a Web Feature Service (WFS) for data relating forecasts and observations to specific geographic features, and a Web Coverage Service (WCS) for sub-selections of gridded data. These are locally rendered as maps or

  3. Remote Sensing of Volcanic ASH at the Met Office

    Science.gov (United States)

    Marenco, F.; Kent, J.; Adam, M.; Buxmann, J.; Francis, P.; Haywood, J.

    2016-06-01

    The eruption of Eyjafjallajökull in 2010 has triggered the rapid development of volcanic ash remote sensing activities at the Met Office. Volcanic ash qualitative and quantitative mapping have been achieved using lidar on board the Facility for Airborne Atmospheric Measurements (FAAM) research aircraft, and using improved satellite retrieval algorithms. After the eruption, a new aircraft facility, the Met Office Civil Contingencies Aircraft (MOCCA), has been set up to enable a rapid response, and a network of ground-based remote sensing sites with lidars and sunphotometers is currently being developed. Thanks to these efforts, the United Kingdom (UK) will be much better equipped to deal with such a crisis, should it happen in the future.

  4. Technology evaluation: MetXia-P450, Oxford Biomedica.

    Science.gov (United States)

    Hunt, S

    2001-12-01

    Oxford BioMedica is developing gene therapies for treating various forms of cancer. The therapies comprise the transfer of several anticancer genes at a time using a recombinant retrovirus approach based on the company's proprietary LTR Deleted Vector and Accelerated Vector Evolution technologies [238147]. MetXia-P450 is a gene therapy construct containing the cytochrome P450 gene CYP2B6, and is designed to be injected directly into tumors to convert them into 'drug factories'. This is achieved because CYP2B6 converts the inactive produg form cyclophosphamide into the active cytotoxic drug. MetXia-P450 is in phase I/II trials for breast cancer [339582].

  5. COMT Val158Met Polymorphism Modulates Huntington's Disease Progression

    Science.gov (United States)

    Rebeix, Isabelle; Dupoux, Emmanuel; Durr, Alexandra; Brice, Alexis; Charles, Perrine; Cleret de Langavant, Laurent; Youssov, Katia; Verny, Christophe; Damotte, Vincent; Azulay, Jean-Philippe; Goizet, Cyril; Simonin, Clémence; Tranchant, Christine; Maison, Patrick; Rialland, Amandine; Schmitz, David; Jacquemot, Charlotte; Fontaine, Bertrand; Bachoud-Lévi, Anne-Catherine

    2016-01-01

    Little is known about the genetic factors modulating the progression of Huntington’s disease (HD). Dopamine levels are affected in HD and modulate executive functions, the main cognitive disorder of HD. We investigated whether the Val158Met polymorphism of the catechol-O-methyltransferase (COMT) gene, which influences dopamine (DA) degradation, affects clinical progression in HD. We carried out a prospective longitudinal multicenter study from 1994 to 2011, on 438 HD gene carriers at different stages of the disease (34 pre-manifest; 172 stage 1; 130 stage 2; 80 stage 3; 17 stage 4; and 5 stage 5), according to Total Functional Capacity (TFC) score. We used the Unified Huntington’s Disease Rating Scale to evaluate motor, cognitive, behavioral and functional decline. We genotyped participants for COMT polymorphism (107 Met-homozygous, 114 Val-homozygous and 217 heterozygous). 367 controls of similar ancestry were also genotyped. We compared clinical progression, on each domain, between groups of COMT polymorphisms, using latent-class mixed models accounting for disease duration and number of CAG (cytosine adenine guanine) repeats. We show that HD gene carriers with fewer CAG repeats and with the Val allele in COMT polymorphism displayed slower cognitive decline. The rate of cognitive decline was greater for Met/Met homozygotes, which displayed a better maintenance of cognitive capacity in earlier stages of the disease, but had a worse performance than Val allele carriers later on. COMT polymorphism did not significantly impact functional and behavioral performance. Since COMT polymorphism influences progression in HD, it could be used for stratification in future clinical trials. Moreover, DA treatments based on the specific COMT polymorphism and adapted according to disease duration could potentially slow HD progression. PMID:27657697

