156 results on '"Vecchione L"'
Search Results
2. Energy and Economic Analysis of a Residential Solar Organic Rankine Plant
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Bocci, E., Villarini, M., Vecchione, L., Sbordone, D., Di Carlo, A., and Dell’Era, A.
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- 2015
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3. DEA (data envelopment analysis)-assisted supporting measures for ground coupled heat pumps implementing in Italy: A case study
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Longo, L., Colantoni, A., Castellucci, S., Carlini, M., Vecchione, L., Savuto, E., Pallozzi, V., Di Carlo, A., Bocci, E., Moneti, M., Cocchi, S., and Boubaker, K.
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- 2015
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4. Distal and proximal colon cancers differ in terms of molecular, pathological, and clinical features
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Missiaglia, E., Jacobs, B., D'Ario, G., Di Narzo, A.F., Soneson, C., Budinska, E., Popovici, V., Vecchione, L., Gerster, S., Yan, P., Roth, A.D., Klingbiel, D., Bosman, F.T., Delorenzi, M., and Tejpar, S.
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- 2014
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5. State of Art of Small Scale Biomass Gasification Power Systems: A Review of the Different Typologies
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Bocci, E., Sisinni, M., Moneti, M., Vecchione, L., Di Carlo, A., and Villarini, M.
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- 2014
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6. Epidermal growth factor-like domain 7 promotes migration and invasion of human trophoblast cells through activation of MAPK, PI3K and NOTCH signaling pathways
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Massimiani, M., Vecchione, L., Piccirilli, D., Spitalieri, P., Amati, F., Salvi, S., Ferrazzani, S., Stuhlmann, H., and Campagnolo, L.
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- 2015
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7. Weekly docetaxel and capecitabine is not effective in the treatment of advanced gastric cancer: a phase II study
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Orditura, M., Martinelli, E., Galizia, G., Carlomagno, C., Aurilio, G., Vecchione, L., Lieto, Eva, De Placido, S., Catalano, G., Ciardiello, F., and De Vita, F.
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- 2006
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8. Panitumumab a novel drug in cancer treatment
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Cartenì, G., Fiorentino, R., Vecchione, L., Chiurazzi, B., and Battista, C.
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- 2007
9. Effects of Goji berries supplementation on the productive performance of rabbit.
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Menchetti, L., Vecchione, L., Filipescu, I., Petrescu, V.F., Fioretti, B., Beccari, T., Ceccarini, M.R., Codini, M., Quattrone, A., Trabalza-Marinucci, M., Barbato, O., and Brecchia, G.
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TRADITIONAL medicine , *BERRIES , *DIETARY supplements , *RABBITS , *NUTRITION - Abstract
Highlights • For the first time, the effects of Goji supplementation were evaluated on the rabbit. • Goji supplementations improve the pre and post weaning productive performance. • The use of Goji berries in rabbit nutrition is proposed. Abstract Recognized by the traditional medicine and recent scientific research studies, Lycium barbarum berries (Goji berries) have beneficial effects on human and animal health. The aim of our study was to evaluate the effects of Goji berries on the productive performance of rabbits. One month before insemination, 60 New Zealand White does were randomly assigned to one of the following 3 dietary treatments: commercial standard diet (C); C supplemented with 1% Goji berries (LG); and C supplemented with 3% Goji berries (HG). After weaning up to 91 days of age, 15 randomly selected rabbits/group were fed the same diet as the mothers (C, LG, and HG). Non-pregnant and lactating does of C group showed the highest feed intake (P < 0.01), although no significant differences in body weight (BW) were observed between groups. Nutritional treatment did not affect the offspring's feed intake. However, the rabbits fed with Goji supplementation showed not only higher mean BW both during growth (P < 0.001) and at slaughter (P < 0.01), but also better feed conversion ratio (FCR; P < 0.01) than the control group. Rabbits of LG group showed the best performances in the pre-weaning period which was probably related to the highest milk production of the LG does (P < 0.001). Indeed, LG group showed lower pre-weaning mortality (P < 0.05), higher litter size (P < 0.05), and higher litter weight (P < 0.05) at day 18 as well as higher litter size at weaning (P = 0.05) compared to C group. In conclusion, the present study demonstrates that a low percentage of dietary supplementation with Goji berry improves both reproductive and productive traits of rabbits. Although further studies are needed, our study paves the way for the use of Goji berries in the rabbit nutrition. [ABSTRACT FROM AUTHOR]
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- 2019
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10. Untersuchungen über das Verhalten der Natriumverteilung und des Gesamtwasserinhalts bei experimentellen Hornhautverpflanzungen
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Delogu, A. and Vecchione, L.
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- 1962
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11. Intrinsic resistance to selumetinib, a selective inhibitor of MEK1/2, by cAMP-dependent protein kinase A activation in human lung and colorectal cancer cells.
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Troiani, T, Vecchione, L, Martinelli, E, Capasso, A, Costantino, S, Ciuffreda, L P, Morgillo, F, Vitagliano, D, D'Aiuto, E, De Palma, R, Tejpar, S, Van Cutsem, E, De Lorenzi, M, Caraglia, M, Berrino, L, and Ciardiello, F
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PROTEIN kinases , *LUNG cancer , *COLON cancer , *CANCER cells , *GENE expression - Abstract
Background:MEK is activated in ∼40% colorectal cancer (CRC) and 20-30% non-small cell lung cancer (NSCLC). Selumetinib is a selective inhibitor of MEK1/2, which is currently in clinical development.Methods:We evaluated the effects of selumetinib in vitro and in vivo in CRC and NSCLC cell lines to identify cancer cell characteristics correlating with sensitivity to MEK inhibition.Results:Five NSCLC and six CRC cell lines were treated with selumetinib and classified according to the median inhibitory concentration (IC50) values as sensitive (1 μM) or resistant (>1 μM). In selumetinib-sensitive cancer cell lines, selumetinib treatment induced G1 cell-cycle arrest and apoptosis and suppression of tumour growth as xenografts in immunodeficient mice. Evaluation of intracellular effector proteins and analysis of gene mutations showed no correlation with selumetinib sensitivity. Microarray gene expression profiles revealed that the activation of cAMP-dependent protein kinase A (PKA) was associated with MEK inhibitor resistance. Combined targeting of both MEK and PKA resulted in cancer cell growth inhibition of MEK inhibitor-resistant cancer cell lines in vitro and in vivo.Conclusion:This study provides molecular insights to explain resistance to an MEK inhibitor in human cancer cell lines. [ABSTRACT FROM AUTHOR]
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- 2012
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12. Energy Characterization and Gasi?cation of Biomass Derived by Hazelnut Cultivation: Analysis of Produced Syngas by Gas Chromatography.
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Monarca, D., Colantoni, A., Cecchini, M., Longo, L., Vecchione, L., Carlini, M., and Manzo, A.
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SYNTHESIS gas ,FOSSIL fuels ,GAS chromatography ,BIOMASS ,ELECTRIC power production research ,COMBUSTION research ,INTERNAL combustion engines - Abstract
Modern agriculture is an extremely energy intensive process. However, high agricultural productivities and the growth of green revolution has been possible only by large amount of energy inputs, especially those coming from fossil fuels. These energy resources have not been able to provide an economically viable solution for agricultural applications. Biomass energy-based systems had been extensively used for transportation and on farm systems during World War II: the most common and reliable solution was wood or biomass gasification. The latter means incomplete combustion of biomass resulting in production of combustible gases which mostly consist of carbon monoxide (CO), hydrogen (H
2 ) and traces of methane (CH4 ). This mixture is called syngas, which can be successfully used to run internal combustion engines (both compression and spark ignition) or as substitute for furnace oil in direct heat applications. The aim of the present paper is to help the experimentation of innovative plants for electric power production using agro-forest biomass derived by hazelnut cultivations. An additional purpose is to point out a connection among the chemical and physical properties of the outgoing syngas by biomass characterization and gas-chromatography analysis. [ABSTRACT FROM AUTHOR]- Published
- 2012
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13. A multicenter phase II study of induction chemotherapy with FOLFOX-4 and cetuximab followed by radiation and cetuximab in locally advanced oesophageal cancer.
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De Vita, F., Orditura, M., Martinelli, E., Vecchione, L., Innocenti, R., Sileni, V. C., Pinto, C., Di Maio, M., Farella, A., Troiani, T., Morgillo, F., Napolitano, V., Ancona, E., Di Martino, N., Ruol, A., Galizia, G., Del Genio, A., and Ciardiello, F.
