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2. The GATA3 X308_Splice breast cancer mutation is a hormone context-dependent oncogenic driver

Author

Hruschka, Natascha, Kalisz, Mark, Subijana, Maria, Graña-Castro, Osvaldo, Del Cano-Ochoa, Francisco, Brunet, Laia Paré, Chernukhin, Igor, Sagrera, Ana, De Reynies, Aurelien, Kloesch, Bernhard, Chin, Suet-Feung, Burgués, Octavio, Andreu, David, Bermejo, Begoña, Cejalvo, Juan Miguel, Sutton, Joe, Caldas, Carlos, Ramón-Maiques, Santiago, Carroll, Jason S., Prat, Aleix, Real, Francisco X., and Martinelli, Paola

Published
2020
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5. Tumor-associated macrophage-secreted 14-3-3ζ signals via AXL to promote pancreatic cancer chemoresistance

Author

D’Errico, Gabriele, Alonso-Nocelo, Marta, Vallespinos, Mireia, Hermann, Patrick C., Alcalá, Sonia, García, Coral Pedrero, Martin-Hijano, Laura, Valle, Sandra, Earl, Julie, Cassiano, Chiara, Lombardia, Luis, Feliu, Jaime, Monti, Maria Chiara, Seufferlein, Thomas, García-Bermejo, Laura, Martinelli, Paola, Carrato, Alfredo, and Sainz, Jr., Bruno

Published
2019
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8. Demographic, clinical, and service-use characteristics related to the clinician’s recommendation to transition from child to adult mental health services