  6. MetWAMer: eukaryotic translation initiation site prediction

    Directory of Open Access Journals (Sweden)

    Brendel Volker

    2008-09-01

    Full Text Available Abstract Background Translation initiation site (TIS identification is an important aspect of the gene annotation process, requisite for the accurate delineation of protein sequences from transcript data. We have developed the MetWAMer package for TIS prediction in eukaryotic open reading frames of non-viral origin. MetWAMer can be used as a stand-alone, third-party tool for post-processing gene structure annotations generated by external computational programs and/or pipelines, or directly integrated into gene structure prediction software implementations. Results MetWAMer currently implements five distinct methods for TIS prediction, the most accurate of which is a routine that combines weighted, signal-based translation initiation site scores and the contrast in coding potential of sequences flanking TISs using a perceptron. Also, our program implements clustering capabilities through use of the k-medoids algorithm, thereby enabling cluster-specific TIS parameter utilization. In practice, our static weight array matrix-based indexing method for parameter set lookup can be used with good results in data sets exhibiting moderate levels of 5'-complete coverage. Conclusion We demonstrate that improvements in statistically-based models for TIS prediction can be achieved by taking the class of each potential start-methionine into account pending certain testing conditions, and that our perceptron-based model is suitable for the TIS identification task. MetWAMer represents a well-documented, extensible, and freely available software system that can be readily re-trained for differing target applications and/or extended with existing and novel TIS prediction methods, to support further research efforts in this area.

  7. El sexo de las metáforas

    Directory of Open Access Journals (Sweden)

    Pérez Sedeño, Eulalia

    2011-02-01

    Full Text Available The hypothesis that states metaphors are structurally determinant in our social relations, routines, and experience has been accepted broadly in the last decades. Moreover, metaphors are to be found in many different levels of scientific practices, and have a diverse set of functions in science. Therefore, they impregnate all scientific enterprise. In this work we examine selected gender metaphors used in biology. We show metaphors are effective precisely because its effectiveness depends on shared social conventions, kinship relations and, authority that, by convention, is given to those that use them.

    La tesis de que las metáforas estructuran gran parte de nuestras relaciones sociales y nuestra experiencia cotidiana ha sido ampliamente aceptada en las últimas décadas. En la ciencia, además, aparecen en muchos niveles y desempeñan diversas funciones, impregnando todo el quehacer científico. En este trabajo se examinan algunas metáforas de género usadas en biología. Se muestra que las metáforas eficaces lo son porque su efectividad depende de las convenciones sociales compartidas, los parecidos de familia ya vigentes y de la autoridad que, por convención, se otorga a quienes las usan.

  8. Quantitative PET imaging of Met-expressing human cancer xenografts with {sup 89}Zr-labelled monoclonal antibody DN30

    Energy Technology Data Exchange (ETDEWEB)

    Perk, Lars R.; Stigter-van Walsum, Marijke; Vosjan, Maria J.W.D.; Leemans, C.R. [VU University Medical Centre, Department of Otolaryngology-Head and Neck Surgery, De Boelelaan 1117, P.O. Box 7057, Amsterdam (Netherlands); Visser, Gerard W.M.; Kloet, Reina W. [VU University Medical Centre, Nuclear Medicine and PET Research, Amsterdam (Netherlands); Giaccone, Giuseppe [National Cancer Institute, Medical Oncology Branch CCR, Bethesda, MD (United States); Albano, Raffaella; Comoglio, Paolo M. [University of Turin Medical School, Division of Molecular Oncology, Institute for Cancer Research and Treatment (IRCC), Turin (Italy); Dongen, Guus A.M.S. van [VU University Medical Centre, Department of Otolaryngology-Head and Neck Surgery, De Boelelaan 1117, P.O. Box 7057, Amsterdam (Netherlands); VU University Medical Centre, Nuclear Medicine and PET Research, Amsterdam (Netherlands)

