M. L. Martins

Instituto Superior de Tecnologia em Ciências da Computação do Rio de Janeiro, Rio de Janeiro, Rio de Janeiro, Brazil

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Publications (26)78.42 Total impact

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    Herman F Fumiã · Marcelo L Martins
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    ABSTRACT: A Boolean dynamical system integrating the main signaling pathways involved in cancer is constructed based on the currently known protein-protein interaction network. This system exhibits stationary protein activation patterns - attractors - dependent on the cell's microenvironment. These dynamical attractors were determined through simulations and their stabilities against mutations were tested. In a higher hierarchical level, it was possible to group the network attractors into distinct cell phenotypes and determine driver mutations that promote phenotypic transitions. We find that driver nodes are not necessarily central in the network topology, but at least they are direct regulators of central components towards which converge or through which crosstalk distinct cancer signaling pathways. The predicted drivers are in agreement with those pointed out by diverse census of cancer genes recently performed for several human cancers. Furthermore, our results demonstrate that cell phenotypes can evolve towards full malignancy through distinct sequences of accumulated mutations. In particular, the network model supports routes of carcinogenesis known for some tumor types. Finally, the Boolean network model is employed to evaluate the outcome of molecularly targeted cancer therapies. The major find is that monotherapies were additive in their effects and that the association of targeted drugs is necessary for cancer eradication.
    Full-text · Article · Jul 2013 · PLoS ONE
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    Leticia R Paiva · Hallan S Silva · Silvio C Ferreira · Marcelo L Martins
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    ABSTRACT: Oncolytic virotherapy-the use of viruses that specifically kill tumor cells-is an innovative and highly promising route for treating cancer. However, its therapeutic outcomes are mainly impaired by the host immune response to the viral infection. In this paper, we propose a multiscale mathematical model to study how the immune response interferes with the viral oncolytic activity. The model assumes that cytotoxic T cells can induce apoptosis in infected cancer cells and that free viruses can be inactivated by neutralizing antibodies or cleared at a constant rate by the innate immune response. Our simulations suggest that reprogramming the immune microenvironment in tumors could substantially enhance the oncolytic virotherapy in immune-competent hosts. Viable routes to such reprogramming are either in situ virus-mediated impairing of CD8(+) T cells motility or blockade of B and T lymphocytes recruitment. Our theoretical results can shed light on the design of viral vectors or new protocols with neat potential impacts on the clinical practice.
    Full-text · Article · Mar 2013 · Physical Biology
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    L R Paiva · M L Martins · S C Ferreira
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    ABSTRACT: One of the most promising strategies to treat cancer is attacking it with viruses designed to exploit specific altered pathways. Here, the effects of oncolytic virotherapy on tumors having compact, papillary, and disconnected morphologies are investigated through computer simulations of a multiscale model coupling macroscopic reaction-diffusion equations for the nutrients with microscopic stochastic rules for the actions of individual cells and viruses. The interaction among viruses and tumor cells involves cell infection, intracellular virus replication, and the release of new viruses in the tissue after cell lysis. The evolution over time of both the viral load and cancer cell population, as well as the probabilities for tumor eradication, were evaluated for a range of multiplicities of infection, viral entries, and burst sizes. It was found that in immunosuppressed hosts, the antitumor efficacy of a virus is primarily determined by its entry efficiency, its replicative capacity within the tumor, and its ability to spread over the tissue. However, the optimal traits for oncolytic viruses depend critically on the tumor growth dynamics and do not necessarily include rapid replication, cytolysis, or spreading, currently assumed as necessary conditions for a successful therapeutic outcome. Our findings have potential implications on the design of new vectors for the viral therapy of cancer.
    Full-text · Article · Oct 2011 · Physical Review E
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    L. R. Paiva · M. L. Martins
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    ABSTRACT: A multiscale model for tumor growth and its chemotherapy using conjugate nanoparticles is presented, and the corresponding therapeutic outcomes are evaluated. It is found that doxorubicin assembled into chimeric polypeptide nanoparticles cannot eradicate either vascularized primary tumors or avascular micrometastasis even administrated at loads close to their maximum tolerated doses. Furthermore, an effective and safety treatment demands for conjugate nanoparticles targeted to the malignant cells with much higher specificity and affinity than those currently observed in order to leave most of the normal tissues unaffected and to ensure a fast intracellular drug accumulation.