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ESOPHAGEAL cancer ,COMBINATION drug therapy ,PATIENTS ,SURGERY ,CETUXIMAB ,RADIOTHERAPY ,CYTOKINES ,NEUTROPENIA ,POSITRON emission tomography - Abstract
Background: Preoperative chemoradiotherapy (CRT) improves the survival of patients with oesophageal cancer when compared with surgery alone.Methods: We conducted a phase II, multicenter trial of FOLFOX-4 and cetuximab in patients with locally advanced oesophageal cancer (LAEC) followed by daily radiotherapy (180 cGy fractions to 5040 cGy) with concurrent weekly cetuximab. Cytokines levels potentially related to cetuximab efficacy were assessed using multiplex-bead assays and enzyme-linked immunosorbent assay at baseline, at week 8 and at week 17. Primary end point was complete pathological response rate (pCR).Results: In all, 41 patients were enroled. Among 30 patients who underwent surgery, a pCR was observed in 8 patients corresponding to a rate of 27%. The most frequent grade 3/4 toxicity was skin (30%) and neutropenia (30%). The 36-month survival rates were 85 and 52% in patients with pathological CR or PR vs 38 and 33% in patients with SD or PD.Conclusions: Incorporating cetuximab into a preoperative regimen for LAEC is feasible; no correlation between cytokines changes and patient outcome was observed. Positron emission tomography/computed tomography study even if influenced by the small number of patients appears to be able to predict patients outcome both as early and late metabolic response. [ABSTRACT FROM AUTHOR]- Published
- 2011
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14. Craniofacial Morphology in Myostatin-deficient Mice.
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Vecchione, L., Byron, C., Cooper, G. M., Barbano, T., Hamrick, M. W., Sciote, J. J., and Mooney, M. P.
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FACIAL muscles ,MASTICATORY muscles ,MASSETER muscle ,MAXILLARY expansion ,MORPHOLOGY ,ONTOGENY ,MANDIBLE ,LABORATORY mice - Abstract
GDF-8 (myostatin) is a negative growth regulator of skeletal muscle, and myostatin-deficient mice are hypermuscular. Muscle size and force production are thought to influence growth of the craniofacial skeleton. To test this relationship, we compared masticatory muscle size and craniofacial dimensions in myostatin-deficient and wild-type CD-1 control mice. Myostatin-deficient mice had significantly (p < 0.01) greater body (by 18%) and masseter muscle weight (by 83%), compared with wild-type controls. Significant differences (p < 0.05) were noted for cranial vault length, maxillary length, mandibular body length, and mandibular shape index. Significant correlations were noted between masseter muscle weight and mandibular body length (r = 0.68; p < 0.01), cranial vault length (r = -0.57; p < 0.05), and the mandibular shape index (r = -0.56; p < 0.05). Masticatory hypermuscularity resulted in significantly altered craniofacial morphology, probably through altered biomechanical stress. These findings emphasize the important role that masticatory muscle function plays in the ontogeny of the cranial vault, the maxilla, and, most notably, the mandible. [ABSTRACT FROM AUTHOR]
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- 2007
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15. STUDIES OF THE MECHANISM OF THE ACTION OF THE SODIUM IODATE ON THE RABBIT RETINA.
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Berardinis, E., Vecchione, L., and Tieri, O.
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- 1964
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16. MONOLATERAL CATARACT PROVOKED WITH IODOACETIC ACID.
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Tieri, O. and Vecchione, L.
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- 1963
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17. L'ACTIVITÉ PHOSPHOGLUCOMUTASIQUE DE LA RÉTINE DE LAPIN.
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Vecchione, L., Tieri, O., and Rinaldi, R.
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- 1962
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18. MONOLATERAL RETINAL DEGENERATION DUE TO SODIUM FLUORIDE.
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Berardinis, E., Tieri, O., and Vecchione, L.
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- 1962
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19. THE ACTION OF ALPHA-CHYMOTRYPSIN UPON THE LACTIC-DEHYDROGENASE OF THE CORNEA.
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Tieri, O. and Vecchione, L.
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- 1962
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20. 6566 A multicenter phase II study of induction CT with Folfox-4 and Cetuximab followed by RT and Cetuximab in locally advanced esophageal cancer (LAEC)
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De Vita, F., Vecchione, L., Orditura, M., Innocente, R., Farella, A., Morgillo, F., Pinto, C., Sileni, V. Chiarion, Ruol, A., and Ciardiello, F.
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- 2009
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21. 6565 The role of PET-TC in predicting the pCR in locally-advanced esophageal cancer (LAEC) after a preoperative CT-RT treatment: data from B152 trial
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Vecchione, L., De Vita, F., Farella, A., Martinelli, E., Orditura, M., Innocente, R., Pinto, C., Sileni, V. Chiarion, Ciardiello, F., and Troiani, T.
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- 2009
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22. 1221 Enhanced sensitivity to Bortezomib pro apoptotic effects in human cancer cells with acquired resistance to anti-EGFR TKIs
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Morgillo, F., Cantile, F., Fasano, M., Troiani, T., Martinelli, E., Vecchione, L., Orditura, M., De Vita, F., and Ciardiello, F.
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- 2009
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23. 1223 A model of synergistic antitumour activity of sorafenib, a multikinase inhibitor of Raf, VEGF and PDGF receptors, with anti-EGFR inhibitors (cetuximab and erlotinib) in a panel of colorectal and lung cancer cell lines
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Martinelli, E., Troiani, T., Morgillo, F., Vecchione, L., Orditura, M., De Vita, F., Rodolico, G., Berrino, L., and Ciardiello, F.
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- 2009
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24. A4. EGFL7 in placenta trophoblast and endothelial cells: implications in the pathogenesis of pre-eclampsia.
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Massimiani, M., Salvi, S., Piccirilli, D., Vecchione, L., Moresi, S., Ferrazzani, S., Stuhlmann, H., and Campagnolo, L.
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FETAL development ,TROPHOBLAST ,ENDOTHELIAL cells ,RISK factors of preeclampsia ,EPIDERMAL growth factor - Abstract
Introduction: Placental development requires invasion and differentiation of trophoblast cells, together with coordinated fetal vasculogenesis and maternal vascular remodeling. During placental development, extravillous cytotrophoblasts invade the uterine spiral arteries of the decidua and myometrium. These invasive cytotrophoblasts replace the endothelial layer of the maternal spiral arteries, transforming them from high-resistance vessels into large-caliber capacitance vessels capable of adequately nourishing the fetus. These events are fine-tuned by a variety of factors critical for a successful pregnancy. Inadequate cytotrophoblast invasion and an incomplete uterine spiral artery remodeling may result in disorders of pregnancy, including intrauterine growth restriction, pre-term labor and preeclampsia (PE). Recent studies suggested that epidermal growth factor-like domain 7 (EGFL7) may play a role in this context. EGFL7, originally identified as an endothelial-restricted gene, is critical for embryonic vascular development. We recently demonstrated that EGFL7 in the placenta is expressed not only by endothelial cells of both the maternal and fetal vasculature, but also by the trophoblast cell lineage, throughout placental development. Previous studies showed that EGFL7 is able to interact with and modulate NOTCH signaling. Moreover, EGFL7 is able to activate EGFR, whose pathways play a major role in trophoblast migration. Methods: To investigate the role of EGFL7 in the trophoblast, we generated stable overexpression and downregulation of EGFL7 in both the human choriocarcinoma cell line Jeg3 and primary human trophoblast. The migration and invasion ability of these cells were tested using wounding and transwell assays. Protein extracts from serum starved EGFL7-overexpressing trophoblast cells were analyzed by western blot for EGFR, ERK and AKT phosphorylation. In addition, we evaluated if EGFL7 overexpression in trophoblast cells is associated to altered expression of the NOTCH signaling pathway using immunofluorescence and qRTPCR. By using inhibitors of both pathways, variations in migration/invasion ability induced by EGFL7 overexpression were investigated. Spatial distribution of EGFL7 was studied by immunofluorescence and qRT-PCR analyses in placental tissues of normal and preeclamptic pregnant women. Results: EGFL7 overexpression in Jeg3 and in primary trophoblast cells resulted in significantly increased cell migration and invasiveness, while its knockdown strongly reduced both phenomena. Analysis of EGFR, MAPK and PI3K pathways and the use of specific inhibitors in transwell assay showed that EGFL7 promoted trophoblast cell motility by activating these pathways. In addition, we demonstrated that EGFL7 triggered migration of trophoblast cells involved a concomitant activation of NOTCH signaling. Immunofluorescence analysis of placental tissues from preeclamptic (n = 10) and normal pregnant women (n = 10) showed lower levels of EGFL7 in both endothelial and trophoblast cells. This observation was quantified by qRT-PCR, which revealed that EGFL7 mRNA expression was significantly decreased by more than 10-fold in PE when compared to normal pregnancies. Conclusions: Our data suggest that EGFL7 regulates cell migration and invasion of trophoblast cells by activating MAPK, PI3K and NOTCH signaling pathways. These results suggest a correlation between EGFL7 reduced expression and the inadequate trophoblast invasion observed in PE. [ABSTRACT FROM PUBLISHER]
- Published
- 2016
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25. Detection of erbB2 copy number variations in plasma of patients with esophageal carcinoma
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Iolascon Achille, Troncone Giancarlo, Gemei Marica, Montanaro Donatella, Capasso Mario, De Antonellis Pasqualino, Vecchione Loredana, Petrosino Giuseppe, Andolfo Immacolata, Orditura Michele, Ciardiello Fortunato, De Vita Fernando, and Zollo Massimo
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esophageal carcinoma ,cell-free DNA ,erbB2 copy number variation ,prognostic marker ,CTCs ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background Mortality is high in patients with esophageal carcinoma as tumors are rarely detected before the disease has progressed to an advanced stage. Here, we sought to isolate cell-free DNA released into the plasma of patients with esophageal carcinoma, to analyze copy number variations of marker genes in the search for early detection of tumor progression. Methods Plasma of 41 patients with esophageal carcinoma was prospectively collected before tumor resection and chemotherapy. Our dataset resulted heterogeneous for clinical data, resembling the characteristics of the tumor. DNA from the plasma was extracted to analyze copy number variations of the erbB2 gene using real-time PCR assays. Results The real-time PCR assays for erbB2 gene showed significant (P = 0.001) copy number variations in the plasma of patients with esophageal carcinoma, as compared to healthy controls with high sensitivity (80%) and specificity (95%). These variations in erbB2 were negatively correlated to the progression free survival of these patients (P = 0.03), and revealed a further risk category stratification of patients with low VEGF expression levels. Conclusion The copy number variation of erbB2 gene from plasma can be used as prognostic marker for early detection of patients at risk of worse clinical outcome in esophageal cancer.