    2008-10-15

    Targeting the c-Met receptor with monoclonal antibodies (MAbs) is an appealing approach for cancer diagnosis and treatment because this receptor plays a prominent role in tumour invasion and metastasis. Positron emission tomography (PET) might be a powerful tool for guidance of therapy with anti-Met MAbs like the recently described MAb DN30 because it allows accurate quantitative imaging of tumour targeting (immuno-PET). We considered the potential of PET with either {sup 89}Zr-labelled (residualising radionuclide) or {sup 124}I-labelled (non-residualising radionuclide) DN30 for imaging of Met-expressing tumours. The biodistribution of co-injected {sup 89}Zr-DN30 and iodine-labelled DN30 was compared in nude mice bearing either the human gastric cancer line GLT-16 (high Met expression) or the head-and-neck cancer line FaDu (low Met expression). PET images were acquired in both xenograft models up to 4 days post-injection (p.i.) and used for quantification of tumour uptake. Biodistribution studies in GTL-16-tumour-bearing mice revealed that {sup 89}Zr-DN30 achieved much higher tumour uptake levels than iodine-labelled DN30 (e.g. 19.6%ID/g vs 5.3%ID/g, 5 days p.i.), while blood levels were similar, indicating internalisation of DN30. Therefore, {sup 89}Zr-DN30 was selected for PET imaging of GLT-16-bearing mice. Tumours as small as 11 mg were readily visualised with immuno-PET. A distinctive lower {sup 89}Zr uptake was observed in FaDu compared to GTL-16 xenografts (e.g. 7.8%ID/g vs 18.1%ID/g, 3 days p.i.). Nevertheless, FaDu xenografts were also clearly visualised with {sup 89}Zr-DN30 immuno-PET. An excellent correlation was found between PET-image-derived {sup 89}Zr tumour uptake and ex-vivo-assessed {sup 89}Zr tumour uptake (R {sup 2} = 0.98). The long-lived positron emitter {sup 89}Zr seems attractive for PET-guided development of therapeutic anti-c-Met MAbs. (orig.)

  9. Aging-like skin changes in metabolic syndrome model mice are mediated by mineralocorticoid receptor signaling.

    Science.gov (United States)

    Nagase, Takashi; Akase, Tomoko; Sanada, Hiromi; Minematsu, Takeo; Ibuki, Ai; Huang, Lijuan; Asada, Mayumi; Yoshimura, Kotaro; Nagase, Miki; Shimada, Tsutomu; Aburada, Masaki; Nakagami, Gojiro; Sugama, Junko

    2013-02-01

    Aging is accelerated, at least in part, by pathological condition such as metabolic syndrome (MetS), and various molecular pathways such as oxidative stress are common mediators of aging and MetS. We previously developed the aging-like skin model by single ultraviolet (UV) irradiation on the MetS model mice. Recent studies revealed that mineralocorticoid receptor (MR) signaling plays a pivotal role for various tissue inflammation and damages in MetS. Although previous studies reported that MR is expressed in the skin and that overexpression of MR in the skin resulted in the skin atrophy, the physiological or pathological functions of MR in the skin are not fully elucidated. Here, we show the involvement of MR signaling in the aging-like skin changes in our own model. Elevations of oxidative stress and inflammation markers were observed in the MetS mice, and the UV-evoked aging-like skin damages were attenuated by topical antioxidant. MR expression was higher in the MetS mouse skin, and notably, expression of its effecter gene Sgk1 was significantly upregulated in the aging-like skin in the UV-irradiated MetS mice. Furthermore, topical application of MR antagonist spironolactone suppressed Sgk1 expression, oxidative stress, inflammation, and the aging-like changes in the skin. The 2-week UV onto the non-MetS mice, the more usual photoaging model, resulted in the skin damages mostly equivalent to the MetS mice with single UV, but they were not associated with upregulation of MR signaling. Our studies suggested an unexpected role of MR signaling in the skin aging in MetS status.