    Full-text · Article · Jan 2011 · Applied Physics Letters
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    S. G. Alves · M. L. Martins
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    ABSTRACT: Aggregation of animal cells in culture comprises a series of motility, collision and adhesion processes of basic relevance for tissue engineering, bioseparations, oncology research and \textit{in vitro} drug testing. In the present paper, a cluster-cluster aggregation model with stochastic particle replication and chemotactically driven motility is investigated as a model for the growth of animal cells in culture. The focus is on the scaling laws governing the aggregation kinetics. Our simulations reveal that in the absence of chemotaxy the mean cluster size and the total number of clusters scale in time as stretched exponentials dependent on the particle replication rate. Also, the dynamical cluster size distribution functions are represented by a scaling relation in which the scaling function involves a stretched exponential of the time. The introduction of chemoattraction among the particles leads to distribution functions decaying as power laws with exponents that decrease in time. The fractal dimensions and size distributions of the simulated clusters are qualitatively discussed in terms of those determined experimentally for several normal and tumoral cell lines growing in culture. It is shown that particle replication and chemotaxy account for the simplest cluster size distributions of cellular aggregates observed in culture. Comment: 14 pages, 8 figures, to appear on Jstat
    Preview · Article · Sep 2010 · Journal of Statistical Mechanics Theory and Experiment
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    D. R. de Souza · M. L. Martins · F. M. S. Carmo
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    ABSTRACT: In the present paper, we propose and study by numerical simulations a multiscale model for plant invasion based on allelopathic suppression in a homogeneous environment. The negative effects on seed production and germination, establishment and mortality of native plants generated by the root-secreted alien phytotoxin constitute the basic mechanism contributing to invasiveness. We obtained the invasion patterns, their success probabilities, the time evolution of plant populations, the gyration radius and the border roughness of the invaded region. As an important result, it was observed that, in addition to the phytotoxin nature (synthesis and degradation rates, diffusivity and phytotoxic threshold), invasive patterns and invasion success depend on the kind of native plants present in the area. In fact, both success and invasion speed decrease in the presence of resistant native plants. Also, self-affine invasion fronts are smooth (Hurst exponent H=1) in the absence of resistant plants, but are rough (H ≠ 1) on the contrary. Furthermore, if the resistant native species are randomly distributed on the landscape, the invasion front exhibits long-range correlations (H ∼ 0.76), while its border is anti-correlated (H ∼ 0.20), if resistant plants are distributed in patches. Finally, the cluster size distribution functions of resistant plants are exponentials with characteristic cluster sizes increasing in time. KeywordsAllelopathy-Plant invasion-Multiscale modeling
    Full-text · Article · Jun 2010 · Biological Invasions
  • M.L. Martins · S.C. Ferreira · M.J. Vilela
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    ABSTRACT: Life, amazingly rich in diversity of shapes and functions, explores the limits of extreme complexity in nature. In this review we shall discuss in general terms the use of multiscale mathematical and computer models to study the dynamics of biological systems. These models permit integration of the rapidly expanding knowledge concerning the molecular basis of biology and its complex, nonlinear relationship with the emerging shapes and functions of cells, tissues and organs in living organisms.
    No preview · Article · Apr 2010 · Current Opinion in Colloid & Interface Science
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    ABSTRACT: One of the most promising strategies to treat cancer is attacking it with viruses. Oncolytic viruses can kill tumor cells specifically or induce anticancer immune response. A multiscale model for virotherapy of cancer is investigated through simulations. It was found that, for intratumoral virus administration, a solid tumor can be completely eradicated or keep growing after a transient remission. Furthermore, the model reveals undamped oscillatory dynamics of tumor cells and virus populations, which demands new in vivo and in vitro quantitative experiments aiming to detect this oscillatory response. The conditions for which each one of the different tumor responses dominates, as well as the occurrence probabilities for the other nondominant therapeutic outcomes, were determined. From a clinical point of view, our findings indicate that a successful, single agent virotherapy requires a strong inhibition of the host immune response and the use of potent virus species with a high intratumoral mobility. Moreover, due to the discrete and stochastic nature of cells and their responses, an optimal range for viral cytotoxicity is predicted because the virotherapy fails if the oncolytic virus demands either a too short or a very large time to kill the tumor cell. This result suggests that the search for viruses able to destroy tumor cells very fast does not necessarily lead to a more effective control of tumor growth.
    Full-text · Article · Feb 2009 · Cancer Research
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    S. G. Alves · S. C. Ferreira Jr · M. L. Martins
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    ABSTRACT: We review some computer algorithms for the simulation of off-lattice clusters grown from a seed, with emphasis on the diffusion-limited aggregation, ballistic aggregation and Eden models. Only those methods which can be immediately extended to distinct off-lattice aggregation processes are discussed. The computer efficiencies of the distinct algorithms are compared.
