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6. Burden of infectious disease studies in Europe and the United Kingdom: a review of methodological design choices

Author

Charalampous, Periklis, primary, Haagsma, Juanita A., additional, Jakobsen, Lea S., additional, Gorasso, Vanessa, additional, Noguer, Isabel, additional, Padron-Monedero, Alicia, additional, Sarmiento, Rodrigo, additional, Santos, João Vasco, additional, McDonald, Scott A., additional, Plass, Dietrich, additional, Wyper, Grant M. A., additional, Assunção, Ricardo, additional, von der Lippe, Elena, additional, Ádám, Balázs, additional, AlKerwi, Ala'a, additional, Arabloo, Jalal, additional, Baltazar, Ana Lúcia, additional, Bikbov, Boris, additional, Borrell-Pages, Maria, additional, Brus, Iris, additional, Burazeri, Genc, additional, Chaintoutis, Serafeim C., additional, Chen-Xu, José, additional, Chkhaberidze, Nino, additional, Cilovic-Lagarija, Seila, additional, Corso, Barbara, additional, Cuschieri, Sarah, additional, Di Bari, Carlotta, additional, Dopelt, Keren, additional, Economou, Mary, additional, Emeto, Theophilus I., additional, Fantke, Peter, additional, Fischer, Florian, additional, Freitas, Alberto, additional, García-González, Juan Manuel, additional, Gazzelloni, Federica, additional, Gissler, Mika, additional, Gkitakou, Artemis, additional, Gulmez, Hakan, additional, Gunes, Sezgin, additional, Haller, Sebastian, additional, Haneef, Romana, additional, Hincapié, Cesar A., additional, Hynds, Paul, additional, Idavain, Jane, additional, Ilic, Milena, additional, Ilic, Irena, additional, Isola, Gaetano, additional, Kabir, Zubair, additional, Kamusheva, Maria, additional, Kolkhir, Pavel, additional, Konar, Naime Meriç, additional, Kostoulas, Polychronis, additional, Kulimbet, Mukhtar, additional, La Vecchia, Carlo, additional, Lauriola, Paolo, additional, Levi, Miriam, additional, Majer, Marjeta, additional, Mechili, Enkeleint A., additional, Monasta, Lorenzo, additional, Mondello, Stefania, additional, Muñoz Laguna, Javier, additional, Nena, Evangelia, additional, Ng, Edmond S. W., additional, Nguewa, Paul, additional, Niranjan, Vikram, additional, Nola, Iskra Alexandra, additional, O'Caoimh, Rónán, additional, Obradović, Marija, additional, Pallari, Elena, additional, Peyroteo, Mariana, additional, Pinheiro, Vera, additional, Pranjic, Nurka, additional, Reina Ortiz, Miguel, additional, Riva, Silvia, additional, Santoso, Cornelia Melinda Adi, additional, Santric Milicevic, Milena, additional, Schmitt, Tugce, additional, Speybroeck, Niko, additional, Sprügel, Maximilian, additional, Steiropoulos, Paschalis, additional, Stevanovic, Aleksandar, additional, Thygesen, Lau Caspar, additional, Tozija, Fimka, additional, Unim, Brigid, additional, Bektaş Uysal, Hilal, additional, Varga, Orsolya, additional, Vasic, Milena, additional, Vieira, Rafael José, additional, Yigit, Vahit, additional, Devleesschauwer, Brecht, additional, and Pires, Sara M., additional

Published
2023
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7. Burden of disease attributable to risk factors in European countries: a scoping literature review