Author

Gerritsen, S. E., van Bodegom, L. S., Dieleman, G. C., Overbeek, M. M., Verhulst, F. C., Wolke, Dieter, Rizopoulos, D., Appleton, R., van Amelsvoort, T. A. M. J., Bodier Rethore, C., Bonnet-Brilhault, F., Charvin, I., Da Fonseca, D., Davidović, N., Dodig-Ćurković, K., Ferrari, A., Fiori, F., Franić, T., Gatherer, C., de Girolamo, G., Heaney, N., Hendrickx, G., Jardri, R., Kolozsvari, A., Lida-Pulik, H., Lievesley, K., Madan, J., Mastroianni, M., Maurice, V., McNicholas, F., Nacinovich, R., Parenti, A., Paul, M., Purper-Ouakil, D., Rivolta, L., de Roeck, V., Russet, F., Saam, M. C., Sagar-Ouriaghli, I., Santosh, P. J., Sartor, A., Schulze, U. M. E., Scocco, P., Signorini, G., Singh, S. P., Singh, J., Speranza, M., Stagi, P., Stagni, P., Street, C., Tah, P., Tanase, E., Tremmery, S., Tuffrey, A., Tuomainen, H., Walker, L., Wilson, A., Maras, A., Adams, Laura, Allibrio, Giovanni, Armando, Marco, Aslan, Sonja, Baccanelli, Nadia, Balaudo, Monica, Bergamo, Fabia, Bertani, Angelo, Berriman, Jo, Boon, Albert, Braamse, Karen, Breuninger, Ulrike, Buttiglione, Maura, Buttle, Sarah, Schandrin, Aurélie, Cammarano, Marco, Canaway, Alastair, Cantini, Fortunata, Cappellari, Cristiano, Carenini, Marta, Carrà, Giuseppe, Ferrari, Cecilia, Chianura, Krizia, Coleman, Philippa, Colonna, Annalisa, Conese, Patrizia, Costanzo, Raffaella, Daffern, Claire, Danckaerts, Marina, de Giacomo, Andrea, Ermans, Jean-Pierre, Farmer, Alan, Fegert, Jörg M., Ferrari, Sabrina, Galea, Giuliana, Gatta, Michela, Gheza, Elisa, Goglia, Giacomo, Grandetto, MariaRosa, Griffin, James, Levi, Flavia Micol, Humbertclaude, Véronique, Ingravallo, Nicola, Invernizzi, Roberta, Kelly, Caoimhe, Killilea, Meghan, Kirwan, James, Klockaerts, Catherine, Kovač, Vlatka, Liew, Ashley, Lippens, Christel, Macchi, Francesca, Manenti, Lidia, Margari, Francesco, Margari, Lucia, Martinelli, Paola, McFadden, Leighton, Menghini, Deny, Miller, Sarah, Monzani, Emiliano, Morini, Giorgia, Mutafov, Todor, O’Hara, Lesley, Negrinotti, Cristina, Nelis, Emmanuel, Neri, Francesca, Nikolova, Paulina, Nossa, Marzia, Cataldo, Maria Giulia, Noterdaeme, Michele, Operto, Francesca, Panaro, Vittoria, Pastore, Adriana, Pemmaraju, Vinuthna, Pepermans, Ann, Petruzzelli, Maria Giuseppina, Presicci, Anna, Prigent, Catherine, Rinaldi, Francesco, Riva, Erika, Roekens, Anne, Rogers, Ben, Ronzini, Pablo, Sakar, Vehbi, Salvetti, Selena, Martinelli, Ottaviano, Sandhu, Tanveer, Schepker, Renate, Siviero, Marco, Slowik, Michael, Smyth, Courtney, Conti, Patrizia, Spadone, Maria Antonietta, Starace, Fabrizio, Stoppa, Patrizia, Tansini, Lucia, Toselli, Cecilia, Trabucchi, Guido, Tubito, Maria, van Dam, Arno, van Gutschoven, Hanne, van West, Dirk, Vanni, Fabio, Vannicola, Chiara, Varuzza, Cristiana, Varvara, Pamela, Ventura, Patrizia, Vicari, Stefano, Vicini, Stefania, von Bentzel, Carolin, Wells, Philip, Williams, Beata, Zabarella, Marina, Zamboni, Anna, Zanetti, Edda, HASH(0x5651c9679ff8), RS: MHeNs - R2 - Mental Health, Psychiatrie & Neuropsychologie, MUMC+: MA Med Staf Spec Psychiatrie (9), Child and Adolescent Psychiatry / Psychology, Epidemiology, Clinical Child and Family Studies, LEARN! - Child rearing, APH - Mental Health, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Lille Neurosciences & Cognition - U 1172 (LilNCog), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre Hospitalier de Versailles André Mignot (CHV), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), CHU Lille, Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, The MILESTONE project was funded by EU FP7 programme under grant number 602442. SPS is part-funded by the National Institute for Health Research (NIHR) Collaboration for Leadership in Applied Health Research and Care West Midlands (NIHR CLAHRC WM), now recommissioned as NIHR Applied Research Collaboration West Midlands. The views expressed in this publication are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. PS is the co-inventor of the HealthTrackerTM and is the Chief Executive Officer and shareholder in HealthTracker Ltd. FF is a Chief Technical Officer and AK is the Chief Finance Officer employed by HealthTracker Ltd, respectively. FCV publishes the Dutch translations of ASEBA, from which he receives remuneration. AM was a speaker and advisor for Neurim, Shire, Infectopharm, and Lilly (all not related to transition research)., European Project: 602442,EC:FP7:HEALTH,FP7-HEALTH-2013-INNOVATION-1,MILESTONE(2014), The Milestone Consortium, Gerritsen, S, van Bodegom, L, Dieleman, G, Overbeek, M, Verhulst, F, Wolke, D, Rizopoulos, D, Appleton, R, van Amelsvoort, T, Bodier Rethore, C, Bonnet-Brilhault, F, Charvin, I, Da Fonseca, D, Davidovic, N, Dodig-Curkovic, K, Ferrari, A, Fiori, F, Franic, T, Gatherer, C, de Girolamo, G, Heaney, N, Hendrickx, G, Jardri, R, Kolozsvari, A, Lida-Pulik, H, Lievesley, K, Madan, J, Mastroianni, M, Maurice, V, Mcnicholas, F, Nacinovich, R, Parenti, A, Paul, M, Purper-Ouakil, D, Rivolta, L, de Roeck, V, Russet, F, Saam, M, Sagar-Ouriaghli, I, Santosh, P, Sartor, A, Schulze, U, Scocco, P, Signorini, G, Singh, S, Singh, J, Speranza, M, Stagi, P, Stagni, P, Street, C, Tah, P, Tanase, E, Tremmery, S, Tuffrey, A, Tuomainen, H, Walker, L, Wilson, A, Maras, A, Adams, L, Allibrio, G, Armando, M, Aslan, S, Baccanelli, N, Balaudo, M, Bergamo, F, Bertani, A, Berriman, J, Boon, A, Braamse, K, Breuninger, U, Buttiglione, M, Buttle, S, Schandrin, A, Cammarano, M, Canaway, A, Cantini, F, Cappellari, C, Carenini, M, Carra, G, Ferrari, C, Chianura, K, Coleman, P, Colonna, A, Conese, P, Costanzo, R, Daffern, C, Danckaerts, M, de Giacomo, A, Ermans, J, Farmer, A, Fegert, J, Ferrari, S, Galea, G, Gatta, M, Gheza, E, Goglia, G, Grandetto, M, Griffin, J, Levi, F, Humbertclaude, V, Ingravallo, N, Invernizzi, R, Kelly, C, Killilea, M, Kirwan, J, Klockaerts, C, Kovac, V, Liew, A, Lippens, C, Macchi, F, Manenti, L, Margari, F, Margari, L, Martinelli, P, Mcfadden, L, Menghini, D, Miller, S, Monzani, E, Morini, G, Mutafov, T, O'Hara, L, Negrinotti, C, Nelis, E, Neri, F, Nikolova, P, Nossa, M, Cataldo, M, Noterdaeme, M, Operto, F, Panaro, V, Pastore, A, Pemmaraju, V, Pepermans, A, Petruzzelli, M, Presicci, A, Prigent, C, Rinaldi, F, Riva, E, Roekens, A, Rogers, B, Ronzini, P, Sakar, V, Salvetti, S, Martinelli, O, Sandhu, T, Schepker, R, Siviero, M, Slowik, M, Smyth, C, Conti, P, Spadone, M, Starace, F, Stoppa, P, Tansini, L, Toselli, C, Trabucchi, G, Tubito, M, van Dam, A, van Gutschoven, H, van West, D, Vanni, F, Vannicola, C, Varuzza, C, Varvara, P, Ventura, P, Vicari, S, Vicini, S, von Bentzel, C, Wells, P, Williams, B, Zabarella, M, Zamboni, A, and Zanetti, E

Subjects
Adult mental health service, Adult, Mental Health Services, Parents, Health (social science), Child and adolescent mental health service, Social Psychology, RJ, Epidemiology, ADOLESCENT, Child and adolescent mental health services, Adult mental health services, Young adults, Transition, SDG 3 - Good Health and Well-being, PEOPLE, SCHIZOPHRENIA, Humans, Family, Child, Demography, Mental Disorders, CARE, Psychiatry and Mental health, Young adult, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, RA
Abstract

Purpose The service configuration with distinct child and adolescent mental health services (CAMHS) and adult mental health services (AMHS) may be a barrier to continuity of care. Because of a lack of transition policy, CAMHS clinicians have to decide whether and when a young person should transition to AMHS. This study describes which characteristics are associated with the clinicians’ advice to continue treatment at AMHS. Methods Demographic, family, clinical, treatment, and service-use characteristics of the MILESTONE cohort of 763 young people from 39 CAMHS in Europe were assessed using multi-informant and standardized assessment tools. Logistic mixed models were fitted to assess the relationship between these characteristics and clinicians’ transition recommendations. Results Young people with higher clinician-rated severity of psychopathology scores, with self- and parent-reported need for ongoing treatment, with lower everyday functional skills and without self-reported psychotic experiences were more likely to be recommended to continue treatment. Among those who had been recommended to continue treatment, young people who used psychotropic medication, who had been in CAMHS for more than a year, and for whom appropriate AMHS were available were more likely to be recommended to continue treatment at AMHS. Young people whose parents indicated a need for ongoing treatment were more likely to be recommended to stay in CAMHS. Conclusion Although the decision regarding continuity of treatment was mostly determined by a small set of clinical characteristics, the recommendation to continue treatment at AMHS was mostly affected by service-use related characteristics, such as the availability of appropriate services.