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- 2011
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26. Hif1α down-regulation is associated with transposition of great arteries in mice treated with a retinoic acid antagonist
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Amati Francesca, Diano Laura, Campagnolo Luisa, Vecchione Lucia, Cipollone Daria, Bueno Susana, Prosperini Gianluca, Desideri Alessandro, Siracusa Gregorio, Chillemi Giovanni, Marino Bruno, and Novelli Giuseppe
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Biotechnology ,TP248.13-248.65 ,Genetics ,QH426-470 - Abstract
Abstract Background Congenital heart defect (CHD) account for 25% of all human congenital abnormalities. However, very few CHD-causing genes have been identified so far. A promising approach for the identification of essential cardiac regulators whose mutations may be linked to human CHD, is the molecular and genetic analysis of heart development. With the use of a triple retinoic acid competitive antagonist (BMS189453) we previously developed a mouse model of congenital heart defects (81%), thymic abnormalities (98%) and neural tube defects (20%). D-TGA (D-transposition of great arteries) was the most prevalent cardiac defect observed (61%). Recently we were able to partially rescue this abnormal phenotype (CHD were reduced to 64.8%, p = 0.05), by oral administration of folic acid (FA). Now we have performed a microarray analysis in our mouse models to discover genes/transcripts potentially implicated in the pathogenesis of this CHD. Results We analysed mouse embryos (8.5 dpc) treated with BMS189453 alone and with BMS189453 plus folic acid (FA) by microarray and qRT-PCR. By selecting a fold change (FC) ≥ ± 1.5, we detected 447 genes that were differentially expressed in BMS-treated embryos vs. untreated control embryos, while 239 genes were differentially expressed in BMS-treated embryos whose mothers had also received FA supplementation vs. BMS-treated embryos. On the basis of microarray and qRT-PCR results, we further analysed the Hif1α gene. In fact Hif1α is down-regulated in BMS-treated embryos vs. untreated controls (FCmicro = -1.79; FCqRT-PCR = -1.76; p = 0.005) and its expression level is increased in BMS+FA-treated embryos compared to BMS-treated embryos (FCmicro = +1.17; FCqRT-PCR = +1.28: p = 0.005). Immunofluorescence experiments confirmed the under-expression of Hif1α protein in BMS-treated embryos compared to untreated and BMS+FA-treated embryos and, moreover, we demonstrated that at 8.5 dpc, Hif1α is mainly expressed in the embryo heart region. Conclusions We propose that Hif1α down-regulation in response to blocking retinoic acid binding may contribute to the development of cardiac defects in mouse newborns. In line with our hypothesis, when Hif1α expression level is restored (by supplementation of folic acid), a decrement of CHD is found. To the best of our knowledge, this is the first report that links retinoic acid metabolism to Hif1α regulation and the development of D-TGA.
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- 2010
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27. DEGENERATION OF THE RETINA CAUSED BY THE P-CHLORO-MERCUROBENZOATE OF SODIUM.
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Berardinis, E., Tieri, O., and Vecchione, L.
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- 1963
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28. 138: 215 MANDIBLE FRACTURES IN 120 CHILDREN: DEMOGRAPHICS, TREATMENT, OUTCOMES, AND GROWTH.
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Smith, DM, Bykowski, MR, Rottgers, SA, Vecchione, L, Cray, JJ, Naran, S, Kinsella, CR, and Losee, JE
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- 2011
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29. ANALYSIS IN VITRO OF GROWTH AND SECRETION OF THE MOUSE SUBMANDIBULAR AND SUBLINGUAL RUDIMENTS, SUBJECTED TO X-RAYS.
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Di Giovine Vecchione, L
- Published
- 1969
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30. Impact of Smoking, Body Weight, Diabetes, Hypertension and Kidney Dysfunction on Survival in Pancreatic Cancer Patients-A Single Center Analysis of 2323 Patients within the Last Decade.
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Neumann CCM, Schneider F, Hilfenhaus G, Vecchione L, Benzing C, Ihlow J, Fehrenbach U, Malinka T, Keilholz U, Stintzing S, and Pelzer U
- Abstract
In addition to being risk factors for pancreatic cancer, parameters such as smoking, diabetes, or obesity might also act as potential prognostic factors for the survival of patients initially diagnosed with pancreatic cancer. By implementing one of the largest retrospective study cohorts of 2323 pancreatic adenocarcinoma (PDAC) patients treated at a single high-volume center, potential prognostic factors for survival were evaluated on the basis of 863 cases. Since parameters such as smoking, obesity, diabetes, and hypertension can cause severe chronic kidney dysfunction, the glomerular filtration rate was also considered. In the univariate analyses, albumin ( p < 0.001), active smoking ( p = 0.024), BMI ( p = 0.018), and GFR ( p = 0.002) were identified as metabolic prognostic markers for overall survival. In multivariate analyses, albumin ( p < 0.001) and chronic kidney disease stage 2 (GFR < 90 mL/min/1.37 m
2 ; p = 0.042) were identified as independent metabolic prognostic markers for survival. Smoking presented a nearly statistically significant independent prognostic factor for survival with a p -value of 0.052. In summary, low BMI, status of active smoking, and reduced kidney function at the time of diagnosis were associated with lower overall survival. No prognostic association could be observed for presence of diabetes or hypertension.- Published
- 2023
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31. Inflammation-Based Prognostic Scores in Pancreatic Cancer Patients-A Single-Center Analysis of 1294 Patients within the Last Decade.
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Neumann CCM, Schneider F, Hilfenhaus G, Vecchione L, Felsenstein M, Ihlow J, Geisel D, Sander S, Pratschke J, Stintzing S, Keilholz U, and Pelzer U
- Abstract
Inflammatory properties are known to promote tumor progression leading to an impaired median overall survival (mOS). Various small studies have focused on a wide range of inflammation-based prognostic indicators. By using sufficient data from 1294 out of 2323 patients diagnosed with pancreatic cancer between 2009 and 2021 at our cancer center, inflammatory markers such as the neutrophil to lymphocyte ratio (NRL), the platelet to lymphocyte ratio (PLR), the lymphocyte to monocyte ratio (LMR) and the CRP to albumin ratio (CAR) were evaluated. We identified a new combined score, termed the inflammatory benchmark index (IBI). We performed univariate and multivariate overall survival analyses and identified optimal prognostic cut-off values for each parameter. In univariate analyses, advanced age ( p < 0.001), gender ( p < 0.001), tumor stage ( p < 0.001), CA19-9 ( p = 0.001), NLR ( p = 0.001), LMR ( p = 0.004), PLR ( p = 0.004), CAR ( p = 0.001) and IBI ( p = 0.001) were identified as prognostic markers. In multivariate analyses advanced age ( p < 0.001), gender ( p = 0.001), tumor stage ( p < 0.001), CA19-9 ( p < 0.001), NLR ( p = 0.001), LMR ( p = 0.038), CAR ( p < 0.001) and IBI ( p < 0.001) were independent prognostic markers. These findings emphasize the impact of inflammation in pancreatic cancer, provide easily accessible prognostic values for the clinician, and may be useful as stratification parameters for trials aimed at patient inflammation or immune response.
- Published
- 2023
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32. NeoRAS wild-type in metastatic colorectal cancer: Myth or truth?-Case series and review of the literature.