  10. Founder effect in the Horn of Africa for an insulin receptor mutation that may impair receptor recycling

    DEFF Research Database (Denmark)

    Raffan, E; Soos, M A; Rocha, N;

    2011-01-01

    Genetic insulin receptoropathies are a rare cause of severe insulin resistance. We identified the Ile119Met missense mutation in the insulin receptor INSR gene, previously reported in a Yemeni kindred, in four unrelated patients with Somali ancestry. We aimed to investigate a possible genetic...... founder effect, and to study the mechanism of loss of function of the mutant receptor....

  11. Association of COMT val158met and DRD2 G>T genetic polymorphisms with individual differences in motor learning and performance in female young adults.

    Science.gov (United States)

    Noohi, Fatemeh; Boyden, Nate B; Kwak, Youngbin; Humfleet, Jennifer; Burke, David T; Müller, Martijn L T M; Bohnen, Nico I; Seidler, Rachael D

    2014-02-01

    Individuals learn new skills at different rates. Given the involvement of corticostriatal pathways in some types of learning, variations in dopaminergic transmission may contribute to these individual differences. Genetic polymorphisms of the catechol-O-methyltransferase (COMT) enzyme and dopamine receptor D2 (DRD2) genes partially determine cortical and striatal dopamine availability, respectively. Individuals who are homozygous for the COMT methionine (met) allele show reduced cortical COMT enzymatic activity, resulting in increased dopamine levels in the prefrontal cortex as opposed to individuals who are carriers of the valine (val) allele. DRD2 G-allele homozygotes benefit from a higher striatal dopamine level compared with T-allele carriers. We hypothesized that individuals who are homozygous for COMT met and DRD2 G alleles would show higher rates of motor learning. Seventy-two young healthy females (20 ± 1.9 yr) performed a sensorimotor adaptation task and a motor sequence learning task. A nonparametric mixed model ANOVA revealed that the COMT val-val group demonstrated poorer performance in the sequence learning task compared with the met-met group and showed a learning deficit in the visuomotor adaptation task compared with both met-met and val-met groups. The DRD2 TT group showed poorer performance in the sequence learning task compared with the GT group, but there was no difference between DRD2 genotype groups in adaptation rate. Although these results did not entirely come out as one might predict based on the known contribution of corticostriatal pathways to motor sequence learning, they support the role of genetic polymorphisms of COMT val158met (rs4680) and DRD2 G>T (rs 1076560) in explaining individual differences in motor performance and motor learning, dependent on task type.

  12. Clinical Significance of Measurement on the Changes of Plasma Leptin and Serum VEGF, HGF Levels After Hemodialysis in Patients with Chronic Renal Failure%慢性肾功能衰竭患者血透前后血浆leptin和血清VEGF、HGF检测的临床意义

    Institute of Scientific and Technical Information of China (English)

    顾涛

    2012-01-01

    Objective To explor the clinical significance of changes on plasma leptin and serum VEGF,HGF levels after hemodi-alysis in patients with chronic renal failure. Methods Plasma leptin (with RIA) , serum VEGF, HGF(with ELISA) levels were measured in 32 patients with chronic renal failure both before and after hemodialysis as well as in 35 normal healthy controls. Results Before hemodialysis plasma leptin and serum VEGF,HGF levels were significantiy higher in the patients than those in controls (P < 0.05). Conclusion The levels of leptin, VEGF and HGF were significantly increased in patients with chronic renal failure. Hemodialysis could increase the clearance rate of leptin, VEGF and HGF and might be useful for clinical assessment.%目的:探讨了慢性肾功能衰竭(CRF)患者血透前后血浆leptin和血清VEGF、HGF水平的变化及意义.方法:应用放射免疫分析和酶联法对32例CRF患者进行了血透前后血浆leptin和血清VEGF、HGF检测,并与35名正常健康人作比较.结果:CRF在血透前血浆leptin和血清VEGF、HGF水平非常显著地高于正常人组(P<0.01).结论:CRF患者存在高leptin、VEGF、HGF血症.血透可增加leptin、VEGF和HGF的清除率,具有重要的临床价值.

