TY  - JOUR
AU  - Ortega-Sabater, Carmen
AU  - F. Calvo, Gabriel
AU  - Dinić, Jelena
AU  - Podolski-Renić, Ana
AU  - Pešić, Milica
AU  - Pérez-García, Víctor
PY  - 2023
UR  - https://link.springer.com/10.1007/s11538-022-01113-4
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/5357
AB  - Evolutionary dynamics allows us to understand many changes happening in a broad variety of biological systems, ranging from individuals to complete ecosystems. It is also behind a number of remarkable organizational changes that happen during the natural history of cancers. These reflect tumour heterogeneity, which is present at all cellular levels, including the genome, proteome and phenome, shaping its development and interrelation with its environment. An intriguing observation in different cohorts of oncological patients is that tumours exhibit an increased proliferation as the disease progresses, while the timescales involved are apparently too short for the fixation of sufficient driver mutations to promote explosive growth. Here, we discuss how phenotypic plasticity, emerging from a single genotype, may play a key role and provide a ground for a continuous acceleration of the proliferation rate of clonal populations with time. We address this question by combining the analysis of real-time growth of non-small-cell lung carcinoma cells (N-H460) together with stochastic and deterministic mathematical models that capture proliferation trait heterogeneity in clonal populations to elucidate the contribution of phenotypic transitions on tumour growth dynamics.
PB  - Springer
T2  - Bulletin of Mathematical Biology
T1  - Stochastic Fluctuations Drive Non-genetic Evolution of Proliferation in Clonal Cancer Cell Populations
IS  - 1
VL  - 85
DO  - 10.1007/s11538-022-01113-4
SP  - 8
ER  - 

@article{
author = "Ortega-Sabater, Carmen and F. Calvo, Gabriel and Dinić, Jelena and Podolski-Renić, Ana and Pešić, Milica and Pérez-García, Víctor",
year = "2023",
abstract = "Evolutionary dynamics allows us to understand many changes happening in a broad variety of biological systems, ranging from individuals to complete ecosystems. It is also behind a number of remarkable organizational changes that happen during the natural history of cancers. These reflect tumour heterogeneity, which is present at all cellular levels, including the genome, proteome and phenome, shaping its development and interrelation with its environment. An intriguing observation in different cohorts of oncological patients is that tumours exhibit an increased proliferation as the disease progresses, while the timescales involved are apparently too short for the fixation of sufficient driver mutations to promote explosive growth. Here, we discuss how phenotypic plasticity, emerging from a single genotype, may play a key role and provide a ground for a continuous acceleration of the proliferation rate of clonal populations with time. We address this question by combining the analysis of real-time growth of non-small-cell lung carcinoma cells (N-H460) together with stochastic and deterministic mathematical models that capture proliferation trait heterogeneity in clonal populations to elucidate the contribution of phenotypic transitions on tumour growth dynamics.",
publisher = "Springer",
journal = "Bulletin of Mathematical Biology",
title = "Stochastic Fluctuations Drive Non-genetic Evolution of Proliferation in Clonal Cancer Cell Populations",
number = "1",
volume = "85",
doi = "10.1007/s11538-022-01113-4",
pages = "8"
}

Ortega-Sabater, C., F. Calvo, G., Dinić, J., Podolski-Renić, A., Pešić, M.,& Pérez-García, V.. (2023). Stochastic Fluctuations Drive Non-genetic Evolution of Proliferation in Clonal Cancer Cell Populations. in Bulletin of Mathematical Biology
Springer., 85(1), 8.
https://doi.org/10.1007/s11538-022-01113-4

Ortega-Sabater C, F. Calvo G, Dinić J, Podolski-Renić A, Pešić M, Pérez-García V. Stochastic Fluctuations Drive Non-genetic Evolution of Proliferation in Clonal Cancer Cell Populations. in Bulletin of Mathematical Biology. 2023;85(1):8.
doi:10.1007/s11538-022-01113-4 .

Ortega-Sabater, Carmen, F. Calvo, Gabriel, Dinić, Jelena, Podolski-Renić, Ana, Pešić, Milica, Pérez-García, Víctor, "Stochastic Fluctuations Drive Non-genetic Evolution of Proliferation in Clonal Cancer Cell Populations" in Bulletin of Mathematical Biology, 85, no. 1 (2023):8,
https://doi.org/10.1007/s11538-022-01113-4 . .