Published
2022

9. Discovery of a Chemical Probe to Study Implications of BPTF Bromodomain Inhibition in Cellular and in vivo Experiments

Author

Martinelli, Paola, primary, Schaaf, Otmar, additional, Mantoulidis, Andreas, additional, Martin, Laetitia J., additional, Fuchs, Julian E., additional, Bader, Gerd, additional, Gollner, Andreas, additional, Wolkerstorfer, Bernhard, additional, Rogers, Catherine, additional, Balıkçı, Esra, additional, Lipp, Jesse J., additional, Mischerikow, Nikolai, additional, Doebel, Sandra, additional, Gerstberger, Thomas, additional, Sommergruber, Wolfgang, additional, Huber, Kilian V. M., additional, and Böttcher, Jark, additional

Published
2023
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10. One-Pot Synthesis of Cereblon Proteolysis Targeting Chimeras via Photoinduced C(sp2)–C(sp3) Cross Coupling and Amide Formation for Proteolysis Targeting Chimera Library Synthesis

Author

Arndt, Christine M., Bitai, Jacqueline, Brunner, Jessica, Opatz, Till, Martinelli, Paola, Gollner, Andreas, Sokol, Kevin R., and Krumb, Matthias

Abstract

In this study, a one-pot synthesis via photoinduced C(sp2)–C(sp3) coupling followed by amide formation to access proteolysis targeting chimeras (PROTACs) was developed. The described protocol was studied on cereblon (CRBN)-based E3-ligase binders and (+)-JQ-1, a bromodomain inhibitor, to generate BET (bromodomain and extra terminal domain) targeting protein degraders. The generated PROTACs were profiled in vitro and tested for their degradation ability with several potent candidates identified. Upfront, the individual reactions of the one-pot transformation were carefully optimized for CRBN binder functionalization and multiple heterobifunctional linker moieties were designed and synthesized. Separate scopes detailing the C(sp2)–C(sp3) coupling and one-pot PROTAC synthesis are described in this report as well as a library miniaturization study showing the high-throughput compatibility. Overall, the developed protocol provides rapid access to PROTACs in a single process, thereby allowing efficient generation of CRBN-based PROTAC libraries.

Published
2023
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13. Cohort profile

Author

Gerritsen, Suzanne E., Maras, Athanasios, van Bodegom, Larissa S., Overbeek, Mathilde M., Verhulst, Frank C., Wolke, Dieter, Appleton, Rebecca, Bertani, Angelo, Cataldo, Maria G., Conti, Patrizia, Da Fonseca, David, Davidović, Nikolina, Dodig-Ćurković, Katarina, Ferrari, Cecilia, Fiori, Federico, Franić, Tomislav, Gatherer, Charlotte, De Girolamo, Giovanni, Heaney, Natalie, Hendrickx, Gaëlle, Kolozsvari, Alfred, Levi, Flavia Micol, Lievesley, Kate, Madan, Jason, Martinelli, Ottaviano, Mastroianni, Mathilde, Maurice, Virginie, McNicholas, Fiona, O'Hara, Lesley, Paul, Moli, Purper-Ouakil, Diane, de Roeck, Veronique, Russet, Frédérick, Saam, Melanie C., Sagar-Ouriaghli, Ilyas, Santosh, Paramala J., Sartor, Anne, Schandrin, Aurélie, Schulze, Ulrike M. E., Signorini, Giulia, Singh, Swaran P., Singh, Jatinder, Street, Cathy, Tah, Priya, Tanase, Elena, Tremmery, Sabine, Tuffrey, Amanda, Tuomainen, Helena, van Amelsvoort, Therese A. M. J., Wilson, Anna, Walker, Leanne, Dieleman, Gwen C., Adams, Laura, Allibrio, Giovanni, Armando, Marco, Aslan, Sonja, Baccanelli, Nadia, Balaudo, Monica, Bergamo, Fabia, Berriman, Jo, Rethore, Chrystèle Bodier, Bonnet-Brilhault, Frédérique, Boon, Albert, Braamse, Karen, Breuninger, Ulrike, Buttiglione, Maura, Buttle, Sarah, Cammarano, Marco, Canaway, Alastair, Cantini, Fortunata, Cappellari, Cristiano, Carenini, Marta, Carrà, Giuseppe, Charvin, Isabelle, Chianura, Krizia, Coleman, Philippa, Colonna, Annalisa, Conese, Patrizia, Costanzo, Raffaella, Daffern, Claire, Danckaerts, Marina, Giacomo, Andrea de, Dineen, Peter, Ermans, Jean-Pierre, Farmer, Alan, Fegert, Jörg M., Ferrari, Alessandro, Ferrari, Sabrina, Galea, Giuliana, Gatta, Michela, Gheza, Elisa, Goglia, Giacomo, Grandetto, MariaRosa, Griffin, James, Healy, Elaine, Holmes, Keith, Humbertclaude, Véronique, Ingravallo, Nicola, Invernizzi, Roberta, Jardri, Renaud, Keeley, Helen, Kelly, Caoimhe, Killilea, Meghan, Kirwan, James, Klockaerts, Catherine, Kovač, Vlatka, Lida-Pulik, Hélène, Liew, Ashley, Lippens, Christel, Lynch, Fionnuala, Macchi, Francesca, Manenti, Lidia, Margari, Francesco, Margari, Lucia, Martinelli, Paola, McDonald, James, McFadden, Leighton, Menghini, Deny, Migone, Maria, Miller, Sarah, Monzani, Emiliano, Morini, Giorgia, Mutafov, Todor, Nacinovich, Renata, Negrinotti, Cristina, Nelis, Emmanuel, Neri, Francesca, Nikolova, Paulina, Nossa, Marzia, Noterdaeme, Michele, Operto, Francesca, Panaro, Vittoria, Parenti, Aesa, Pastore, Adriana, Pemmaraju, Vinuthna, Pepermans, Ann, Petruzzelli, Maria Giuseppina, Presicci, Anna, Prigent, Catherine, Rinaldi, Francesco, Riva, Erika, Rivolta, Laura, Roekens, Anne, Rogers, Ben, Ronzini, Pablo, Sakar, Vehbi, Salvetti, Selena, Sandhu, Tanveer, Schepker, Renate, Scocco, Paolo, Siviero, Marco, Slowik, Michael, Smyth, Courtney, Spadone, Maria Antonietta, Speranza, Mario, Stagi, Paolo, Stagni, Pamela, Starace, Fabrizio, Stoppa, Patrizia, Tansini, Lucia, Toselli, Cecilia, Trabucchi, Guido, Tubito, Maria, Dam, Arno van, Gutschoven, Hanne Van, West, Dirk van, Vanni, Fabio, Vannicola, Chiara, Varuzza, Cristiana, Varvara, Pamela, Ventura, Patrizia, Vicari, Stefano, Vicini, Stefania, Bentzel, Carolin von, Wells, Philip, Williams, Beata, Zabarella, Marina, Zamboni, Anna, Zanetti, Edda, RS: MHeNs - R2 - Mental Health, Psychiatrie & Neuropsychologie, MUMC+: MA Med Staf Spec Psychiatrie (9), Child and Adolescent Psychiatry / Psychology, Clinical Child and Family Studies, LEARN! - Child rearing, and APH - Mental Health