  13. Metaphors and activity Metáfora e atividade

    Directory of Open Access Journals (Sweden)

    Jacob L. Mey

    2006-01-01

    Full Text Available This paper considers metaphor as a kind of activity in the spirit of Levinson's 'Activity Types' or of Mey's 'Pragmatic Acts'. Contrary to what has been suggested in the literature, metaphors neither belong exclusively to the domain of abstract reasoning (such as by analogy; Max Black, nor are they merely linguistic and/or psychological processes (of cognition; George Lakoff. Metaphors do not originate and live in the brain only, neither do they exclusively belong to some conceptual domain from which they can establish relations to other domains, or blend with them. Metaphors are primarily pragmatic activities.In my contribution, I will concentrate on the pragmatics of what is called 'embodiment': while metaphors represent, respectively support or illustrate, an activity that is performed by the total human being, the body part of the metaphoric deal is often neglected. Yet, as many researchers in the humanities and the sciences have shown, the role of the body in solving problems through appropriate metaphoring cannot be overestimated. An embodied perspective on thought, and especially on metaphor, will allow us to form a better understanding of the things we do with words, when we use words to do things.Este artigo considera a metáfora um tipo de atividade no espírito dos " Tipos de Atividades" de Levinson ou dos "Atos Pragmáticos" de Mey. Contrariando o que tem sido sugerido pela literatura, as metáforas não pertencem exclusivamente ao domínio do raciocínio abstrato (por exemplo, por analogia; Max Black, nem são elas meramente processos lingüísticos e/ou psicológicos (da cognição; George Lakoff. As metáforas não tem sua origem e vivem apenas no cérebro, nem pertencem exclusivamente a algum domínio conceitual, a partir do qual elas possam estabelecer relações ou fusões com outros domínios.As metáforas são primordialmente atividades pragmáticas. Na minha contribuição, eu me concentrarei na pragmática do que tem sido

  14. Farnesoid X receptor activation improves erectile dysfunction in models of metabolic syndrome and diabetes.

    Science.gov (United States)

    Morelli, Annamaria; Vignozzi, Linda; Maggi, Mario; Adorini, Luciano

    2011-08-01

    The metabolic syndrome (MetS) is an insulin-resistant state characterized by a cluster of cardiovascular risk factors, including abdominal obesity, hyperglycemia, elevated blood pressure and combined dyslipidemia. In this review, we discuss the potential of farnesoid X receptor (FXR) agonists in the treatment of erectile dysfunction (ED), a multifactorial disorder often comorbid with MetS. FXR not only regulates lipid and glucose homeostasis but also influences endothelial function and atherosclerosis, suggesting a regulatory role for this hormone nuclear receptor in the cardiovascular complications associated with the MetS, including ED. MetS induces ED via several mechanisms, and in particular through endothelial dysfunction in penile vessels. In a high-fat diet rabbit model of MetS, a 3-month treatment with the potent and selective FXR agonist INT-747 restores endothelium-dependent relaxation in isolated cavernous tissue, normalizing responsiveness to acetylcholine and to electrical field stimulation. Accordingly, eNOS expression in the penis is greatly up-regulated by INT-747 treatment. Experiments in a rat model of chemically-induced type 1 diabetes further demonstrate that INT-747 treatment preserves erectile function induced by electrical stimulation of the cavernous nerve. These results add a new facet to the pleiotropic activities mediated by FXR, and reveal novel beneficial effects of FXR activation with potential clinical relevance. This article is part of a Special Issue entitled: Translating nuclear receptors from health to disease.