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Osumi H, Vecchione L, Keilholz U, Vollbrecht C, Alig AHS, von Einem JC, Stahler A, Striefler JK, Kurreck A, Kind A, Modest DP, Stintzing S, and Jelas I
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- Colorectal Neoplasms pathology, Female, Humans, Male, Middle Aged, Neoplasm Metastasis, Circulating Tumor DNA metabolism, Colorectal Neoplasms genetics, ras Proteins genetics
- Abstract
Upfront KRAS and NRAS gene testing ('RAS') is the standard of care for metastatic colorectal cancer (mCRC), to guide first-line treatment. The presence of RAS mutation (MT) is a negative predictor for the efficacy of anti-EGFR antibodies and the use of cetuximab and panitumumab is restricted to RAS wild-type (WT) mCRC. Conversion from RAS WT to RAS MT mCRC after treatment with anti-EGFR antibodies is a known and well-described acquired resistance mechanism. The by far less frequent 'NeoRAS wild-type' phenomenon (reversion from RAS MT to RAS WT) has recently drawn attention. The proposed effect of chemotherapy on RAS status in mCRC patients is not fully understood. Because of the intriguing biological consequence of a RAS MT to RAS WT reversion, subsequent treatment of NeoRAS WT patients with anti-EGFR antibodies is increasingly being discussed. Here, we report three clinical cases of NeoRAS WT mCRC patients, which received standard-of-care regimens for RAS MT mCRC. Anti-EGFR antibodies were used in two out of three patients after progression of the disease. One of the patients had a long-term response. In line with our observations, NeoRAS WT phenomenon occurs in clinical practice. Retesting of RAS status during treatment should be discussed in patients with unusual long-term clinical courses of RAS MT mCRC to optimise treatment strategy and to evaluate the use of anti-EGFR antibodies., Competing Interests: Conflicts of interest statement L.V. received research funding from Pierre Fabre, participant in the Charité-BIH Clinician Scientist Program funded by the Charité Universitätsmedizin Berlin and Berlin Institute of Health. L.V. spouse is an employee and shareholder of Bayer AG. U.K. received honoraria from AstraZeneca, Bayer Schering Pharma, Bristol-Myers Squibb, Glycotope GmbH, Merck KGaA, MSD Oncology, Novartis, Pfizer, Roche/Genentech; consulting or advisory role for AstraZeneca, Bristol-Myers Squibb, Merck Serono, MSD Oncology, Pfizer; speakers' bureau for AstraZeneca, Bayer Schering Pharma, Bristol-Myers Squibb, Merck Serono, MSD Oncology, Novartis; and received research funding from AstraZeneca/MedImmune (Inst), Pfizer (Inst), Travel, Accommodations, Expenses: AstraZeneca, Bayer Schering Pharma, Ipsen, Merck Serono, MSD Oncology, Pierre Fabre. A.H.S.A. consulting or advisory role for Roche and received travel, accommodations, expenses from Pfizer, Roche, Eli Lilly, Novartis, PharmaMar. J.C.v.E. received honoraria from Merck, Roche, Amgen, Sanofi, Pierre Fabre, Servier, Taiho, BMS, Eisai, Novartis; consulting or advisory role for Amgen, Pierre Fabre, BMS, Servier; travel, accommodations, expenses: AstraZeneca, Apceth. A.S. received honoraria from Roche, Servier; travel, accommodations, expenses from Roche, Merck KgA, MSD Sharp & Dohme, Pfizer, Amgen. A.K. received honoraria from Taiho Pharmaceutical, Servier; travel, accommodations, expenses: Roche, Medac. D.P.M. received honoraria from Amgen, Bristol-Myers Squibb, Merck Serono, Merck Sharp & Dohme, Pfizer, Roche, Servier, Taiho Pharmaceutical; consulting or advisory role: Amgen, Merck Serono, Merck Sharp & Dohme, Roche, Servier; received research funding from Amgen (Inst), Merck Serono (Inst), Roche (Inst); travel, accommodations, expenses: Amgen, Bayer, Bristol-Myers Squibb, Merck Serono, Roche, Servier. S.S. received honoraria Amgen, Bayer, Lilly, Merck KGaA, Pierre Fabre, Roche, Sanofi, Servier, Sirtex Medical, Taiho Pharmaceutical, Takeda; consulting or advisory role: Amgen, Bayer, Boehringer Ingelheim, Lilly, Merck KGaA, MSD, Pierre Fabre, Roche; Sanofi, Servier, Takeda; research funding: Merck Serono (Inst), Pierre Fabre (Inst), Roche Molecular Diagnostics (Inst); travel, accommodations, expenses: Amgen, Bayer, Lilly, Merck KGaA, Pierre Fabre, Roche, Sanofi, Sirtex Medical, Takeda. I.J. received honoraria from Bristol-Myers Squibb, Roche. All remaining authors have declared no conflicts of interest., (Copyright © 2021 Elsevier Ltd. All rights reserved.)
- Published
- 2021
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33. Identification of BCL-XL as highly active survival factor and promising therapeutic target in colorectal cancer.
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Scherr AL, Mock A, Gdynia G, Schmitt N, Heilig CE, Korell F, Rhadakrishnan P, Hoffmeister P, Metzeler KH, Schulze-Osthoff K, Illert AL, Boerries M, Trojan J, Waidmann O, Falkenhorst J, Siveke J, Jost PJ, Bitzer M, Malek NP, Vecchione L, Jelas I, Brors B, Glimm H, Stenzinger A, Grekova SP, Gehrig T, Schulze-Bergkamen H, Jäger D, Schirmacher P, Heikenwalder M, Goeppert B, Schneider M, Fröhling S, and Köhler BC
- Subjects
- Apoptosis drug effects, Cell Line, Tumor, Cell Proliferation drug effects, Colonic Neoplasms drug therapy, Colorectal Neoplasms pathology, Humans, Myeloid Cell Leukemia Sequence 1 Protein drug effects, Myeloid Cell Leukemia Sequence 1 Protein metabolism, Proto-Oncogene Proteins c-bcl-2 drug effects, Proto-Oncogene Proteins c-bcl-2 metabolism, bcl-X Protein drug effects, Antineoplastic Agents pharmacology, Colorectal Neoplasms drug therapy, Colorectal Neoplasms metabolism, bcl-X Protein metabolism
- Abstract
Since metastatic colorectal cancer (CRC) is a leading cause of cancer-related death, therapeutic approaches overcoming primary and acquired therapy resistance are an urgent medical need. In this study, the efficacy and toxicity of high-affinity inhibitors targeting antiapoptotic BCL-2 proteins (BCL-2, BCL-XL, and MCL-1) were evaluated. By RNA sequencing analysis of a pan-cancer cohort comprising >1500 patients and subsequent prediction of protein activity, BCL-XL was identified as the only antiapoptotic BCL-2 protein that is overactivated in CRC. Consistently, pharmacologic and genetic inhibition of BCL-XL induced apoptosis in human CRC cell lines. In a combined treatment approach, targeting BCL-XL augmented the efficacy of chemotherapy in vitro, in a murine CRC model, and in human ex vivo derived CRC tissue cultures. Collectively, these data show that targeting of BCL-XL is efficient and safe in preclinical CRC models, observations that pave the way for clinical translation.
- Published
- 2020
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34. Investigating the concordance in molecular subtypes of primary colorectal tumors and their matched synchronous liver metastasis.
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Schlicker A, Ellappalayam A, Beumer IJ, Snel MHJ, Mittempergher L, Diosdado B, Dreezen C, Tian S, Salazar R, Loupakis F, Pietrantonio F, Santos Vivas C, Martinez-Villacampa MM, Villanueva A, Sanjuán X, Schirripa M, Fassan M, Martinetti A, Fucà G, Lonardi S, Keilholz U, Glas AM, Bernards R, and Vecchione L
- Subjects
- Aged, Colorectal Neoplasms metabolism, Female, Humans, Liver Neoplasms metabolism, Male, Middle Aged, Retrospective Studies, Transforming Growth Factor beta metabolism, Tumor Microenvironment physiology, Colorectal Neoplasms pathology, Liver Neoplasms pathology, Neoplasm Metastasis pathology
- Abstract
To date, no systematic analyses are available assessing concordance of molecular classifications between primary tumors (PT) and matched liver metastases (LM) of metastatic colorectal cancer (mCRC). We investigated concordance between PT and LM for four clinically relevant CRC gene signatures. Twenty-seven fresh and 55 formalin-fixed paraffin-embedded pairs of PT and synchronous LM of untreated mCRC patients were retrospectively collected and classified according to the MSI-like, BRAF-like, TGFB activated-like and the Consensus Molecular Subtypes (CMS) classification. We investigated classification concordance between PT and LM and association of TGFBa-like and CMS classification with overall survival. Fifty-one successfully profiled matched pairs were used for analyses. PT and matched LM were highly concordant in terms of BRAF-like and MSI-like signatures, (90.2% and 98% concordance, respectively). In contrast, 40% to 70% of PT that were classified as mesenchymal-like, based on the CMS and the TGFBa-like signature, respectively, lost this phenotype in their matched LM (60.8% and 76.5% concordance, respectively). This molecular switch was independent of the microenvironment composition. In addition, the significant change in subtypes was observed also by using methods developed to detect cancer cell-intrinsic subtypes. More importantly, the molecular switch did not influence the survival. PT classified as mesenchymal had worse survival as compared to nonmesenchymal PT (CMS4 vs CMS2, hazard ratio [HR] = 5.2, 95% CI = 1.5-18.5, P = .0048; TGFBa-like vs TGFBi-like, HR = 2.5, 95% CI = 1.1-5.6, P = .028). The same was not true for LM. Our study highlights that the origin of the tissue may have major consequences for precision medicine in mCRC., (© 2020 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)
- Published
- 2020
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35. ESMO management and treatment adapted recommendations in the COVID-19 era: colorectal cancer.