Subjects
Adult, Internationality, SAMPLE, RJ, child & adolescent psychiatry, ADOLESCENT, Jugendpsychiatrie, Cohort Studies, SDG 3 - Good Health and Well-being, ddc:150, QUALITY-OF-LIFE, Psychiatrische Versorgung, Child psychiatry, Humans, Prospective Studies, SCALE, Demography, Retrospective Studies, Psychiatry, Internationalität, OUTCOMES, DDC 150 / Psychology, Adolescent psychiatry, international health services, General Medicine, WHOQOL-BREF, Europe, Mental Health, Mental health services, CROSS, Adolescent Health Services, EXPERIENCE, Kinderpsychiatrie, adult psychiatry, RA, TRANSITION, RC
Abstract

PurposeThe presence of distinct child and adolescent mental health services (CAMHS) and adult mental health services (AMHS) impacts continuity of mental health treatment for young people. However, we do not know the extent of discontinuity of care in Europe nor the effects of discontinuity on the mental health of young people. Current research is limited, as the majority of existing studies are retrospective, based on small samples or used non-standardised information from medical records. The MILESTONE prospective cohort study aims to examine associations between service use, mental health and other outcomes over 24 months, using information from self, parent and clinician reports.ParticipantsSeven hundred sixty-three young people from 39 CAMHS in 8 European countries, their parents and CAMHS clinicians who completed interviews and online questionnaires and were followed up for 2 years after reaching the upper age limit of the CAMHS they receive treatment at.Findings to dateThis cohort profile describes the baseline characteristics of the MILESTONE cohort. The mental health of young people reaching the upper age limit of their CAMHS varied greatly in type and severity: 32.8% of young people reported clinical levels of self-reported problems and 18.6% were rated to be ‘markedly ill’, ‘severely ill’ or ‘among the most extremely ill’ by their clinician. Fifty-seven per cent of young people reported psychotropic medication use in the previous half year.Future plansAnalysis of longitudinal data from the MILESTONE cohort will be used to assess relationships between the demographic and clinical characteristics of young people reaching the upper age limit of their CAMHS and the type of care the young person uses over the next 2 years, such as whether the young person transitions to AMHS. At 2 years follow-up, the mental health outcomes of young people following different care pathways will be compared.Trial registration numberNCT03013595., publishedVersion

Published
2021

14. GATA4 and GATA6 loss-of-expression is associated with extinction of the classical programme and poor outcome in pancreatic ductal adenocarcinoma

Author

de Andrés, Mónica P, primary, Jackson, Richard J, additional, Felipe, Irene, additional, Zagorac, Sladjana, additional, Pilarsky, Christian, additional, Schlitter, Anna Melissa, additional, Martinez de Villareal, Jaime, additional, Jang, Gun Ho, additional, Costello, Eithne, additional, Gallinger, Steve, additional, Ghaneh, Paula, additional, Greenhalf, William, additional, Knösel, Thomas, additional, Palmer, Daniel H, additional, Ruemmele, Petra, additional, Weichert, Wilko, additional, Buechler, Markus, additional, Hackert, Thilo, additional, Neoptolemos, John P, additional, Notta, Faiyaz, additional, Malats, Núria, additional, Martinelli, Paola, additional, and Real, Francisco X, additional

Published
2022
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15. Macrophages direct cancer cells through a LOXL2-mediated metastatic cascade in pancreatic ductal adenocarcinoma

Author

Alonso-Nocelo, Marta, primary, Ruiz-Cañas, Laura, additional, Sancho, Patricia, additional, Görgülü, Kıvanç, additional, Alcalá, Sonia, additional, Pedrero, Coral, additional, Vallespinos, Mireia, additional, López-Gil, Juan Carlos, additional, Ochando, Marina, additional, García-García, Elena, additional, David Trabulo, Sara Maria, additional, Martinelli, Paola, additional, Sánchez-Tomero, Patricia, additional, Sánchez-Palomo, Carmen, additional, Gonzalez-Santamaría, Patricia, additional, Yuste, Lourdes, additional, Wörmann, Sonja Maria, additional, Kabacaoğlu, Derya, additional, Earl, Julie, additional, Martin, Alberto, additional, Salvador, Fernando, additional, Valle, Sandra, additional, Martin-Hijano, Laura, additional, Carrato, Alfredo, additional, Erkan, Mert, additional, García-Bermejo, Laura, additional, Hermann, Patrick C, additional, Algül, Hana, additional, Moreno-Bueno, Gema, additional, Heeschen, Christopher, additional, Portillo, Francisco, additional, Cano, Amparo, additional, and Sainz, Bruno, additional