  15. Sandscape - engaging people in Met Office science through sand sculpture

    Science.gov (United States)

    Liggins, Felicity; Dowell, Ellen; Wardley, Jamie; Jamieson, Claire

    2017-04-01

    In 2015, the Met Office's award-winning outreach programme, designed to inspire the next generation of scientists and engineers, delivered one of its most ambitious and creative activities to date. It explored how scientists and artists can come together to create an engaging experience for young people and families. This activity was called Sandscape. Sandscape is an interactive sand sculpture workshop exploring how weather and climate affect our health. Budding sand sculptors are shown how to fashion elaborate structures from sand and water - creating a landscape with bridges, skyscrapers, forests and factories. As they work, participants are encouraged by the scientists delivering the activity to reflect on what makes a healthy city, considering how the natural and built environments influence air quality and circulation and how this impacts our health. Topics discussed include urban heat islands, air pollution and dispersion modelling, pollen forecasting and predicting the wind-borne spread of animal diseases. Each hour long workshop culminates in a dramatic demonstration that uses dry ice to represent clean air circulating from mountains, along rivers and into cities. Here we present an overview of Sandscape, identify the strengths and challenges of such a collaborative, innovative and playful approach to public engagement and share the results of our evaluation. Sandscape was originally supported by the Met Office and the Wellcome Trust, and produced by Einstein's Garden in collaboration with the Met Office, scientists from the University of Exeter and sand sculptors from Sand in Your Eye. It was first presented in Einstein's Garden at Green Man festival 2015, an independent music and arts festival held annually in Wales, and has since been invited to run at the 2015 Bournemouth Arts By the Sea Festival and Teignmouth's TRAIL Sculpture Festival in the summer of 2016.

  16. La familia de números metálicos

    OpenAIRE

    de Spinadel, Vera W.

    2004-01-01

    En este trabajo vamos a introducir una nueva familia de números irracionales cuadráticos positivos. Se llama familia de números metálicos [1], [2], [3], [4] y su miembro más importante es el número de oro φ . Entre sus parientes, podemos mencionar el número de plata, el número de bronce, el número de cobre, el número de níquel, etc. Los miembros de dicha familia gozan de propiedades matemáticas comunes que son fundamentales en la investigación actual sobre la estabilidad d...

  17. Piezas metálicas de la Protohistoria. Navarra: Armas

    Directory of Open Access Journals (Sweden)

    Amparo CASTIELLA RODRÍGUEZ

    2009-10-01

    Full Text Available El presente artículo es un intento de ampliar el conocimiento acerca de los testimonios materiales pertenecientes a los pueblos protohistóricos asentados en Navarra. Entre los instrumentos metálicos se debe señalar el número de armas —hasta 111 piezas— clasificadas en diferentes grupos. Se ofrece una valoración arqueológica, dibujos e información cartográfica en apoyo a las conclusiones del trabajo.

  18. LoVo colon cancer cells resistant to oxaliplatin overexpress c-MET and VEGFR-1 and respond to VEGF with dephosphorylation of c-MET.

    Science.gov (United States)

    Mezquita, Belén; Pineda, Estela; Mezquita, Jovita; Mezquita, Pau; Pau, Montserrat; Codony-Servat, Jordi; Martínez-Balibrea, Eva; Mora, Conchi; Maurel, Joan; Mezquita, Cristóbal

    2016-05-01

    Oxaliplatin-resistant LoVo colon cancer cells overexpressing c-MET and VEGFR-1 were selected to study several signaling pathways involved in chemoresistance, as well as the effect of increasing amounts of VEGF in the regulation of c-MET. In comparison with chemosensitive LoVo colon cancer cells, oxaliplatin-resistant cells (LoVoR) overexpress and phosphorylate c-MET, upregulate the expression of transmembrane and soluble VEGFR-1 and, unexpectedly, downregulate VEGF. In addition, LoVoR cells activate other transduction pathways involved in chemoresistance such as Akt, β-catenin-TCF4 and E-cadherin. While c-MET is phosphorylated in LoVoR cells expressing low levels of VEGF, c-MET phosphorylation decreases when recombinant VEGF is added into the culture medium. Inhibition of c-MET by VEGF is mediated by VEGFR-1, since phosphorylation of c-MET in the presence of VEGF is restored after silencing VEGFR-1. Dephosphorylation of c-MET by VEGF suggests that tumors coexpressing VEGFR-1 and c-MET may activate c-MET as a result of anti-VEGF therapy. © 2015 Wiley Periodicals, Inc.