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Vecchione L, Stintzing S, Pentheroudakis G, Douillard JY, and Lordick F
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- Betacoronavirus, COVID-19, Colorectal Neoplasms diagnosis, Colorectal Neoplasms pathology, Coronavirus Infections prevention & control, Delivery of Health Care standards, Humans, Medical Oncology organization & administration, Pneumonia, Viral prevention & control, Practice Guidelines as Topic, SARS-CoV-2, Telemedicine standards, Colorectal Neoplasms therapy, Coronavirus Infections epidemiology, Medical Oncology standards, Pandemics prevention & control, Pneumonia, Viral epidemiology
- Abstract
COVID-19 pandemic challenges health system capacities in many countries. National healthcare services have to manage unexpected shortage of healthcare resources that have to be reallocated according to the principles of fair and ethical prioritisation, in order to maintain the highest levels of care to all patients, ensure the safety of patients and healthcare workers and save as many lives as possible. Beyond that, cancer care services have to pursue restructuring, following the same evidence-based dispositions. In this article, we propose guidance to the management of colorectal cancer during the pandemic, prioritised according to a three-tiered framework, based on expert clinical judgement and magnitude of benefit expected from specific interventions. Since the availability of resources for diagnostic procedures, surgery and postoperative care, systemic therapy and radiotherapy may differ, authors did separate prioritisation analyses. The impact of postponing or abrogating cancer interventions on outcomes according to a high, medium or low priority scale, is outlined and discussed. The implementation of healthcare services using telemedicine is explored: it reveals itself as functional and effective for limiting patients' need to travel to centres and thereby has the potential to reduce diffusion of severe acute respiratory syndrome coronavirus 2. Colorectal cancer demands a considerable amount of medical resources. Therefore, the redefinition of its diagnostic and therapeutic algorithms with a rigorous method is crucial in order to ensure the highest quality of continuum of care in the broader context of the pandemic and the challenged healthcare systems., Competing Interests: Competing interests: LV is a member of the GI connect group, spouse is employee and shareholder of Bayer AG. LV reported grants for translational research from Pierre Fabre und is participant in the Charité-BIH Clinician Scientist Program funded by the Charité Universitaetsmedizin Berlin und Berlin Institute of Health. SS: personal fees from Amgen, Bayer, Isofol, Lilly, Merck KGaA, MSD, Nordic Pharma, Pierre-Fabre, Roche, Sanofi, Sirtex, Servier, Takeda, Taiho, research grants from Pierre-Fabre, Merck KGaA, Roche. GP: Research grants from Amgen, AstraZeneca, Roche, MSD, BMS, Merck, outside of the submitted work. FL: personal fees from Amgen, Astellas, AstraZeneca, Biontech, Eli Lilly, Elsevier, Excerpta Medica, Imedex, Infomedica, Medscape, MedUpdate, Merck Serono, Merck Sharp & Dohme, Oncovis, Promedicis, Springer Nature, StreamedUp!, and Zymeworks; and research grants and personal fees from Bristol-Myers Squibb and Iomedico, outside the submitted work., (© Author (s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. Published by BMJ on behalf of the European Society for Medical Oncology.)
- Published
- 2020
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36. Liquid biopsy assessment of synchronous malignancies: a case report and review of the literature.
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Liebs S, Nonnenmacher A, Klauschen F, Keilholz U, and Vecchione L
- Abstract
Assessment of patients with synchronous primary cancers and metastases is challenging, as it can be difficult to assign the metastases to the correct primary due to low differentiation, high similarity on histology or inaccessibility of tumour tissue. Systemic treatment for metastatic disease, however, needs to be directed at the leading histology or cover multiple tumour types with the same regimen. Considering the additional obstacles in cancer management, including tumour heterogeneity and clonal evolution, blood-based genomic profiling ('liquid biopsy') is suggested to be a useful tool to provide accessible tumour-derived biomarkers. We herein report a case of a patient with independent primary tumours of the colon and pancreas, as well as liver metastases. All lesions were resected and genotyped revealing KRAS mutations G12C and G12D in the primary tumours, respectively. The G12D mutation detected in the pancreatic tumour was retrieved in the metastasis, thus confirming the pancreatic cancer to be the origin of the liver lesions. The prevalence of the pancreatic tumour was additionally verified by the detection of the G12D variant in circulating cell-free DNA (cfDNA). This case demonstrates the utility of liquid biopsy to identify the predominant tumour burden in patients with multiple primary cancers, based on the detection of the tumour-associated gene mutation in the plasma. Serial monitoring through liquid biopsies might allow disease surveillance to guide cancer management. The review of the literature highlights the importance of liquid biopsies in personalised oncology, even though only one case report refers to the benefit of cfDNA analysis in a patient affected by synchronous primary tumours., Competing Interests: Competing interests: LV is a member of the GI connect group, spouse is employee and shareholder of Bayer AG. SL, AN, FK and UK have no conflicts of interest to declare.
- Published
- 2019
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37. Importance of genetic screens in precision oncology.
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Mulero-Sánchez A, Pogacar Z, and Vecchione L
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Precision oncology aims to distinguish which patients are eligible for a specific treatment in order to achieve the best possible outcome. In the last few years, genetic screens have shown their potential to find the new targets and drug combinations as well as predictive biomarkers for response and/or resistance to cancer treatment. In this review, we outline how precision oncology is changing over time and describe the different applications of genetic screens. Finally, we present some practical examples that describe the utility and the limitations of genetic screens in precision oncology., Competing Interests: Competing interests: LV is a member of the GI connect group, spouse is employee and shareholder of Bayer AG.
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- 2019
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38. Relevance to investigate different stages of pregnancy to highlight toxic effects of nanoparticles: The example of silica.
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Pietroiusti A, Vecchione L, Malvindi MA, Aru C, Massimiani M, Camaioni A, Magrini A, Bernardini R, Sabella S, Pompa PP, and Campagnolo L
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- Animals, Dose-Response Relationship, Drug, Female, Maternal-Fetal Exchange physiology, Mice, Nanoparticles metabolism, Nanoparticles toxicity, Particle Size, Placenta metabolism, Pregnancy metabolism, Silicon Dioxide metabolism, Silicon Dioxide toxicity, Tissue Distribution drug effects, Tissue Distribution physiology, Maternal-Fetal Exchange drug effects, Nanoparticles administration & dosage, Placenta drug effects, Pregnancy drug effects, Silicon Dioxide administration & dosage
- Abstract
Amorphous silica nanoparticles (SiO
2 NPs) have been recognized as safe nanomaterial, hence their use in biomedical applications has been explored. Data, however, suggest potential toxicity of SiO2 NPs in pregnant individuals. However, no studies relating nanoparticle biokinetic/toxicity to the different gestational stages are currently available. In this respect, we have investigated the possible embryotoxic effects of three-size and two-surface functionalization SiO2 NPs in mice. After intravenous administration of different concentrations at different stages of pregnancy, clinical and histopathological evaluations, performed close to parturition, did not show signs of maternal toxicity, nor effects on placental/fetal development, except for amino-functionalized 25 nm NPs. Biodistribution was studied by ICP-AES 24 h after administration, and demonstrates that all particles distributed to placenta and conceptuses/fetuses, although size, surface charge and gestational stage influenced biodistribution. Our data suggest the need of comprehensive toxicological studies, covering the entire gestation to reliably assess the safety of nanoparticle exposure during pregnancy., (Copyright © 2018 Elsevier Inc. All rights reserved.)- Published
- 2018
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39. Should cT2 esophageal cancer get neoadjuvant treatment before surgery?
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Thuss-Patience P, Vecchione L, and Keilholz U
- Abstract
Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.
- Published
- 2017
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40. Silver nanoparticles inhaled during pregnancy reach and affect the placenta and the foetus.
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Campagnolo L, Massimiani M, Vecchione L, Piccirilli D, Toschi N, Magrini A, Bonanno E, Scimeca M, Castagnozzi L, Buonanno G, Stabile L, Cubadda F, Aureli F, Fokkens PH, Kreyling WG, Cassee FR, and Pietroiusti A
- Subjects
- Animals, Cytokines analysis, Female, Mice, Pregnancy, Inhalation Exposure adverse effects, Inhalation Exposure analysis, Maternal Exposure adverse effects, Metal Nanoparticles administration & dosage, Metal Nanoparticles toxicity, Placenta chemistry, Placenta drug effects, Silver administration & dosage, Silver pharmacokinetics, Silver toxicity
- Abstract
Recently, interest for the potential impact of consumer-relevant engineered nanoparticles on pregnancy has dramatically increased. This study investigates whether inhaled silver nanoparticles (AgNPs) reach and cross mouse placental barrier and induce adverse effects. Apart from their relevance for the growing use in consumer products and biomedical applications, AgNPs are selected since they can be unequivocally identified in tissues. Pregnant mouse females are exposed during the first 15 days of gestation by nose-only inhalation to a freshly produced aerosol of 18-20 nm AgNPs for either 1 or 4 h, at a particle number concentration of 3.80 × 107 part./cm
-3 and at a mass concentration of 640 μg/m³. AgNPs are identified and quantitated in maternal tissues, placentas and foetuses by transmission electron microscopy coupled with energy-dispersive X-ray spectroscopy and single-particle inductively coupled plasma mass spectrometry. Inhalation of AgNPs results in increased number of resorbed foetuses associated with reduced oestrogen plasma levels, in the 4 h/day exposed mothers. Increased expression of pregnancy-relevant inflammatory cytokines is also detected in the placentas of both groups. These results prove that NPs are able to reach and cross the mouse placenta and suggest that precaution should be taken with respect to acute exposure to nanoparticles during pregnancy.- Published
- 2017
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41. Immunotherapy in Gastrointestinal Cancers.