Published
2022
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17. NOTCH pathway inactivation promotes bladder cancer progression

Author

Maraver, Antonio, Fernandez-Marcos, Pablo J., Cash, Timothy P., Mendez-Pertuz, Marinela, Duenas, Marta, Maietta, Paolo, Martinelli, Paola, Munoz-Martin, Maribel, Martinez-Fernandez, Monica, Canamero, Marta, Roncador, Giovanna, Martinez-Torrecuadrada, Jorge L., Grivas, Dimitrios, de la Pompa, Jose Luis, Valencia, Alfonso, Paramio, Jesus M., Real, Francisco X., and Serrano, Manuel

Subjects
Gene mutations -- Health aspects, Bladder cancer -- Genetic aspects -- Development and progression, Cellular signal transduction -- Genetic aspects, Health care industry
Abstract

NOTCH signaling suppresses tumor growth and proliferation in several types of stratified epithelia. Here, we show that missense mutations in NOTCH1 and NOTCH2 found in human bladder cancers result in loss of function. In murine models, genetic ablation of the NOTCH pathway accelerated bladder tumorigenesis and promoted the formation of squamous cell carcinomas, with areas of mesenchymal features. Using bladder cancer cells, we determined that the NOTCH pathway stabilizes the epithelial phenotype through its effector HES1 and, consequently, loss of NOTCH activity favors the process of epithelial-mesenchymal transition. Evaluation of human bladder cancer samples revealed that tumors with low levels of HES1 present mesenchymal features and are more aggressive. Together, our results indicate that NOTCH serves as a tumor suppressor in the bladder and that loss of this pathway promotes mesenchymal and invasive features., Introduction NOTCH is a single-pass transmembrane receptor activated by interaction with transmembrane ligands of the DSL (Delta-like and Jagged) family present on the membrane of neighboring cells. There are 4 [...]

Published
2015
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20. GATA4 and GATA6 loss-of-expression is associated with extinction of the classical programme and poor outcome in pancreatic ductal adenocarcinoma

Author

de Andrés, Mónica P., primary, Jackson, Richard, additional, Pilarsky, Christian, additional, Schlitter, Anna Melissa, additional, Costello, Eithne, additional, Greenhalf, William, additional, Ghaneh, Paula, additional, Knösel, Thomas, additional, Palmer, Daniel, additional, Rümmele, Petra, additional, Weichert, Wilko, additional, Büchler, Markus, additional, Hackert, Thilo, additional, Neoptolemos, John P., additional, Malats, Núria, additional, Martinelli, Paola, additional, and Real, Francisco X., additional

Published
2021
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21. Transcriptional regulation by NR5A2 links differentiation and inflammation in the pancreas

Author

Cobo, Isidoro, Martinelli, Paola, Flndez, Marta, Bakiri, Latifa, Zhang, Mingfeng, Carrillo-de-Santa-Pau, Enrique, Jia, Jinping, Snchez-Arvalo Lobo, Vctor J., Megas, Diego, Felipe, Irene, del Pozo, Natalia, Milln, Irene, Thommesen, Liv, Bruland, Torunn, Olson, Sara H., Smith, Jill, Schoonjans, Kristina, Bamlet, William R., Petersen, Gloria M., Malats, Nria, Amundadottir, Laufey T., Wagner, Erwin F., and Real, Francisco X.

Subjects
Transcription (Genetics) -- Observations, Pancreas -- Genetic aspects -- Health aspects, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Author(s): Isidoro Cobo [1]; Paola Martinelli [1]; Marta Flndez [1]; Latifa Bakiri [2]; Mingfeng Zhang [3]; Enrique Carrillo-de-Santa-Pau [1]; Jinping Jia [3]; Vctor J. Snchez-Arvalo Lobo [1]; Diego Megas [4]; [...]

Published
2018
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22. GATA4 and GATA6 loss-of-expression is associated with extinction of the classical programme and poor outcome in pancreatic ductal adenocarcinoma

Author

de Andrés, Mónica P, Jackson, Richard J, Felipe, Irene, Zagorac, Sladjana, Pilarsky, Christian, Schlitter, Anna Melissa, Martinez de Villareal, Jaime, Jang, Gun Ho, Costello, Eithne, Gallinger, Steve, Ghaneh, Paula, Greenhalf, William, Kno¨sel, Thomas, Palmer, Daniel H, Ruemmele, Petra, Weichert, Wilko, Buechler, Markus, Hackert, Thilo, Neoptolemos, John P, Notta, Faiyaz, Malats, Núria, Martinelli, Paola, and Real, Francisco X

Abstract

ObjectiveGATA6 is a key regulator of the classical phenotype in pancreatic ductal adenocarcinoma (PDAC). Low GATA6 expression associates with poor patient outcome. GATA4is the second most expressed GATA factor in the pancreas. We assessed whether, and how, GATA4 contributes to PDAC phenotype and analysed the association of expression with outcome and response to chemotherapy.DesignWe analysed PDAC transcriptomic data, stratifying cases according to GATA4and GATA6expression and identified differentially expressed genes and pathways. The genome-wide distribution of GATA4 was assessed, as well as the effects of GATA4knockdown. A multicentre tissue microarray study to assess GATA4 and GATA6 expression in samples (n=745) from patients with resectable was performed. GATA4 and GATA6 levels were dichotomised into high/low categorical variables; association with outcome was assessed using univariable and multivariable Cox regression models.ResultsGATA4messenger RNA is enriched in classical, compared with basal-like tumours. We classified samples in 4 groups as high/low for GATA4and GATA6. Reduced expression of GATA4had a minor transcriptional impact but low expression of GATA4enhanced the effects of GATA6low expression. GATA4 and GATA6 display a partially overlapping genome-wide distribution, mainly at promoters. Reduced expression of both proteins in tumours was associated with the worst patient survival. GATA4and GATA6expression significantly decreased in metastases and negatively correlated with basal markers.ConclusionsGATA4and GATA6cooperate to maintain the classical phenotype. Our findings provide compelling rationale to assess their expression as biomarkers of poor prognosis and therapeutic response.