  19. Correlation between plasma calcium, parathyroid hormone (PTH) and the metabolic syndrome (MetS) in a community-based cohort of men and women.

    Science.gov (United States)

    Ahlström, Tommy; Hagström, Emil; Larsson, Anders; Rudberg, Claes; Lind, Lars; Hellman, Per

    2009-11-01

    In recent years, an association has been noted between several abnormalities that characterize the metabolic syndrome (MetS) and primary hyperparathyroidism (pHPT). These abnormalities include dyslipidaemia, obesity, insulin resistance and hypertension. The correlations between plasma calcium, parathyroid hormone (PTH) and the variables in the MetS in a normal population are still unclear. To describe correlations between plasma calcium and PTH and the various abnormalities present in the MetS in a healthy population. We studied 1016 healthy individuals from the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) population of 70 years old, by means of plasma analyses of calcium, PTH, creatinine, lipids, insulin and glucose, as well as by standardized blood pressure measurements. Further, body mass index (BMI) and waist circumference were determined. The more National Cholesterol Education Program (NCEP) criteria for the MetS that were met, the higher the s-PTH and albumin-corrected s-calcium. Further, positive correlations between plasma calcium and BMI (P = 0.0003), waist circumference (P = 0.0009) and insulin resistance (P = 0.079) were found. PTH and BMI (P < 0.0001), waist circumference (P < 0.0001), systolic blood pressure (P = 0.0034), diastolic blood pressure (P = 0.0008), serum triglycerides (P = 0.0003) and insulin resistance (P = 0.0003) were positively correlated, whereas serum high density lipoproteins (HDL) (P = 0.036) and PTH were negatively correlated. We conclude that PTH correlates with several of the metabolic factors included in the MetS within a normocalcaemic population. In addition, individuals with mild pHPT present significantly more NCEP criteria for MetS. We postulate that increased levels of PTH in pHPT may be associated with the increased cardiovascular morbidity and mortality seen in pHPT.

  20. COMT Val158Met and PPARγ Pro12Ala polymorphisms and susceptibility to Alzheimer's disease: a meta-analysis.

    Science.gov (United States)

    Lee, Young Ho; Song, Gwan Gyu

    2014-05-01

    The aim of this study was to explore whether the catechol-O-methyltransferase (COMT) Val158Met or the peroxisome proliferator-activated receptor-gamma (PPARγ) Pro12Ala polymorphisms are associated with susceptibility to Alzheimer's disease (AD). We conducted a meta-analysis of the associations between the COMT Val158Met and the PPARγ Pro12Ala polymorphisms and AD in subjects. Meta-analysis showed no association between AD and the COMT G allele in any of the study subjects [odds ratio (OR) = 0.972, 95 % confidence intervals (95 % CI) = 0.893-1.059, p = 0.515]. Stratification by ethnicity indicated an association between the COMT GG+GA genotype and AD in an Asian group (OR = 0.702, 95 % CI = 0.517-0.953, p = 0.023), but not in Europeans (OR = 1.058, 95 % CI = 0.868-1.289, p = 0.579). Homozygote contrast analysis showed the same pattern for the COMT GG+GA genotype. Meta-analysis showed no association between AD and the PPARγ polymorphism (OR for the C allele = 0.963, 95 % CI = 0.818-1.134, p = 0.649). This meta-analysis identified an association between AD and the COMT Val158Met polymorphism in Asians but not in Europeans, but it revealed no association between AD and the PPARγ Pro12Ala polymorphism.