TY  - JOUR
AU  - Segura-Collar, Berta
AU  - Jiménez-Sánchez, Juan
AU  - Gargini, Ricardo
AU  - Dragoj, Miodrag
AU  - Sepúlveda-Sánchez, Juan M
AU  - Pešić, Milica
AU  - Ramírez, María A
AU  - Ayala-Hernández, Luis E
AU  - Sánchez-Gómez, Pilar
AU  - Pérez-García, Víctor M
PY  - 2022
UR  - http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=PMC9616068
UR  - https://academic.oup.com/noa/article/doi/10.1093/noajnl/vdac155/6722624
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/5182
AB  - Background Temozolomide (TMZ) is an oral alkylating agent active against gliomas with a favorable toxicity profile. It is part of the standard of care in the management of glioblastoma (GBM), and is commonly used in low-grade gliomas (LGG). In-silico mathematical models can potentially be used to personalize treatments and to accelerate the discovery of optimal drug delivery schemes. Methods Agent-based mathematical models fed with either mouse or patient data were developed for the in-silico studies. The experimental test beds used to confirm the results were: mouse glioma models obtained by retroviral expression of EGFR-wt/EGFR-vIII in primary progenitors from p16/p19 ko mice and grown in-vitro and in-vivo in orthotopic allografts, and human GBM U251 cells immobilized in alginate microfibers. The patient data used to parametrize the model were obtained from the TCGA/TCIA databases and the TOG clinical study. Results Slow-growth "virtual" murine GBMs benefited from increasing TMZ dose separation in-silico. In line with the simulation results, improved survival, reduced toxicity, lower expression of resistance factors, and reduction of the tumor mesenchymal component were observed in experimental models subject to long-cycle treatment, particularly in slowly growing tumors. Tissue analysis after long-cycle TMZ treatments revealed epigenetically driven changes in tumor phenotype, which could explain the reduction in GBM growth speed. In-silico trials provided support for implementation methods in human patients. Conclusions In-silico simulations, in-vitro and in-vivo studies show that TMZ administration schedules with increased time between doses may reduce toxicity, delay the appearance of resistances and lead to survival benefits mediated by changes in the tumor phenotype in slowly-growing GBMs.
PB  - Oxford: Oxford University Press
T2  - Neuro-Oncology Advances
T1  - On optimal temozolomide scheduling for slowly growing glioblastomas
IS  - 1
VL  - 4
DO  - 10.1093/noajnl/vdac155
SP  - vdac155
ER  - 

@article{
author = "Segura-Collar, Berta and Jiménez-Sánchez, Juan and Gargini, Ricardo and Dragoj, Miodrag and Sepúlveda-Sánchez, Juan M and Pešić, Milica and Ramírez, María A and Ayala-Hernández, Luis E and Sánchez-Gómez, Pilar and Pérez-García, Víctor M",
year = "2022",
abstract = "Background Temozolomide (TMZ) is an oral alkylating agent active against gliomas with a favorable toxicity profile. It is part of the standard of care in the management of glioblastoma (GBM), and is commonly used in low-grade gliomas (LGG). In-silico mathematical models can potentially be used to personalize treatments and to accelerate the discovery of optimal drug delivery schemes. Methods Agent-based mathematical models fed with either mouse or patient data were developed for the in-silico studies. The experimental test beds used to confirm the results were: mouse glioma models obtained by retroviral expression of EGFR-wt/EGFR-vIII in primary progenitors from p16/p19 ko mice and grown in-vitro and in-vivo in orthotopic allografts, and human GBM U251 cells immobilized in alginate microfibers. The patient data used to parametrize the model were obtained from the TCGA/TCIA databases and the TOG clinical study. Results Slow-growth "virtual" murine GBMs benefited from increasing TMZ dose separation in-silico. In line with the simulation results, improved survival, reduced toxicity, lower expression of resistance factors, and reduction of the tumor mesenchymal component were observed in experimental models subject to long-cycle treatment, particularly in slowly growing tumors. Tissue analysis after long-cycle TMZ treatments revealed epigenetically driven changes in tumor phenotype, which could explain the reduction in GBM growth speed. In-silico trials provided support for implementation methods in human patients. Conclusions In-silico simulations, in-vitro and in-vivo studies show that TMZ administration schedules with increased time between doses may reduce toxicity, delay the appearance of resistances and lead to survival benefits mediated by changes in the tumor phenotype in slowly-growing GBMs.",
publisher = "Oxford: Oxford University Press",
journal = "Neuro-Oncology Advances",
title = "On optimal temozolomide scheduling for slowly growing glioblastomas",
number = "1",
volume = "4",
doi = "10.1093/noajnl/vdac155",
pages = "vdac155"
}