Published
2023
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23. Macrophages direct cancer cells through a LOXL2-mediated metastatic cascade in pancreatic ductal adenocarcinoma

Author

Alonso-Nocelo, Marta, Ruiz-Cañas, Laura, Sancho, Patricia, Go¨rgu¨lu¨, Kıvanc, Alcalá, Sonia, Pedrero, Coral, Vallespinos, Mireia, López-Gil, Juan Carlos, Ochando, Marina, García-García, Elena, David Trabulo, Sara Maria, Martinelli, Paola, Sánchez-Tomero, Patricia, Sánchez-Palomo, Carmen, Gonzalez-Santamaría, Patricia, Yuste, Lourdes, Wo¨rmann, Sonja Maria, Kabacaoğlu, Derya, Earl, Julie, Martin, Alberto, Salvador, Fernando, Valle, Sandra, Martin-Hijano, Laura, Carrato, Alfredo, Erkan, Mert, García-Bermejo, Laura, Hermann, Patrick C, Algu¨l, Hana, Moreno-Bueno, Gema, Heeschen, Christopher, Portillo, Francisco, Cano, Amparo, and Sainz, Bruno

Abstract

ObjectiveThe lysyl oxidase-like protein 2 (LOXL2) contributes to tumour progression and metastasis in different tumour entities, but its role in pancreatic ductal adenocarcinoma (PDAC) has not been evaluated in immunocompetent in vivo PDAC models.DesignTowards this end, we used PDAC patient data sets, patient-derived xenograft in vivo and in vitro models, and four conditional genetically-engineered mouse models (GEMMS) to dissect the role of LOXL2 in PDAC. For GEMM-based studies, K-Ras+/LSL-G12D;Trp53LSL-R172H;Pdx1-Cremice (KPC) and the K-Ras+/LSL-G12D;Pdx1-Cremice (KC) were crossed with Loxl2allele floxed mice (Loxl2Exon2fl/fl) or conditional Loxl2overexpressing mice (R26Loxl2KI/KI) to generate KPCL2KOor KCL2KOand KPCL2KIor KCL2KImice, which were used to study overall survival; tumour incidence, burden and differentiation; metastases; epithelial to mesenchymal transition (EMT); stemness and extracellular collagen matrix (ECM) organisation.ResultsUsing these PDAC mouse models, we show that while Loxl2ablation had little effect on primary tumour development and growth, its loss significantly decreased metastasis and increased overall survival. We attribute this effect to non-cell autonomous factors, primarily ECM remodelling. Loxl2overexpression, on the other hand, promoted primary and metastatic tumour growth and decreased overall survival, which could be linked to increased EMT and stemness. We also identified tumour-associated macrophage-secreted oncostatin M (OSM) as an inducer of LOXL2 expression, and show that targeting macrophages in vivo affects Osmand Loxl2expression and collagen fibre alignment.ConclusionTaken together, our findings establish novel pathophysiological roles and functions for LOXL2 in PDAC, which could be potentially exploited to treat metastatic disease.

Published
2023
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24. AFG3L2 supports mitochondrial protein synthesis and Purkinje cell survival

Author

Almajan, Eva R., Richter, Ricarda, Paeger, Lars, Martinelli, Paola, Barth, Esther, Decker, Thorsten, Larsson, Nils-Goran, Kloppenburg, Peter, Langer, Thomas, and Rugarli, Elena I.

Subjects
Genetic translation -- Research, Protein biosynthesis -- Research, Mitochondria -- Properties, Purkinje cells -- Genetic aspects, Health care industry
Abstract

Mutations in the AFG3L2 gene have been linked to spinocerebellar ataxia type 28 and spastic ataxia-neuropathy syndrome in humans; however, the pathogenic mechanism is still unclear. AFG3L2 encodes a subunit of the mitochondrial m-AAA protease, previously implicated in quality control of misfolded inner mitochondrial membrane proteins and in regulatory functions via processing of specific substrates. Here, we used a conditional Afg3l2 mouse model that allows restricted deletion of the gene in Purkinje cells (PCs) to shed light on the pathogenic cascade in the neurons mainly affected in the human diseases. We demonstrate a cell-autonomous requirement of AFG3L2 for survival of PCs. Examination of PCs prior to neurodegeneration revealed fragmentation and altered distribution of mitochondria in the dendritic tree, indicating that abnormal mitochondrial dynamics is an early event in the pathogenic process. Moreover, PCs displayed features pointing to defects in mitochondrially encoded respiratory chain subunits at early stages. To unravel the underlying mechanism, we examined a constitutive knockout of Afg3l2, which revealed a decreased rate of mitochondrial protein synthesis associated with impaired mitochondrial ribosome assembly. We therefore propose that defective mitochondrial protein synthesis, leading to early-onset fragmentation of the mitochondrial network, is a central causative factor in AFG3L2-related neurodegeneration., Introduction Eukaryotic cells monitor the quality of their mitochondria using mechanisms acting at the interorganelle or intraorganelle level. Mitochondrial fusion and fission ensure maintenance of a functional network, whereas intramitochondrial [...]

Published
2012
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25. A GATA6-centred gene regulatory network involving HNFs and ΔNp63 controls plasticity and immune escape in pancreatic cancer

Author

Kloesch, Bernhard, primary, Ionasz, Vivien, additional, Paliwal, Sumit, additional, Hruschka, Natascha, additional, Martinez de Villarreal, Jaime, additional, Öllinger, Rupert, additional, Mueller, Sebastian, additional, Dienes, Hans Peter, additional, Schindl, Martin, additional, Gruber, Elisabeth S, additional, Stift, Judith, additional, Herndler-Brandstetter, Dietmar, additional, Lomberk, Gwen A, additional, Seidler, Barbara, additional, Saur, Dieter, additional, Rad, Roland, additional, Urrutia, Raul A, additional, Real, Francisco X, additional, and Martinelli, Paola, additional

Published
2021
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27. A GATA6-centred gene regulatory network involving HNFs and ΔNp63 controls plasticity and immune escape in pancreatic cancer.