Author

Gorasso, Vanessa, Morgado, Joana Nazaré, Charalampous, Periklis, Pires, Sara M., Haagsma, Juanita A., Santos, João Vasco, Idavain, Jane, Ngwa, Che Henry, Noguer, Isabel, Padron-Monedero, Alicia, Sarmiento, Rodrigo, Pinheiro, Vera, Von der Lippe, Elena, Jakobsen, Lea Sletting, Devleesschauwer, Brecht, Plass, Dietrich, Aasvang, Gunn Marit, Ádám, Balázs, Alkerwi, Ala’a, Arabloo, Jalal, Baltazar, Ana Lúcia, Uysal, Hilal Bektas, Bikbov, Boris, Bolling, Anette Kocbach, Borrell-Pages, Maria, Carreras, Giulia, Castelpietra, Giulio, Chen-Xu, José, Lagarija, Šeila Cilović, Corso, Barbara, Cuschieri, Sarah, De Pauw, Robby, Dhaouadi, Sonia, Dokova, Klara, Dopelt, Keren, Economou, Mary, Emeto, Theophilus I., Fantke, Peter, Fischer, Florian, Freitas, Alberto, Galluzzo, Lucia, García-González, Juan Manuel, Gazzelloni, Federica, Gissler, Mika, Gkitakou, Artemis, Gubes, Sezgin, Canu, Irina Guseva, Hincapié, Cesar A., Hynds, Paul, Ilic, Irena, Ilic, Milena, Isola, Gaetano, Kabir, Zubair, Kolkhir, Pavel, Konar, Naime Meriç, Kretzschmar, Mirjam, Kulimbet, Mukhtar, La Vecchia, Carlo, Ladeira, Carina, Lassen, Brian, Lauriola, Paolo, Lehtomäki, Heli, Levi, Miriam, Majer, Marjeta, McDonald, Scott A., Mechili, Enkeleint A., Misins, Janis, Monasta, Lorenzo, Laguna, Javier Muñoz, Namorado, Sónia, Nena, Evangelia, Ng, Edmond S. W., Nguewa, Paul, Niranjan, Vikram, Nola, Iskra Alexandra, Obradović, Marija, O’Caoimh, Rónán, Öztürk, Nazife, Pastorinho, M. Ramiro, Petrou, Panagiotis, Peyroteo, Mariana, Ortiz, Miguel Reina, Riva, Silvia, Rocha-Gomes, João, Santoso, Cornelia Melinda Adi, Schmitt, Tugce, Shigdel, Rajesh, Sigurvinsdottir, Rannveig, Soriano, Joan B., Sousa, Ana Catarina, Sprügel, Maximilian, Steiropoulos, Paschalis, Tozija, Fimka, Unim, Brigid, Vandeninden, Bram, Varga, Orsolya, Vasic, Milena, Viegas, Susana, Vieira, Rafael, Violante, Francesco S., Wyper, Grant M. A., Yigit, Vahit, Zaletel, Jelka, and The COST Action CA18218 participants, [missing]

Subjects
Risk factors, Medicine and Health Sciences, Burden of disease, Comparative risk assessment
Abstract

Objectives Within the framework of the burden of disease (BoD) approach, disease and injury burden estimates attributable to risk factors are a useful guide for policy formulation and priority setting in disease prevention. Considering the important differences in methods, and their impact on burden estimates, we conducted a scoping literature review to: (1) map the BoD assessments including risk factors performed across Europe; and (2) identify the methodological choices in comparative risk assessment (CRA) and risk assessment methods. Methods We searched multiple literature databases, including grey literature websites and targeted public health agencies websites. Results A total of 113 studies were included in the synthesis and further divided into independent BoD assessments (54 studies) and studies linked to the Global Burden of Disease (59 papers). Our results showed that the methods used to perform CRA varied substantially across independent European BoD studies. While there were some methodological choices that were more common than others, we did not observe patterns in terms of country, year or risk factor. Each methodological choice can affect the comparability of estimates between and within countries and/or risk factors, since they might significantly influence the quantification of the attributable burden. From our analysis we observed that the use of CRA was less common for some types of risk factors and outcomes. These included environmental and occupational risk factors, which are more likely to use bottom-up approaches for health outcomes where disease envelopes may not be available. Conclusions Our review also highlighted misreporting, the lack of uncertainty analysis and the under-investigation of causal relationships in BoD studies. Development and use of guidelines for performing and reporting BoD studies will help understand differences, avoid misinterpretations thus improving comparability among estimates. Registration The study protocol has been registered on PROSPERO, CRD42020177477 (available at: https://www.crd.york.ac.uk/PROSPERO/).