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Procaccio L, Schirripa M, Fassan M, Vecchione L, Bergamo F, Prete AA, Intini R, Manai C, Dadduzio V, Boscolo A, Zagonel V, and Lonardi S
- Subjects
- Humans, Biomarkers, Tumor immunology, Gastrointestinal Neoplasms immunology, Gastrointestinal Neoplasms therapy, Immunotherapy methods, Translational Research, Biomedical methods
- Abstract
Gastrointestinal cancers represent a major public health problem worldwide. Immunotherapeutic strategies are currently under investigation in this setting and preliminary results of ongoing trials adopting checkpoint inhibitors are striking. Indeed, although a poor immunogenicity for GI has been reported, a strong biological rationale supports the development of immunotherapy in this field. The clinical and translational research on immunotherapy for the treatment of GI cancers started firstly with the identification of immune-related mechanisms possibly relevant to GI tumours and secondly with the development of immunotherapy-based agents in clinical trials. In the present review a general overview is firstly provided followed by a focus on major findings on gastric, colorectal, and hepatocellular carcinomas. Finally, pathological and molecular perspectives are provided since many efforts are ongoing in order to identify possible predictive biomarkers and to improve patients' selection. Many issues are still unsolved in this field; however, we strongly believe that immunotherapy might positively affect the natural history of a subgroup of GI cancer patients improving outcome and the overall quality of life.
- Published
- 2017
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42. A Vulnerability of a Subset of Colon Cancers with Potential Clinical Utility.
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Vecchione L, Gambino V, Raaijmakers J, Schlicker A, Fumagalli A, Russo M, Villanueva A, Beerling E, Bartolini A, Mollevi DG, El-Murr N, Chiron M, Calvet L, Nicolazzi C, Combeau C, Henry C, Simon IM, Tian S, in 't Veld S, D'ario G, Mainardi S, Beijersbergen RL, Lieftink C, Linn S, Rumpf-Kienzl C, Delorenzi M, Wessels L, Salazar R, Di Nicolantonio F, Bardelli A, van Rheenen J, Medema RH, Tejpar S, and Bernards R
- Subjects
- Animals, Antineoplastic Agents, Phytogenic administration & dosage, Cells, Cultured, Colonic Neoplasms classification, Colonic Neoplasms drug therapy, Heterografts, Humans, Mice, Mice, Nude, Microtubules drug effects, Microtubules metabolism, Molecular Chaperones genetics, Neoplasm Transplantation, Nuclear Pore Complex Proteins genetics, Proto-Oncogene Proteins B-raf genetics, Vinblastine administration & dosage, Vinblastine pharmacology, Vinorelbine, Antineoplastic Agents, Phytogenic pharmacology, Colonic Neoplasms genetics, Colonic Neoplasms pathology, Vinblastine analogs & derivatives
- Abstract
BRAF(V600E) mutant colon cancers (CCs) have a characteristic gene expression signature that is also found in some tumors lacking this mutation. Collectively, they are referred to as "BRAF-like" tumors and represent some 20% of CCs. We used a shRNA-based genetic screen focused on genes upregulated in BRAF(V600E) CCs to identify vulnerabilities of this tumor subtype that might be exploited therapeutically. Here, we identify RANBP2 (also known as NUP358) as essential for survival of BRAF-like, but not for non-BRAF-like, CC cells. Suppression of RANBP2 results in mitotic defects only in BRAF-like CC cells, leading to cell death. Mechanistically, RANBP2 silencing reduces microtubule outgrowth from the kinetochores, thereby inducing spindle perturbations, providing an explanation for the observed mitotic defects. We find that BRAF-like CCs display far greater sensitivity to the microtubule poison vinorelbine both in vitro and in vivo, suggesting that vinorelbine is a potential tailored treatment for BRAF-like CCs., (Copyright © 2016 Elsevier Inc. All rights reserved.)
- Published
- 2016
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43. PTPN11 Is a Central Node in Intrinsic and Acquired Resistance to Targeted Cancer Drugs.
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Prahallad A, Heynen GJ, Germano G, Willems SM, Evers B, Vecchione L, Gambino V, Lieftink C, Beijersbergen RL, Di Nicolantonio F, Bardelli A, and Bernards R
- Subjects
- Animals, Cell Line, Tumor, Colonic Neoplasms genetics, Colonic Neoplasms metabolism, Colonic Neoplasms pathology, Drug Resistance, Neoplasm genetics, ErbB Receptors genetics, ErbB Receptors metabolism, Genetic Vectors, Genomic Library, High-Throughput Nucleotide Sequencing, Humans, Indoles pharmacology, Lentivirus genetics, MAP Kinase Signaling System, Melanoma genetics, Melanoma metabolism, Melanoma pathology, Mice, Mice, Inbred NOD, Protein Tyrosine Phosphatase, Non-Receptor Type 11 antagonists & inhibitors, Protein Tyrosine Phosphatase, Non-Receptor Type 11 metabolism, Proto-Oncogene Proteins B-raf genetics, Proto-Oncogene Proteins B-raf metabolism, RNA, Small Interfering genetics, RNA, Small Interfering metabolism, Sulfonamides pharmacology, Transduction, Genetic, Vemurafenib, Xenograft Model Antitumor Assays, ras Proteins genetics, ras Proteins metabolism, Antineoplastic Agents pharmacology, Colonic Neoplasms drug therapy, Drug Resistance, Neoplasm drug effects, Gene Expression Regulation, Neoplastic, Melanoma drug therapy, Protein Tyrosine Phosphatase, Non-Receptor Type 11 genetics
- Abstract
Most BRAF (V600E) mutant melanomas are sensitive to selective BRAF inhibitors, but BRAF mutant colon cancers are intrinsically resistant to these drugs because of feedback activation of EGFR. We performed an RNA-interference-based genetic screen in BRAF mutant colon cancer cells to search for phosphatases whose knockdown induces sensitivity to BRAF inhibition. We found that suppression of protein tyrosine phosphatase non-receptor type 11 (PTPN11) confers sensitivity to BRAF inhibitors in colon cancer. Mechanistically, we found that inhibition of PTPN11 blocks signaling from receptor tyrosine kinases (RTKs) to the RAS-MEK-ERK pathway. PTPN11 suppression is lethal to cells that are driven by activated RTKs and prevents acquired resistance to targeted cancer drugs that results from RTK activation. Our findings identify PTPN11 as a drug target to combat both intrinsic and acquired resistance to several targeted cancer drugs. Moreover, activated PTPN11 can serve as a biomarker of drug resistance resulting from RTK activation., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2015
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44. FCGR polymorphisms and cetuximab efficacy in chemorefractory metastatic colorectal cancer: an international consortium study.
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Geva R, Vecchione L, Kalogeras KT, Jensen BV, Lenz HJ, Yoshino T, Paez D, Montagut C, Souglakos J, Cappuzzo F, Cervantes A, Frattini M, Fountzilas G, Johansen JS, Høgdall EV, Zhang W, Yang D, Yamazaki K, Nishina T, Papamichael D, Vincenzi B, Macarulla T, Loupakis F, De Schutter J, Spindler KL, Pfeiffer P, Ciardiello F, Piessevaux H, and Tejpar S
- Subjects
- Adult, Aged, Aged, 80 and over, Antineoplastic Agents therapeutic use, Cetuximab, Colorectal Neoplasms mortality, Colorectal Neoplasms pathology, Disease-Free Survival, Female, Genotyping Techniques standards, Humans, Male, Middle Aged, Neoplasm Metastasis, Survival Rate, Young Adult, Antibodies, Monoclonal, Humanized therapeutic use, Colorectal Neoplasms drug therapy, Colorectal Neoplasms genetics, ErbB Receptors antagonists & inhibitors, Germ-Line Mutation, Polymorphism, Genetic, Receptors, IgG genetics
- Abstract
Objective: We aimed to better clarify the role of germline variants of the FCG2 receptor, FCGR2A-H131R and FCGR3A-V158F, on the therapeutic efficacy of cetuximab in metastatic colorectal cancer (mCRC). A large cohort with sufficient statistical power was assembled., Design: To show a HR advantage of 0.6 in progression-free survival (PFS) for FCGR2A-HH versus the rest and FCGR3A-VV versus the rest, with an 80% power, 80 Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) wild-type (KRAS-WT) and 52 KRAS-WT patients are required, respectively. This leads to a total sample size of 952 and 619 patients, respectively. Samples were collected from 1123 mCRC patients from 15 European centres treated with cetuximab alone or in combination with chemotherapy. Fc gamma receptor (FCGR) status was centrally genotyped. Two additional externally genotyped series were included., Results: Incidences of FCGR2A-HH and FCGR3A-VV in KRAS-WT patients were 220/660 (33%) and 109/676 (16.1%) respectively. There was no difference in median PFS (mPFS) for KRAS-WT patients with FCGR2A-HH (22.0 weeks; 95% CI18.8 to 25.2) versus non-HH (22.0 weeks; 95% CI 19.4 to 24.6) or for FCGR3A-VV (16.4 weeks; 95% CI 13.0 to 19.8) versus non-VV (23 weeks; 95% CI 21.1 to 24.9) (p=0.06). Median overall survival, response rate and disease control rate assessments showed no benefit for either HH or VV., Conclusions: No differences in mPFS were found between the FCGR polymorphisms HH and the others and VV versus the others in KRAS-WT mCRC patients refractory to irinotecan, oxaliplatin and 5-fluorouracil treated with cetuximab. We cannot confirm the effects of other IgG1 antibodies, which may be weaker than previously suggested. Other markers may be needed to study the actual host antibody response to cetuximab., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)
- Published
- 2015
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45. Comprehensive In Vitro Toxicity Testing of a Panel of Representative Oxide Nanomaterials: First Steps towards an Intelligent Testing Strategy.