Author

Kloesch, Bernhard, Ionasz, Vivien, Paliwal, Sumit, Hruschka, Natascha, Martinez de Villarreal, Jaime, Öllinger, Rupert, Mueller, Sebastian, Dienes, Hans Peter, Schindl, Martin, Gruber, Elisabeth S., Stift, Judith, Herndler-Brandstetter, Dietmar, Lomberk, Gwen A., Seidler, Barbara, Saur, Dieter, Rad, Roland, Urrutia, Raul A., Real, Francisco X., and Martinelli, Paola

Subjects
GENE regulatory networks, PANCREATIC tumors, PANCREATIC cancer, MEDICAL ethics
Published
2022
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30. A GATA6-centered gene regulatory network involving HNFs and ΔNp63 controls plasticity and immune escape in pancreatic cancer

Author

Kloesch, Bernhard, primary, Hruschka, Natascha, additional, Ionasz, Vivien, additional, Oellinger, Rupert, additional, Mueller, Sebastian, additional, de Villareal, Jaime Martinez, additional, Dienes, Hans-Peter, additional, Schindl, Martin, additional, Gruber, Elisabeth, additional, Stift, Judith, additional, Lomberk, Gwen, additional, Seidler, Barbara, additional, Saur, Dieter, additional, Rad, Roland, additional, Urrutia, Raul, additional, Real, Francisco X., additional, and Martinelli, Paola, additional

Published
2020
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33. Serotonin uptake is required for Rac1 activation in Kras-induced acinar-to-ductal metaplasia in the pancreas

Author

Saponara, Enrica, Visentin, Michele, Baschieri, Francesco, Seleznik, Gitta, Martinelli, Paola, Esposito, Irene, Buschmann, Johanna, Chen, Rong, Parrotta, Rossella, Borgeaud, Nathalie, Bombardo, Marta, Malagola, Ermanno, Caflisch, Amedeo, Farhan, Hesso, Graf, Rolf, Sonda, Sabrina, University of Zurich, and Sonda, Sabrina

Subjects
2734 Pathology and Forensic Medicine, 10019 Department of Biochemistry, 610 Medicine & health, 10266 Clinic for Reconstructive Surgery
Published
2018

34. Intracellular Trapping of the Selective Phosphoglycerate Dehydrogenase (PHGDH) Inhibitor BI-4924 Disrupts Serine Biosynthesis

Author

Weinstabl, Harald, primary, Treu, Matthias, additional, Rinnenthal, Joerg, additional, Zahn, Stephan K., additional, Ettmayer, Peter, additional, Bader, Gerd, additional, Dahmann, Georg, additional, Kessler, Dirk, additional, Rumpel, Klaus, additional, Mischerikow, Nikolai, additional, Savarese, Fabio, additional, Gerstberger, Thomas, additional, Mayer, Moriz, additional, Zoephel, Andreas, additional, Schnitzer, Renate, additional, Sommergruber, Wolfgang, additional, Martinelli, Paola, additional, Arnhof, Heribert, additional, Peric-Simov, Biljana, additional, Hofbauer, Karin S., additional, Garavel, Géraldine, additional, Scherbantin, Yvonne, additional, Mitzner, Sophie, additional, Fett, Thomas N., additional, Scholz, Guido, additional, Bruchhaus, Jens, additional, Burkard, Michelle, additional, Kousek, Roland, additional, Ciftci, Tuncay, additional, Sharps, Bernadette, additional, Schrenk, Andreas, additional, Harrer, Christoph, additional, Haering, Daniela, additional, Wolkerstorfer, Bernhard, additional, Zhang, Xuechun, additional, Lv, Xiaobing, additional, Du, Alicia, additional, Li, Dongyang, additional, Li, Yali, additional, Quant, Jens, additional, Pearson, Mark, additional, and McConnell, Darryl B., additional

Published
2019
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35. The GATA3 X308_Splice breast cancer mutation is a hormone context-dependent oncogenic driver

Author

Hruschka, Natascha, primary, Subijana, Maria, additional, Graña-Castro, Osvaldo, additional, Del Cano-Ochoa, Francisco, additional, Brunet, Laia Paré, additional, Sagrera, Ana, additional, De Reynies, Aurelien, additional, Andreu, David, additional, Sutton, Joe, additional, Chernukhin, Igor, additional, Chin, Suet-Feung, additional, Caldas, Carlos, additional, Lluch, Ana, additional, Burgués, Octavio, additional, Bermejo, Begoña, additional, Ramón-Maiques, Santiago, additional, Carroll, Jason S, additional, Prat, Aleix, additional, Real, Francisco X, additional, and Martinelli, Paola, additional

Published
2019
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37. Serotonin uptake is required for Rac1 activation in Kras-induced acinar-to-ductal metaplasia in the pancreas

Author

Saponara, Enrica, primary, Visentin, Michele, additional, Baschieri, Francesco, additional, Seleznik, Gitta, additional, Martinelli, Paola, additional, Esposito, Irene, additional, Buschmann, Johanna, additional, Chen, Rong, additional, Parrotta, Rossella, additional, Borgeaud, Nathalie, additional, Bombardo, Marta, additional, Malagola, Ermanno, additional, Caflisch, Amedeo, additional, Farhan, Hesso, additional, Graf, Rolf, additional, and Sonda, Sabrina, additional

Published
2018
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38. Intracellular Trapping of the Selective Phosphoglycerate Dehydrogenase (PHGDH) Inhibitor BI-4924Disrupts Serine Biosynthesis