Published
2023

14. Unravelling data for rapid evidence-based response to COVID-19: a summary of the unCoVer protocol

Author

Peñalvo, José L., primary, Mertens, Elly, additional, Ademović, Enisa, additional, Akgun, Seval, additional, Baltazar, Ana Lúcia, additional, Buonfrate, Dora, additional, Čoklo, Miran, additional, Devleesschauwer, Brecht, additional, Diaz Valencia, Paula Andrea, additional, Fernandes, João C., additional, Gómez, Enrique Javier, additional, Hynds, Paul, additional, Kabir, Zubair, additional, Klein, Jörn, additional, Kostoulas, Polychronis, additional, Llanos Jiménez, Lucía, additional, Lotrean, Lucia Maria, additional, Majdan, Marek, additional, Menasalvas, Ernestina, additional, Nguewa, Paul, additional, Oh, In-Hwan, additional, O’Sullivan, Georgie, additional, Pereira, David M., additional, Reina Ortiz, Miguel, additional, Riva, Silvia, additional, Soriano, Gloria, additional, Soriano, Joan B., additional, Spilki, Fernando, additional, Tamang, Mary Elizabeth, additional, Trofor, Antigona Carmen, additional, Vaillant, Michel, additional, Van Ierssel, Sabrina, additional, Vuković, Jakov, additional, and Castellano, José M., additional

Published
2021
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18. The host mTOR pathway and parasitic diseases pathogenesis

Author

Rashidi, Sajad, Mansouri, Reza, Ali-Hassanzadeh, Mohammad, Mojtahedi, Zahra, Shafiei, Reza, Savardashtaki, Amir, Hamidizadeh, Nasrin, Karimazar, Mohammadreza, Nguewa, Paul, Manzano Román, Raúl, Fundación 'la Caixa', Fundación Caja Navarra, Diputación Foral de Navarra, Fundación M. Francisca de Roviralta, and European Cooperation in Science and Technology

Subjects
Modulation, Therapies, mTOR, Parasites, Rapamycin, Signaling
Abstract

The mechanistic (or mammalian) target of rapamycin (mTOR) is considered as a critical regulatory enzyme involved in essential signaling pathways affecting cell growth, cell proliferation, protein translation, regulation of cellular metabolism, and cytoskeletal structure. Also, mTOR signaling has crucial roles in cell homeostasis via processes such as autophagy. Autophagy prevents many pathogen infections and is involved on immunosurveillance and pathogenesis. Immune responses and autophagy are therefore key host responses and both are linked by complex mTOR regulatory mechanisms. In recent years, the mTOR pathway has been highlighted in different diseases such as diabetes, cancer, and infectious and parasitic diseases including leishmaniasis, toxoplasmosis, and malaria. The current review underlines the implications of mTOR signals and intricate networks on pathogen infections and the modulation of this master regulator by parasites. Parasitic infections are able to induce dynamic metabolic reprogramming leading to mTOR alterations in spite of many other ways impacting this regulatory network. Accordingly, the identification of parasite effects and interactions over such a complex modulation might reveal novel information regarding the biology of the abovementioned parasites and might allow the development of therapeutic strategies against parasitic diseases. In this sense, the effects of inhibiting the mTOR pathways are also considered in this context in the light of their potential for the prevention and treatment of parasitic diseases. PN thanks La Fundación La Caixa (LCF/PR/PR13/11080005), Fundación Caja Navarra, Gobierno de Navarra-Salud (12/2017), Fundación Roviralta, Ubesol, Government of Navarre, Laser Ebro, Inversiones Garcilaso de la Vega and COST Actions CA18217 and CA18218 for their support.