    Full-text · Article · Apr 2008 · Brazilian Journal of Physics
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    ABSTRACT: A novel approach to integrating quantitative description of cell aggregation dynamics and proteome analysis was used to identify early epigenetic transformations in cultured human breast cells. A transition from a power law to an exponential decay in MCF-7 cell aggregation was found and correlated with a down-regulation of calreticulin expression. A similar transition was not observed in the aggregation dynamics of MCF-10 nor in MDA-MB-231 cells, although they also exhibit changes in their global protein expression patterns during their prolonged culture. The down-regulation of calreticulin in MCF-7 cells may be associated with decreased cell–cell and cell–matrix adhesiveness and triggering the dynamic transition observed in their aggregation. The simple operational model presented here may be a relevant tool for uncovering fundamental early steps involved in neoplastic transformation in culture and carcinogenesis in vivo.
    No preview · Article · Dec 2007 · Journal of Statistical Mechanics Theory and Experiment
  • S G Alves · F L Braga · M L Martins
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    ABSTRACT: Electrochemical ferromagnetic deposits grown under a planar magnetic field exhibit a striking morphological symmetry breaking. The present paper demonstrate through two-dimensional off-lattice simulations of an extended diffusion-limited aggregation (DLA) model that the competition between magnetic dipolar interactions and electric forces can impose locally the experimentally observed angle selection in a two-dimensional extended DLA model. The long-range correlations in the orientation of dipoles interacting with the applied and dipolar fields preserve this order over a macroscopic scale. Hence, the magnetic dipolar interactions alone cannot impose the field-induced symmetry breaking observed in ferromagnetic electrochemical deposition (ECD).
    No preview · Article · Oct 2007 · Journal of Statistical Mechanics Theory and Experiment
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    Silvio C Ferreira · Marcelo L Martins
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    ABSTRACT: Inspired by dengue and yellow fever epidemics, we investigated the contact process (CP) in a multiscale network constituted by one-dimensional chains connected through a Barabási-Albert scale-free network. In addition to the CP dynamics inside the chains, the exchange of individuals between connected chains (travels) occurs at a constant rate. A finite epidemic threshold and an epidemic mean lifetime diverging exponentially in the subcritical phase, concomitantly with a power law divergence of the outbreak's duration, were found. A generalized scaling function involving both regular and SF components was proposed for the quasistationary analysis and the associated critical exponents determined, demonstrating that the CP on this hybrid network and nonvanishing travel rates establishes a new universality class.
    Full-text · Article · Oct 2007 · Physical Review E
  • M.L. Martins · S.C. Ferreira · M.J. Vilela
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    ABSTRACT: In the past 30 years we have witnessed an extraordinary progress on the research in the molecular biology of cancer, but its medical treatment, widely based on empirically established protocols, still has many limitations. One of the reasons for that is the limited quantitative understanding of the dynamics of tumor growth and drug response in the organism. In this review we shall discuss in general terms the use of mathematical modeling and computer simulations related to cancer growth and its applications to improve tumor therapy. Particular emphasis is devoted to multiscale models which permit integration of the rapidly expanding knowledge concerning the molecular basis of cancer and the complex, nonlinear interactions among tumor cells and their microenvironment that will determine the neoplastic growth at the tissue level.
    No preview · Article · Jun 2007 · Physics of Life Reviews
  • H S Silva · M L Martins · M J Vilela · Ruy Jaeger · B Kachar
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    ABSTRACT: Membrane ruffle fluctuations of amphibian epithelial cells A6 (CCL102) cultured in normal and upside down oriented plates have been analyzed through video microscopy. Our results reveal that their edge ruffle fluctuations exhibit a stochastic dynamics with 1/f(alpha) power spectrum over at least two decades at low frequencies and long range correlated, self-affine lateral border profiles. In a few and small areas of the membrane, probably nearby focal contacts, we found periodic oscillations which could be induced by myosin driven contraction of stress fibers. Furthermore, whereas the different gravitational orientations had none or little effect on the structure (power spectra and surface roughness) of these membrane ruffle fluctuations, their dynamic parameters were differentially affected. Indeed, the decay time of ruffles remained unchanged, but the period of lamellipodia oscillations near the focal adhesion points was significantly altered in A6 cells cultured upside down.