Segura-Collar, B., Jiménez-Sánchez, J., Gargini, R., Dragoj, M., Sepúlveda-Sánchez, J. M., Pešić, M., Ramírez, M. A., Ayala-Hernández, L. E., Sánchez-Gómez, P.,& Pérez-García, V. M.. (2022). On optimal temozolomide scheduling for slowly growing glioblastomas. in Neuro-Oncology Advances
Oxford: Oxford University Press., 4(1), vdac155.
https://doi.org/10.1093/noajnl/vdac155

Segura-Collar B, Jiménez-Sánchez J, Gargini R, Dragoj M, Sepúlveda-Sánchez JM, Pešić M, Ramírez MA, Ayala-Hernández LE, Sánchez-Gómez P, Pérez-García VM. On optimal temozolomide scheduling for slowly growing glioblastomas. in Neuro-Oncology Advances. 2022;4(1):vdac155.
doi:10.1093/noajnl/vdac155 .

Segura-Collar, Berta, Jiménez-Sánchez, Juan, Gargini, Ricardo, Dragoj, Miodrag, Sepúlveda-Sánchez, Juan M, Pešić, Milica, Ramírez, María A, Ayala-Hernández, Luis E, Sánchez-Gómez, Pilar, Pérez-García, Víctor M, "On optimal temozolomide scheduling for slowly growing glioblastomas" in Neuro-Oncology Advances, 4, no. 1 (2022):vdac155,
https://doi.org/10.1093/noajnl/vdac155 . .

TY  - JOUR
AU  - Frontiñán-Rubio, Javier
AU  - Santiago-Mora, Raquel María
AU  - Nieva-Velasco, Consuelo María
AU  - Ferrín, Gustavo
AU  - Martínez-González, Alicia
AU  - Gómez, María Victoria
AU  - Moreno, María
AU  - Ariza, Julia
AU  - Lozano, Eva
AU  - Arjona-Gutiérrez, Jacinto
AU  - Gil-Agudo, Antonio
AU  - De la Mata, Manuel
AU  - Pešić, Milica
AU  - Peinado, Juan Ramón
AU  - Villalba, José M.
AU  - Pérez-Romasanta, Luis
AU  - Pérez-García, Víctor M.
AU  - Alcaín, Francisco J.
AU  - Durán-Prado, Mario
PY  - 2018
UR  - https://www.sciencedirect.com/science/article/pii/S0167814018302408?via%3Dihub
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/3070
AB  - OBJECTIVES To investigate how the modulation of the oxidative balance affects cytotoxic therapies in glioblastoma, in vitro. MATERIAL AND METHODS Human glioblastoma U251 and T98 cells and normal astrocytes C8D1A were loaded with coenzyme Q10 (CoQ). Mitochondrial superoxide ion (O2-) and H2O2 were measured by fluorescence microscopy. OXPHOS performance was assessed in U251 cells with an oxytherm Clark-type electrode. Radio- and chemotherapy cytotoxicity was assessed by immunostaining of γH2AX (24 h), annexin V and nuclei morphology, at short (72 h) and long (15 d) time. Hif-1α, SOD1, SOD2 and NQO1 were determined by immunolabeling. Catalase activity was measured by classic enzymatic assay. Glutathione levels and total antioxidant capacity were quantified using commercial kits. RESULTS CoQ did not affect oxygen consumption but reduced the level of O2- and H2O2 while shifted to a pro-oxidant cell status mainly due to a decrease in catalase activity and SOD2 level. Hif-1α was dampened, echoed by a decrease lactate and several key metabolites involved in glutathione synthesis. CoQ-treated cells were twofold more sensitive than control to radiation-induced DNA damage and apoptosis in short and long-term clonogenic assays, potentiating TMZ-induced cytotoxicity, without affecting non-transformed astrocytes. CONCLUSIONS CoQ acts as sensitizer for cytotoxic therapies, disarming GBM cells, but not normal astrocytes, against further pro-oxidant injuries, being potentially useful in clinical practice for this fatal pathology.
T2  - Radiotherapy and Oncology
T1  - Regulation of the oxidative balance with coenzyme Q10 sensitizes human glioblastoma cells to radiation and temozolomide.
DO  - 10.1016/j.radonc.2018.04.033
ER  - 