Published
2021

19. The main post-translational modifications and related regulatory pathways in the malaria parasite Plasmodium falciparum: An update

Author

Rashidi, Sajad, Tuteja, Renu, Mansouri, Reza, Ali-Hassanzadeh, Mohammad, Shafiei, Reza, Ghani, Esmaeel, Karimazar, Mohammadreza, Nguewa, Paul, Manzano Román, Raúl, Fundación 'la Caixa', Fundación Caja Navarra, Diputación Foral de Navarra, Fundación M. Francisca de Roviralta, and European Cooperation in Science and Technology

Subjects
Essential pathways, Plasmodium falciparum, Therapeutic targets, Regulatory proteins, Post-translational modification
Abstract

There are important challenges when investigating individual post-translational modifications (PTMs) or protein interaction network and delineating if PTMs or their changes and cross-talks are involved during infection, disease initiation or as a result of disease progression. Proteomics and in silico approaches now offer the possibility to complement each other to further understand the regulatory involvement of these modifications in parasites and infection biology. Accordingly, the current review highlights key expressed or altered proteins and PTMs are invisible switches that turn on and off the function of most of the proteins. PTMs include phosphorylation, glycosylation, ubiquitylation, palmitoylation, myristoylation, prenylation, acetylation, methylation, and epigenetic PTMs in P. falciparum which have been recently identified. But also other low-abundant or overlooked PTMs that might be important for the parasite's survival, infectivity, antigenicity, immunomodulation and pathogenesis. We here emphasize the PTMs as regulatory pathways playing major roles in the biology, pathogenicity, metabolic pathways, survival, host-parasite interactions and the life cycle of P. falciparum. Further validations and functional characterizations of such proteins might confirm the discovery of therapeutic targets and might most likely provide valuable data for the treatment of P. falciparum, the main cause of severe malaria in human. PN gratefully acknowledges the support provided by Fundación La Caixa (LCF/PR/PR13/11080005) and Fundación Caja Navarra, Gobierno Navarra Salud (12/2017), Fundación Roviralta, Ubesol, Government of Navarre, Laser Ebro, and Inversores Garcilaso de la Vega S.L. and COST actions CA18217 (ENOVAT) and CA18218.

Published
2021

20. Potential therapeutic targets shared between leishmaniasis and cancer

Author

Rashidi, Sajad, Fernández-Rubio, Celia, Manzano Román, Raúl, Mansouri, Reza, Shafiei, Reza, Ali-Hassanzadeh, Mohammad, Barazesh, Afshin, Karimazar, Mohammadreza, Hatam, Gholamreza, Nguewa, Paul, and National Institute for Medical Research (UK)

Subjects
Therapeutic target, Drug, Common protein, Leishmaniasis, Cancer
Abstract

© The Author(s), 2021. The association of leishmaniasis and malignancies in human and animal models has been highlighted in recent years. The misdiagnosis of coexistence of leishmaniasis and cancer and the use of common drugs in the treatment of such diseases prompt us to further survey the molecular biology of Leishmania parasites and cancer cells. The information regarding common expressed proteins, as possible therapeutic targets, in Leishmania parasites and cancer cells is scarce. Therefore, the current study reviews proteins, and investigates the regulation and functions of several key proteins in Leishmania parasites and cancer cells. The up- and down-regulations of such proteins were mostly related to survival, development, pathogenicity, metabolic pathways and vital signalling in Leishmania parasites and cancer cells. The presence of common expressed proteins in Leishmania parasites and cancer cells reveals valuable information regarding the possible shared mechanisms of pathogenicity and opportunities for therapeutic targeting in leishmaniasis and cancers in the future. This study was supported by the National Institute for Medical Research Development (NIMAD), Tehran, Iran, grant number 971405.

Published
2021

22. Potential therapeutic targets shared between leishmaniasis and cancer

Author

Rashidi, Sajad, primary, Fernández-Rubio, Celia, additional, Manzano-Román, Raúl, additional, Mansouri, Reza, additional, Shafiei, Reza, additional, Ali-Hassanzadeh, Mohammad, additional, Barazesh, Afshin, additional, Karimazar, Mohammadreza, additional, Hatam, Gholamreza, additional, and Nguewa, Paul, additional

Published
2021
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27. Leishmanicidal Activity of Isoselenocyanate Derivatives

Author

Fernández-Rubio, Celia, primary, Larrea, Esther, additional, Peña Guerrero, José, additional, Sesma Herrero, Eduardo, additional, Gamboa, Iñigo, additional, Berrio, Carlos, additional, Plano, Daniel, additional, Amin, Shantu, additional, Sharma, Arun K., additional, and Nguewa, Paul A., additional

Published
2019
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28. Highlighting the interplay of microRNAs from Leishmania parasites and infected-host cells.