    No preview · Article · Nov 2006 · Physical Review E
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    S.C. Ferreira Jr · M.L. Martins · M.J. Vilela
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    ABSTRACT: One of the most promising strategies to treat cancer is attacking it with viruses. Viruses can kill tumor cells specifically or act as carriers that deliver normal genes into cancer cells. A model for virotherapy of cancer is investigated and its predictions are in agreement with results obtained from experimental tumors. Furthermore, the model reveals an oscillatory (periodic or aperiodic) response of tumor cells and virus populations which may make clinical prognosis difficult. These results suggest the need for new in vivo and in vitro experiments aiming to detect this oscillatory response.
    Full-text · Article · Oct 2003 · Physica A: Statistical Mechanics and its Applications
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    S C Ferreira · M L Martins · M J Vilela
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    ABSTRACT: Recently, we have proposed a nutrient-limited model for the avascular growth of tumors including cell proliferation, motility, and death [S. C. Ferreira, Jr., M. L. Martins, and M. J. Vilela, Phys. Rev. E 65, 021907 (2002)], which qualitatively reproduces commonly observed morphologies for carcinomas in situ. In the present work, we analyze the effects of distinct chemotherapeutic strategies on the patterns, scaling, and growth laws obtained for the nutrient-limited model. Two kinds of chemotherapeutic strategies were considered, namely, those that kill cancer cells and those that block cell mitosis but allow the cell to survive for some time. Depending on the chemotherapeutic schedule used, the tumors are completely eliminated, reach a stationary size, or grow following power laws. The model suggests that the scaling properties of the tumors are not affected by the mild cytotoxic treatments, although a reduction in growth rates and an increase in invasiveness are observed. For the strategies based on antimitotic drugs, a morphological transition in which compact tumors become more fractal under aggressive treatments was seen.
    Full-text · Article · Jun 2003 · Physical Review E
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    S. G. Alves · N. M. Oliveira Neto · M. L. Martins
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    ABSTRACT: Nowadays, in societies threatened by atomization, selfishness, short-term thinking, and alienation from political life, there is a renewed debate about classical questions concerning the quality of democratic decision-making. In this work a cellular automata (CA) model for the dynamics of free elections based on the social impact theory is proposed. By using computer simulations, power law distributions for the size of electoral clusters and decision time have been obtained. The major role of broadcasted electoral surveys in guiding opinion formation and stabilizing the ``{\it status quo}'' was demonstrated. Furthermore, it was shown that in societies where these surveys are manipulated within the universally accepted statistical error bars, even a majoritary opposition could be hindered from reaching the power through the electoral path. Comment: 15 pages, 9 figures
    Preview · Article · Apr 2002 · Physica A: Statistical Mechanics and its Applications
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    S C Ferreira · M L Martins · M J Vilela
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    ABSTRACT: A nutrient-limited model for avascular cancer growth including cell proliferation, motility, and death is presented. The model qualitatively reproduces commonly observed morphologies for primary tumors, and the simulated patterns are characterized by its gyration radius, total number of cancer cells, and number of cells on tumor periphery. These very distinct morphological patterns follow Gompertz growth curves, but exhibit different scaling laws for their surfaces. Also, the simulated tumors incorporate a spatial structure composed of a central necrotic core, an inner rim of quiescent cells and a narrow outer shell of proliferating cells in agreement with biological data. Finally, our results indicate that the competition for nutrients among normal and cancer cells may be a determining factor in generating papillary tumor morphology.
    Full-text · Article · Mar 2002 · Physical Review E
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    ABSTRACT: The growth patterns of established normal and cancer cell lines, cultured in monolayer and collagen gel, have been characterized using the cluster size distribution of cellular aggregates. HN-5 (cancer) cells exhibit, either in gel or in monolayer, power-law distributions at any time in culture, whereas for MDCK (“normal”) and Hep-2 (cancer) cells there is a transition from an exponential behavior to a power-law distribution after a transient time in culture. These results suggest that the transitions in growth regimes observed in MDCK and Hep-2 cell lines might be associated to changes in the control of replication or in the expression patterns of cell adhesion molecules of cell–cell and cell–matrix type related to intracellular signalling. These transitions are irreversible and seems to be an adaptative response to the growth constraints imposed by high cell population density or long permanence in culture.
    No preview · Article · Sep 2001 · Physica A: Statistical Mechanics and its Applications
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    ABSTRACT: A review of the main results obtained by a cellular automata model recently proposed to analyze the progress of citrus variegated chlorosis epidemics is done. In this model epidemiological and environmental features, such as motility of sharpshooter vectors which perform Lévy flights, hydric and nutritional level of plant stress and seasonal climatic effects, are included. The observed epidemics data were quantitatively reproduced by the proposed model varying the parameters controlling vectors motility, plant stress and initial population of diseased plants.
    Full-text · Article · Jun 2001 · Physica A: Statistical Mechanics and its Applications