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Farcal L, Torres Andón F, Di Cristo L, Rotoli BM, Bussolati O, Bergamaschi E, Mech A, Hartmann NB, Rasmussen K, Riego-Sintes J, Ponti J, Kinsner-Ovaskainen A, Rossi F, Oomen A, Bos P, Chen R, Bai R, Chen C, Rocks L, Fulton N, Ross B, Hutchison G, Tran L, Mues S, Ossig R, Schnekenburger J, Campagnolo L, Vecchione L, Pietroiusti A, and Fadeel B
- Subjects
- Animals, Cell Culture Techniques, Embryonic Stem Cells drug effects, Epithelial Cells drug effects, Humans, In Vitro Techniques, Inhibitory Concentration 50, Leydig Cells drug effects, Macrophages drug effects, Male, Mice, Sertoli Cells drug effects, Silicon Dioxide, Titanium, Zinc Oxide, Nanostructures chemistry, Nanostructures toxicity, Oxides chemistry, Oxides toxicity, Toxicity Tests
- Abstract
Nanomaterials (NMs) display many unique and useful physico-chemical properties. However, reliable approaches are needed for risk assessment of NMs. The present study was performed in the FP7-MARINA project, with the objective to identify and evaluate in vitro test methods for toxicity assessment in order to facilitate the development of an intelligent testing strategy (ITS). Six representative oxide NMs provided by the EC-JRC Nanomaterials Repository were tested in nine laboratories. The in vitro toxicity of NMs was evaluated in 12 cellular models representing 6 different target organs/systems (immune system, respiratory system, gastrointestinal system, reproductive organs, kidney and embryonic tissues). The toxicity assessment was conducted using 10 different assays for cytotoxicity, embryotoxicity, epithelial integrity, cytokine secretion and oxidative stress. Thorough physico-chemical characterization was performed for all tested NMs. Commercially relevant NMs with different physico-chemical properties were selected: two TiO2 NMs with different surface chemistry - hydrophilic (NM-103) and hydrophobic (NM-104), two forms of ZnO - uncoated (NM-110) and coated with triethoxycapryl silane (NM-111) and two SiO2 NMs produced by two different manufacturing techniques - precipitated (NM-200) and pyrogenic (NM-203). Cell specific toxicity effects of all NMs were observed; macrophages were the most sensitive cell type after short-term exposures (24-72h) (ZnO>SiO2>TiO2). Longer term exposure (7 to 21 days) significantly affected the cell barrier integrity in the presence of ZnO, but not TiO2 and SiO2, while the embryonic stem cell test (EST) classified the TiO2 NMs as potentially 'weak-embryotoxic' and ZnO and SiO2 NMs as 'non-embryotoxic'. A hazard ranking could be established for the representative NMs tested (ZnO NM-110 > ZnO NM-111 > SiO2 NM-203 > SiO2 NM-200 > TiO2 NM-104 > TiO2 NM-103). This ranking was different in the case of embryonic tissues, for which TiO2 displayed higher toxicity compared with ZnO and SiO2. Importantly, the in vitro methodology applied could identify cell- and NM-specific responses, with a low variability observed between different test assays. Overall, this testing approach, based on a battery of cellular systems and test assays, complemented by an exhaustive physico-chemical characterization of NMs, could be deployed for the development of an ITS suitable for risk assessment of NMs. This study also provides a rich source of data for modeling of NM effects.
- Published
- 2015
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46. Epidermal growth factor-like domain 7 promotes migration and invasion of human trophoblast cells through activation of MAPK, PI3K and NOTCH signaling pathways.
- Author
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Massimiani M, Vecchione L, Piccirilli D, Spitalieri P, Amati F, Salvi S, Ferrazzani S, Stuhlmann H, and Campagnolo L
- Subjects
- Calcium-Binding Proteins, Cell Line, Tumor, Cell Movement drug effects, Cells, Cultured, EGF Family of Proteins, Endothelial Growth Factors antagonists & inhibitors, Endothelial Growth Factors genetics, Enzyme Inhibitors pharmacology, ErbB Receptors agonists, ErbB Receptors metabolism, Female, HEK293 Cells, Human Umbilical Vein Endothelial Cells cytology, Human Umbilical Vein Endothelial Cells drug effects, Human Umbilical Vein Endothelial Cells metabolism, Humans, MAP Kinase Signaling System drug effects, Phosphoinositide-3 Kinase Inhibitors, Placentation drug effects, Pregnancy, RNA Interference, Receptor, Notch1 antagonists & inhibitors, Receptor, Notch1 genetics, Receptor, Notch1 metabolism, Recombinant Proteins chemistry, Recombinant Proteins metabolism, Trophoblasts cytology, Trophoblasts drug effects, Endothelial Growth Factors metabolism, Phosphatidylinositol 3-Kinase metabolism, Receptor, Notch1 agonists, Signal Transduction drug effects, Trophoblasts metabolism, Up-Regulation drug effects
- Abstract
Epidermal growth factor-like domain 7 (Egfl7) is a gene that encodes a partially secreted protein and whose expression is largely restricted to the endothelia. We recently reported that EGFL7 is also expressed by trophoblast cells in mouse and human placentas. Here, we investigated the molecular pathways that are regulated by EGFL7 in trophoblast cells. Stable EGFL7 overexpression in a Jeg3 human choriocarcinoma cell line resulted in significantly increased cell migration and invasiveness, while cell proliferation was unaffected. Analysis of mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K) pathways showed that EGFL7 promotes Jeg3 cell motility by activating both pathways. We show that EGFL7 activates the epidermal growth factor receptor (EGFR) in Jeg3 cells, resulting in downstream activation of extracellular regulated kinases (ERKs). In addition, we provide evidence that EGFL7-triggered migration of Jeg3 cells involves activation of NOTCH signaling. EGFL7 and NOTCH1 are co-expressed in Jeg3 cells, and blocking of NOTCH activation abrogates enhanced migration of Jeg3 cells overexpressing EGFL7. We also demonstrate that signaling through EGFR and NOTCH converged to mediate EGFL7 effects. Reduction of endogenous EGFL7 expression in Jeg3 cells significantly decreased cell migration. We further confirmed that EGFL7 stimulates cell migration by using primary human first trimester trophoblast (PTB) cells overexpressing EGFL7. In conclusion, our data suggest that in trophoblast cells, EGFL7 regulates cell migration and invasion by activating multiple signaling pathways. Our results provide a possible explanation for the correlation between reduced expression of EGFL7 and inadequate trophoblast invasion observed in placentopathies., (© The Author 2015. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)
- Published
- 2015
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47. The tyrosine phosphatase PTPRO sensitizes colon cancer cells to anti-EGFR therapy through activation of SRC-mediated EGFR signaling.
- Author
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Asbagh LA, Vazquez I, Vecchione L, Budinska E, De Vriendt V, Baietti MF, Steklov M, Jacobs B, Hoe N, Singh S, Imjeti NS, Zimmermann P, Sablina A, and Tejpar S
- Subjects
- Caco-2 Cells, Cell Line, Tumor, Colonic Neoplasms drug therapy, Colonic Neoplasms genetics, Colonic Neoplasms pathology, Epidermal Growth Factor pharmacology, ErbB Receptors metabolism, Gefitinib, HCT116 Cells, HEK293 Cells, HT29 Cells, Humans, MAP Kinase Signaling System, Phosphorylation, Protein Kinase Inhibitors pharmacology, Proto-Oncogene Proteins c-cbl metabolism, Quinazolines pharmacology, RNA, Messenger genetics, RNA, Messenger metabolism, Receptor-Like Protein Tyrosine Phosphatases, Class 3 biosynthesis, Receptor-Like Protein Tyrosine Phosphatases, Class 3 genetics, Signal Transduction, Colonic Neoplasms enzymology, ErbB Receptors antagonists & inhibitors, Receptor-Like Protein Tyrosine Phosphatases, Class 3 metabolism, src-Family Kinases metabolism
- Abstract
Inappropriate activation of epidermal growth factor receptor (EGFR) plays a causal role in many cancers including colon cancer. The activation of EGFR by phosphorylation is balanced by receptor kinase and protein tyrosine phosphatase activities. However, the mechanisms of negative EGFR regulation by tyrosine phosphatases remain largely unexplored. Our previous results indicate that protein tyrosine phosphatase receptor type O (PTPRO) is down-regulated in a subset of colorectal cancer (CRC) patients with a poor prognosis. Here we identified PTPRO as a phosphatase that negatively regulates SRC by directly dephosphorylating Y416 phosphorylation site. SRC activation triggered by PTPRO down-regulation induces phosphorylation of both EGFR at Y845 and the c-CBL ubiquitin ligase at Y731. Increased EGFR phosphorylation at Y845 promotes its receptor activity, whereas enhanced phosphorylation of c-CBL triggers its degradation promoting EGFR stability. Importantly, hyperactivation of SRC/EGFR signaling triggered by loss of PTPRO leads to high resistance of colon cancer to EGFR inhibitors. Our results not only highlight the PTPRO contribution in negative regulation of SRC/EGFR signaling but also suggest that tumors with low PTPRO expression may be therapeutically targetable by anti-SRC therapies.