Author

Rashidi, Sajad, Mansouri, Reza, Ali-Hassanzadeh, Mohammad, Ghani, Esmaeel, Barazesh, Afshin, Karimazar, Mohammadreza, Nguewa, Paul, and Carrera Silva, Eugenio Antonio

Subjects
LEISHMANIASIS, CELL communication, LEISHMANIA, MICRORNA, PARASITES, DRUG target
Abstract

Leishmania parasites, the causative agents of leishmaniasis, are protozoan parasites with the ability to modify the signalling pathway and cell responses of their infected host cells. These parasite strategies alter the host cell environment and conditions favouring their replication, survival and pathogenesis. Since microRNAs (miRNAs) are able to post-transcriptionally regulate gene expression processes, these biomolecules can exert critical roles in controlling Leishmania-host cell interplay. Therefore, the identification of relevant miRNAs differentially expressed in Leishmania parasites as well as in infected cells, which affect the host fitness, could be critical to understand the infection biology, pathogenicity and immune response against these parasites. Accordingly, the current review aims to address the differentially expressed miRNAs in both, the parasite and infected host cells and how these biomolecules change cell signalling and host immune responses during infection. A deep understanding of these processes could provide novel guidelines and therapeutic strategies for managing and treating leishmaniasis. [ABSTRACT FROM AUTHOR]

Published
2021
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29. Antitumor and antiangiogenic effect of the dual EGFR and HER-2 tyrosine kinase inhibitor lapatinib in a lung cancer model

Author

Collantes Maria, Peñuelas Ivan, Catena Raul, Redrado Miriam, Manrique Irene, Perez-Stable Carlos, Parrondo Ricardo, Nguewa Paul A, Diaz Roque, Díaz-González Juan, and Calvo Alfonso

Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Background There is strong evidence demonstrating that activation of epidermal growth factor receptors (EGFRs) leads to tumor growth, progression, invasion and metastasis. Erlotinib and gefitinib, two EGFR-targeted agents, have been shown to be relevant drugs for lung cancer treatment. Recent studies demonstrate that lapatinib, a dual tyrosine kinase inhibitor of EGFR and HER-2 receptors, is clinically effective against HER-2-overexpressing metastatic breast cancer. In this report, we investigated the activity of lapatinib against non-small cell lung cancer (NSCLC). Methods We selected the lung cancer cell line A549, which harbors genomic amplification of EGFR and HER-2. Proliferation, cell cycle analysis, clonogenic assays, and signaling cascade analyses (by western blot) were performed in vitro. In vivo experiments with A549 cells xenotransplanted into nude mice treated with lapatinib (with or without radiotherapy) were also carried out. Results Lapatinib dramatically reduced cell proliferation (P < 0.0001), DNA synthesis (P < 0.006), and colony formation capacity (P < 0.0001) in A549 cells in vitro. Furthermore, lapatinib induced G1 cell cycle arrest (P < 0.0001) and apoptotic cell death (P < 0.0006) and reduced cyclin A and B1 levels, which are regulators of S and G2/M cell cycle stages, respectively. Stimulation of apoptosis in lapatinib-treated A549 cells was correlated with increased cleaved PARP, active caspase-3, and proapoptotic Bak-1 levels, and reduction in the antiapoptic IAP-2 and Bcl-xL protein levels. We also demonstrate that lapatinib altered EGFR/HER-2 signaling pathways reducing p-EGFR, p-HER-2, p-ERK1/2, p-AKT, c-Myc and PCNA levels. In vivo experiments revealed that A549 tumor-bearing mice treated with lapatinib had significantly less active tumors (as assessed by PET analysis) (P < 0.04) and smaller in size than controls. In addition, tumors from lapatinib-treated mice showed a dramatic reduction in angiogenesis (P < 0.0001). Conclusion Overall, these data suggest that lapatinib may be a clinically useful agent for the treatment of lung cancer.