Author

Weinstabl, Harald, Treu, Matthias, Rinnenthal, Joerg, Zahn, Stephan K., Ettmayer, Peter, Bader, Gerd, Dahmann, Georg, Kessler, Dirk, Rumpel, Klaus, Mischerikow, Nikolai, Savarese, Fabio, Gerstberger, Thomas, Mayer, Moriz, Zoephel, Andreas, Schnitzer, Renate, Sommergruber, Wolfgang, Martinelli, Paola, Arnhof, Heribert, Peric-Simov, Biljana, Hofbauer, Karin S., Garavel, Géraldine, Scherbantin, Yvonne, Mitzner, Sophie, Fett, Thomas N., Scholz, Guido, Bruchhaus, Jens, Burkard, Michelle, Kousek, Roland, Ciftci, Tuncay, Sharps, Bernadette, Schrenk, Andreas, Harrer, Christoph, Haering, Daniela, Wolkerstorfer, Bernhard, Zhang, Xuechun, Lv, Xiaobing, Du, Alicia, Li, Dongyang, Li, Yali, Quant, Jens, Pearson, Mark, and McConnell, Darryl B.

Abstract

Phosphoglycerate dehydrogenase (PHGDH) is known to be the rate-limiting enzyme in the serine synthesis pathway in humans. It converts glycolysis-derived 3-phosphoglycerate to 3-phosphopyruvate in a co-factor-dependent oxidation reaction. Herein, we report the discovery of BI-4916, a prodrug of the co-factor nicotinamide adenine dinucleotide (NADH/NAD+)-competitive PHGDH inhibitor BI-4924, which has shown high selectivity against the majority of other dehydrogenase targets. Starting with a fragment-based screening, a subsequent hit optimization using structure-based drug design was conducted to deliver a single-digit nanomolar lead series and to improve potency by 6 orders of magnitude. To this end, an intracellular ester cleavage mechanism of the ester prodrug was utilized to achieve intracellular enrichment of the actual carboxylic acid based drug and thus overcome high cytosolic levels of the competitive cofactors NADH/NAD+.

Published
2024
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39. GATA6 Controls Insulin Biosynthesis and Secretion in Adult β-Cells

Author

Villamayor, Laura, primary, Rodríguez-Seguel, Elisa, additional, Araujo, Raquel, additional, Carrasco, Manuel, additional, Bru-Tarí, Eva, additional, Mellado-Gil, José Manuel, additional, Gauthier, Benoit R., additional, Martinelli, Paola, additional, Quesada, Iván, additional, Soria, Bernat, additional, Martín, Franz, additional, Cano, David A., additional, and Rojas, Anabel, additional

Published
2017
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40. Transcriptional regulation by NR5A2 couples cell differentiation and inflammation in the pancreas

Author

Cobo, Isidoro, primary, Martinelli, Paola, additional, Flández, Marta, additional, Bakiri, Latifa, additional, Zhang, Mingfeng, additional, Carrillo-de-Santa-Pau, Enrique, additional, Jia, Jinping, additional, Thommesen, Liv, additional, Bruland, Torunn, additional, del Pozo, Natalia, additional, Olson, Sara, additional, Smith, Jill, additional, Bamlet, William R., additional, Petersen, Gloria M, additional, Malats, Núria, additional, Amundadottir, Laufey T, additional, Wagner, Erwin F., additional, and Real, Francisco X, additional

Published
2017
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43. GATA6 regulates EMT and tumour dissemination, and is a marker of response to adjuvant chemotherapy in pancreatic cancer

Author

Martinelli, Paola, primary, Carrillo-de Santa Pau, Enrique, additional, Cox, Trevor, additional, Sainz, Bruno, additional, Dusetti, Nelson, additional, Greenhalf, William, additional, Rinaldi, Lorenzo, additional, Costello, Eithne, additional, Ghaneh, Paula, additional, Malats, Núria, additional, Büchler, Markus, additional, Pajic, Marina, additional, Biankin, Andrew V, additional, Iovanna, Juan, additional, Neoptolemos, John, additional, and Real, Francisco X, additional

Published
2016
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44. GATA6 regulates EMT and tumor dissemination, and correlates with response to chemotherapy in pancreatic cancer

Author

Martinelli, Paola, primary, Santa Pau, Enrique Carrillo-de, additional, Cox, Trevor, additional, Saint, Bruno, additional, Dusetti, Nelson, additional, Greenhalf, William, additional, Rinaldi, Lorenzo, additional, Costello, Eithne, additional, Ghaneh, Paula, additional, Malats, Núria, additional, Büchler, Markus, additional, Jovanna, Juan, additional, Neoptolemos, John, additional, and Real, Francisco, additional

Published
2016
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46. GATA6 Controls Insulin Biosynthesis and Secretion in Adult β-Cells.

Author

Villamayor, Laura, Rodríguez-Seguel, Elisa, Araujo, Raquel, Carrasco, Manuel, Bru-Tarí, Eva, Mellado-Gil, José Manuel, Gauthier, Benoit R., Martinelli, Paola, Quesada, Iván, Soria, Bernat, Martín, Franz, Cano, David A., and Rojas, Anabel

Abstract

GATA4 and GATA6 play essential, but redundant, roles in pancreas formation in mice, and GATA6 mutations cause pancreatic agenesis in humans. GATA6 mutations have also recently been linked to adult-onset diabetes, with subclinical or no exocrine insufficiency, suggesting an important role for GATA6 in human β-cell physiology. To investigate the role of GATA6 in the adult endocrine pancreas, we generated mice in which Gata6 is specifically inactivated in the pancreas. These mice develop glucose intolerance. Islets deficient in GATA6 activity display decreased insulin content and impaired insulin secretion. Gata6-deficient β-cells exhibit ultrastructural abnormalities, including increased immature insulin granules, swollen mitochondria, and disorganized endoplasmic reticulum. We also demonstrate that Pdx1 expression in adult β-cells depends on GATA sites in transgenic reporter mice and that loss of GATA6 greatly affects β-cell-specific gene expression. These findings demonstrate the essential role of GATA6 in β-cell function. [ABSTRACT FROM AUTHOR]

Published
2018
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