- Published
- 2014
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48. Intraoperative high-dose epinephrine infiltration in cleft palate repair.
- Author
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Kinsella CR Jr, Castillo N, Naran S, Smith DM, DeCesare GE, Cladis FP, Ford MD, Vecchione L, Jiang S, and Losee JE
- Subjects
- Adolescent, Child, Child, Preschool, Dose-Response Relationship, Drug, Electrocardiography drug effects, Female, Hemodynamics drug effects, Humans, Infant, Intraoperative Complications chemically induced, Intraoperative Complications diagnosis, Male, Retrospective Studies, United States, Vasoconstriction drug effects, Anesthesia, Local, Cleft Palate surgery, Epinephrine administration & dosage, Epinephrine adverse effects
- Abstract
Objective: Local infiltration of epinephrine before surgical procedures is a well-accepted technique to promote vasoconstriction. Typically, the dose of epinephrine is limited by the co-administration of local anesthetic as well as the risk for arrhythmogenesis and hemodynamic changes. In addition, some controversy exists regarding the acceptable dose of epinephrine given to children. This retrospective review examines the use and safety of "high-dose" epinephrine in palatoplasty at our cleft-craniofacial center., Design: A retrospective review of epinephrine use in primary palatoplasty at a tertiary children's hospital from 2003 to 2007 was performed. Operative and anesthetic records were reviewed for hypertension (systolic blood pressure, >120 or diastolic blood pressure, >70) and tachycardia (>190 beats per min) as defined by the American Heart Association guidelines, as well as dysrhythmias, intraoperative complications, and postoperative complications., Results: A total of 102 patients who underwent consecutive primary palatoplasties performed by a single surgeon were identified. After the induction of anesthesia and before incision, the patients received an initial epinephrine infiltration (without local anesthetic) up to a maximum 10 μg/kg. The average total dose of epinephrine administered during palatoplasty was 12.8 μg/kg (range, 3.2-75.0 μg/kg). Doses up to a maximum of 10 μg/kg were administered as needed at 30-minute intervals. No instances of clinically unstable tachycardia or hypertension occurred. A total of 21.6% of the patients (22/102) experienced an instance of hypertension, and only 13.7% of these (14/102) were related to epinephrine administration. One (1%) postoperative fistula was identified., Conclusions: Locally infiltrated high-dose epinephrine during palatoplasty can be safely used as a means of vasoconstriction. Doses reaching a maximum of 10 μg/kg, administered as needed at 30-minute intervals, do not seem to be a significant risk for hemodynamic instability, intraoperative complications, or postoperative complications.
- Published
- 2014
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49. Antitumor activity of pimasertib, a selective MEK 1/2 inhibitor, in combination with PI3K/mTOR inhibitors or with multi-targeted kinase inhibitors in pimasertib-resistant human lung and colorectal cancer cells.
- Author
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Martinelli E, Troiani T, D'Aiuto E, Morgillo F, Vitagliano D, Capasso A, Costantino S, Ciuffreda LP, Merolla F, Vecchione L, De Vriendt V, Tejpar S, Nappi A, Sforza V, Martini G, Berrino L, De Palma R, and Ciardiello F
- Subjects
- Animals, Apoptosis drug effects, Biomarkers, Tumor genetics, Biomarkers, Tumor metabolism, Blotting, Western, Cell Cycle drug effects, Cell Proliferation drug effects, Colorectal Neoplasms metabolism, Colorectal Neoplasms pathology, Female, Gene Expression Profiling, Humans, Lung Neoplasms metabolism, Lung Neoplasms pathology, MAP Kinase Kinase 1 metabolism, MAP Kinase Kinase 2 metabolism, Mice, Mice, Inbred BALB C, Oligonucleotide Array Sequence Analysis, PTEN Phosphohydrolase metabolism, Phenylurea Compounds pharmacology, Phosphatidylinositol 3-Kinase metabolism, Proto-Oncogene Proteins c-akt antagonists & inhibitors, Proto-Oncogene Proteins c-akt metabolism, Pyridines pharmacology, Signal Transduction drug effects, TOR Serine-Threonine Kinases metabolism, Tumor Cells, Cultured, Xenograft Model Antitumor Assays, Colorectal Neoplasms drug therapy, Drug Resistance, Neoplasm drug effects, Lung Neoplasms drug therapy, MAP Kinase Kinase 1 antagonists & inhibitors, MAP Kinase Kinase 2 antagonists & inhibitors, Phosphoinositide-3 Kinase Inhibitors, Protein Kinase Inhibitors pharmacology, TOR Serine-Threonine Kinases antagonists & inhibitors
- Abstract
The RAS/RAF/MEK/MAPK and the PTEN/PI3K/AKT/mTOR pathways are key regulators of proliferation and survival in human cancer cells. Selective inhibitors of different transducer molecules in these pathways have been developed as molecular targeted anti-cancer therapies. The in vitro and in vivo anti-tumor activity of pimasertib, a selective MEK 1/2 inhibitor, alone or in combination with a PI3K inhibitor (PI3Ki), a mTOR inhibitor (everolimus), or with multi-targeted kinase inhibitors (sorafenib and regorafenib), that block also BRAF and CRAF, were tested in a panel of eight human lung and colon cancer cell lines. Following pimasertib treatment, cancer cell lines were classified as pimasertib-sensitive (IC50 for cell growth inhibition of 0.001 µM) or pimasertib-resistant. Evaluation of basal gene expression profiles by microarrays identified several genes that were up-regulated in pimasertib-resistant cancer cells and that were involved in both RAS/RAF/MEK/MAPK and PTEN/PI3K/AKT/mTOR pathways. Therefore, a series of combination experiments with pimasertib and either PI3Ki, everolimus, sorafenib or regorafenib were conducted, demonstrating a synergistic effect in cell growth inhibition and induction of apoptosis with sustained blockade in MAPK- and AKT-dependent signaling pathways in pimasertib-resistant human colon carcinoma (HCT15) and lung adenocarcinoma (H1975) cells. Finally, in nude mice bearing established HCT15 and H1975 subcutaneous tumor xenografts, the combined treatment with pimasertib and BEZ235 (a dual PI3K/mTOR inhibitor) or with sorafenib caused significant tumor growth delays and increase in mice survival as compared to single agent treatment. These results suggest that dual blockade of MAPK and PI3K pathways could overcome intrinsic resistance to MEK inhibition., (Copyright © 2013 UICC.)
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- 2013
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50. DUSP 4 expression identifies a subset of colorectal cancer tumors that differ in MAPK activation, regardless of the genotype.
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De Vriendt V, De Roock W, Di Narzo AF, Tian S, Biesmans B, Jacobs B, Budinska E, Sagaert X, Rossi S, D'Ario G, Delorenzi M, Simon I, Vecchione L, and Tejpar S
- Subjects
- Cell Line, Tumor, Colorectal Neoplasms enzymology, Colorectal Neoplasms genetics, Dual Specificity Phosphatase 6 genetics, Enzyme Activation, Genotype, Humans, Survival Analysis, Biomarkers, Tumor genetics, Colorectal Neoplasms classification, Dual-Specificity Phosphatases genetics, Mitogen-Activated Protein Kinase Phosphatases genetics, Mitogen-Activated Protein Kinases metabolism
- Abstract
As dual-specificity phosphatase (DUSP) expression has been correlated to sensitivity to MEK inhibitors, DUSP expression levels may indicate activation of the mitogen-activated protein kinase (MAPK) pathway in many tumor types. In this study, we investigate if DUSP levels can indicate different levels of MAPK activation within colorectal cancer (CRC) patients. In three different CRC patient microarray datasets, we analyzed the expression of DUSP1. DUSP4 and DUSP6 according to mutational status, their correlation with survival and their association with different clinical characteristics. DUSP4 was significantly differentially expressed between all mutational subgroups with the highest expression in BRAF mutated tumors. Moreover, high DUSP4 expression was associated with a worse overall survival and with clinical characteristics typical for BRAF mutant patients. The use of DUSP expression as a predictive biomarker towards MAPK targeted therapy in CRC patients needs further investigation.
- Published
- 2013
- Full Text
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