Published
2010
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32. Novel Heteroaryl Selenocyanates and Diselenides as Potent Antileishmanial Agents

Author

Baquedano, Ylenia, primary, Alcolea, Verónica, additional, Toro, Miguel Ángel, additional, Gutiérrez, Killian Jesús, additional, Nguewa, Paul, additional, Font, María, additional, Moreno, Esther, additional, Espuelas, Socorro, additional, Jiménez-Ruiz, Antonio, additional, Palop, Juan Antonio, additional, Plano, Daniel, additional, and Sanmartín, Carmen, additional

Published
2016
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33. Leishmanicidal Activities of Novel Methylseleno-Imidocarbamates

Author

Fernández-Rubio, Celia, primary, Campbell, Daphne, additional, Vacas, Andrés, additional, Ibañez, Elena, additional, Moreno, Esther, additional, Espuelas, Socorro, additional, Calvo, Alfonso, additional, Palop, Juan Antonio, additional, Plano, Daniel, additional, Sanmartin, Carmen, additional, and Nguewa, Paul A., additional

Published
2015
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34. Inhibitor of Differentiation-1 as a Novel Prognostic Factor in NSCLC Patients with Adenocarcinoma Histology and Its Potential Contribution to Therapy Resistance

Author

Ponz-Sarvisé, Mariano, primary, Nguewa, Paul A., additional, Pajares, María J., additional, Agorreta, Jackeline, additional, Lozano, María D., additional, Redrado, Miriam, additional, Pio, Ruben, additional, Behrens, Carmen, additional, Wistuba, Ignacio I., additional, García-Franco, Carlos E., additional, García-Foncillas, Jesús, additional, Montuenga, Luis M., additional, Calvo, Alfonso, additional, and Gil-Bazo, Ignacio, additional

Published
2011
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35. Abstract 2219: Inhibitor of differentiation-1 is a novel prognostic factor among NSCLC patients with adenocarcinoma histology and contributes to therapy resistance

Author

Ponz-Sarvise, Mariano, primary, Nguewa, Paul A., additional, Pajares, Maria J., additional, Agorreta, Jackeline, additional, Lozano, Maria D., additional, Redrado, Miriam, additional, Pio, Ruben, additional, Behrens, Carmen, additional, Wistuba, Ignacio, additional, Garcia-Foncillas, Jesus, additional, Montuenga, Luis M., additional, Calvo, Alfonso, additional, and Gil-Bazo, Ignacio, additional

Published
2011
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37. Antitumor and antiangiogenic effect of the dual EGFR and HER-2 tyrosine kinase inhibitor lapatinib in a lung cancer model

Author

Diaz, Roque, primary, Nguewa, Paul A, additional, Parrondo, Ricardo, additional, Perez-Stable, Carlos, additional, Manrique, Irene, additional, Redrado, Miriam, additional, Catena, Raul, additional, Collantes, Maria, additional, Peñuelas, Ivan, additional, Díaz-González, Juan Antonio, additional, and Calvo, Alfonso, additional

Published
2010
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39. Identification of Importin 8 (IPO8) as the most accurate reference gene for the clinicopathological analysis of lung specimens

Author

Nguewa, Paul A, primary, Agorreta, Jackeline, additional, Blanco, David, additional, Lozano, Maria, additional, Gomez-Roman, Javier, additional, Sanchez, Blas A, additional, Valles, Iñaki, additional, Pajares, Maria J, additional, Pio, Ruben, additional, Rodriguez, Maria, additional, Montuenga, Luis M, additional, and Calvo, Alfonso, additional

Published
2008
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41. Antitumor and antiangiogenic effect of the dualEGFR and HER-2 tyrosine kinase inhibitor lapatinibin a lung cancer model.