@article{
author = "Frontiñán-Rubio, Javier and Santiago-Mora, Raquel María and Nieva-Velasco, Consuelo María and Ferrín, Gustavo and Martínez-González, Alicia and Gómez, María Victoria and Moreno, María and Ariza, Julia and Lozano, Eva and Arjona-Gutiérrez, Jacinto and Gil-Agudo, Antonio and De la Mata, Manuel and Pešić, Milica and Peinado, Juan Ramón and Villalba, José M. and Pérez-Romasanta, Luis and Pérez-García, Víctor M. and Alcaín, Francisco J. and Durán-Prado, Mario",
year = "2018",
abstract = "OBJECTIVES To investigate how the modulation of the oxidative balance affects cytotoxic therapies in glioblastoma, in vitro. MATERIAL AND METHODS Human glioblastoma U251 and T98 cells and normal astrocytes C8D1A were loaded with coenzyme Q10 (CoQ). Mitochondrial superoxide ion (O2-) and H2O2 were measured by fluorescence microscopy. OXPHOS performance was assessed in U251 cells with an oxytherm Clark-type electrode. Radio- and chemotherapy cytotoxicity was assessed by immunostaining of γH2AX (24 h), annexin V and nuclei morphology, at short (72 h) and long (15 d) time. Hif-1α, SOD1, SOD2 and NQO1 were determined by immunolabeling. Catalase activity was measured by classic enzymatic assay. Glutathione levels and total antioxidant capacity were quantified using commercial kits. RESULTS CoQ did not affect oxygen consumption but reduced the level of O2- and H2O2 while shifted to a pro-oxidant cell status mainly due to a decrease in catalase activity and SOD2 level. Hif-1α was dampened, echoed by a decrease lactate and several key metabolites involved in glutathione synthesis. CoQ-treated cells were twofold more sensitive than control to radiation-induced DNA damage and apoptosis in short and long-term clonogenic assays, potentiating TMZ-induced cytotoxicity, without affecting non-transformed astrocytes. CONCLUSIONS CoQ acts as sensitizer for cytotoxic therapies, disarming GBM cells, but not normal astrocytes, against further pro-oxidant injuries, being potentially useful in clinical practice for this fatal pathology.",
journal = "Radiotherapy and Oncology",
title = "Regulation of the oxidative balance with coenzyme Q10 sensitizes human glioblastoma cells to radiation and temozolomide.",
doi = "10.1016/j.radonc.2018.04.033"
}

Frontiñán-Rubio, J., Santiago-Mora, R. M., Nieva-Velasco, C. M., Ferrín, G., Martínez-González, A., Gómez, M. V., Moreno, M., Ariza, J., Lozano, E., Arjona-Gutiérrez, J., Gil-Agudo, A., De la Mata, M., Pešić, M., Peinado, J. R., Villalba, J. M., Pérez-Romasanta, L., Pérez-García, V. M., Alcaín, F. J.,& Durán-Prado, M.. (2018). Regulation of the oxidative balance with coenzyme Q10 sensitizes human glioblastoma cells to radiation and temozolomide.. in Radiotherapy and Oncology.
https://doi.org/10.1016/j.radonc.2018.04.033

Frontiñán-Rubio J, Santiago-Mora RM, Nieva-Velasco CM, Ferrín G, Martínez-González A, Gómez MV, Moreno M, Ariza J, Lozano E, Arjona-Gutiérrez J, Gil-Agudo A, De la Mata M, Pešić M, Peinado JR, Villalba JM, Pérez-Romasanta L, Pérez-García VM, Alcaín FJ, Durán-Prado M. Regulation of the oxidative balance with coenzyme Q10 sensitizes human glioblastoma cells to radiation and temozolomide.. in Radiotherapy and Oncology. 2018;.
doi:10.1016/j.radonc.2018.04.033 .

Frontiñán-Rubio, Javier, Santiago-Mora, Raquel María, Nieva-Velasco, Consuelo María, Ferrín, Gustavo, Martínez-González, Alicia, Gómez, María Victoria, Moreno, María, Ariza, Julia, Lozano, Eva, Arjona-Gutiérrez, Jacinto, Gil-Agudo, Antonio, De la Mata, Manuel, Pešić, Milica, Peinado, Juan Ramón, Villalba, José M., Pérez-Romasanta, Luis, Pérez-García, Víctor M., Alcaín, Francisco J., Durán-Prado, Mario, "Regulation of the oxidative balance with coenzyme Q10 sensitizes human glioblastoma cells to radiation and temozolomide." in Radiotherapy and Oncology (2018),
https://doi.org/10.1016/j.radonc.2018.04.033 . .