Author

Diaz, Roque, Nguewa, Paul A., Parrondo, Ricardo, Perez-Stable, Carlos, Manrique, Irene, Redrado, Miriam, Catena, Raul, Collantes, Maria, Peñuelas, Ivan, Díaz-González, Juan Antonio, and Calvo, Alfonso

Subjects
*EPIDERMAL growth factor, *CANCER treatment, *LUNG cancer, *CELL cycle, *LABORATORY mice
Abstract

Background: There is strong evidence demonstrating that activation of epidermal growth factor receptors (EGFRs) leads to tumor growth, progression, invasion and metastasis. Erlotinib and gefitinib, two EGFR-targeted agents, have been shown to be relevant drugs for lung cancer treatment. Recent studies demonstrate that lapatinib, a dual tyrosine kinase inhibitor of EGFR and HER-2 receptors, is clinically effective against HER-2-overexpressing metastatic breast cancer. In this report, we investigated the activity of lapatinib against non-small cell lung cancer (NSCLC). Methods: We selected the lung cancer cell line A549, which harbors genomic amplification of EGFR and HER-2. Proliferation, cell cycle analysis, clonogenic assays, and signaling cascade analyses (by western blot) were performed in vitro. In vivo experiments with A549 cells xenotransplanted into nude mice treated with lapatinib (with or without radiotherapy) were also carried out. Results: Lapatinib dramatically reduced cell proliferation (P < 0.0001), DNA synthesis (P < 0.006), and colony formation capacity (P < 0.0001) in A549 cells in vitro. Furthermore, lapatinib induced G1 cell cycle arrest (P < 0.0001) and apoptotic cell death (P < 0.0006) and reduced cyclin A and B1 levels, which are regulators of S and G2/M cell cycle stages, respectively. Stimulation of apoptosis in lapatinib-treated A549 cells was correlated with increased cleaved PARP, active caspase-3, and proapoptotic Bak-1 levels, and reduction in the antiapoptic IAP-2 and Bcl-xL protein levels. We also demonstrate that lapatinib altered EGFR/HER-2 signaling pathways reducing p-EGFR, p-HER-2, p-ERK1/2, p-AKT, c-Myc and PCNA levels. In vivo experiments revealed that A549 tumor-bearing mice treated with lapatinib had significantly less active tumors (as assessed by PET analysis) (P < 0.04) and smaller in size than controls. In addition, tumors from lapatinib-treated mice showed a dramatic reduction in angiogenesis (P < 0.0001). Conclusion: Overall, these data suggest that lapatinib may be a clinically useful agent for the treatment of lung cancer. [ABSTRACT FROM AUTHOR]

Published
2010
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42. The Novel Serine/Threonine Protein Kinase LmjF.22.0810 from Leishmania major May Be Involved in the Resistance to Drugs such as Paromomycin.

Author

Vacas, Andrés, Fernández-Rubio, Celia, Algarabel, Miriam, Peña-Guerrero, José, Larrea, Esther, Rocha Formiga, Fabio, García-Sosa, Alfonso T., and Nguewa, Paul A.

Subjects
LEISHMANIA major, DRUG resistance, PROTEIN kinases, SMALL molecules, MOLECULAR dynamics, SERINE/THREONINE kinases
Abstract

The identification and clarification of the mechanisms of action of drugs used against leishmaniasis may improve their administration regimens and prevent the development of resistant strains. Herein, for the first time, we describe the structure of the putatively essential Ser/Thr kinase LmjF.22.0810 from Leishmania major. Molecular dynamics simulations were performed to assess the stability of the kinase model. The analysis of its sequence and structure revealed two druggable sites on the protein. Furthermore, in silico docking of small molecules showed that aminoglycosides preferentially bind to the phosphorylation site of the protein. Given that transgenic LmjF.22.0810-overexpressing parasites displayed less sensitivity to aminoglycosides such as paromomycin, our predicted models support the idea that the mechanism of drug resistance observed in those transgenic parasites is the tight binding of such compounds to LmjF.22.0810 associated with its overexpression. These results may be helpful to understand the complex machinery of drug response in Leishmania. [ABSTRACT FROM AUTHOR]

Published
2019
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43. Leishmanicidal Activity of Isoselenocyanate Derivatives

Author

Fernández-Rubio, Celia, Larrea, Esther, Peña Guerrero, José, Sesma Herrero, Eduardo, Gamboa, Iñigo, Berrio, Carlos, Plano, Daniel, Amin, Shantu, Sharma, Arun K., and Nguewa, Paul A.

Abstract

Conventional chemotherapy against leishmaniasis includes agents exhibiting considerable toxicity. In addition, reports of drug resistance are not uncommon.

Published
2018
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