M. Kolev - Academia.edu (original) (raw)

Papers by M. Kolev

Research paper thumbnail of Mathematical modelling of the competition between tumors and immune system considering the role of the antibodies

Mathematical and Computer Modelling, 2003

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Research paper thumbnail of A mathematical model of cellular immune response to leukemia

Mathematical and Computer Modelling, 2005

ABSTRACT The cell-mediated immune response is a very important part of the defence mechanism agai... more ABSTRACT The cell-mediated immune response is a very important part of the defence mechanism against cancer. In this paper, we present a model of the cellular immune response to leukemia. The model is developed with statistical methods analogous to those of kinetic theory. The cells of the interacting populations are characterized by a microscopic functional state variable. The development of the concept of inner functional state is considered. A new possibility for definition of the activation state, suitable for experimental evaluation, for three particular cell populations is proposed. The presented simulations are related to the modelling of three types of vaccinations.

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Research paper thumbnail of Anticancer activity of spin-labeled nitrosoureas as a function of the LUMO energy

2008 Conference on Human System Interactions, 2008

Full geometry optimization of spin-labeled nitrosoureas has been performed using the B3LYP functi... more Full geometry optimization of spin-labeled nitrosoureas has been performed using the B3LYP functional at the density functional level of theory (DFT). A significant linear correlation has been found between the energy of the lowest unoccupied molecular orbital (LUMO) and the anti-cancer activity against P388 murine lymphotic leukemia. The correlation is explained with the high compound-receptor interaction capabilities of active compounds having low LUMO energy.

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Research paper thumbnail of CD46 co-stimulation is crucial for the induction of the key metabolic switch that drives Th1 lineage differentiation

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Research paper thumbnail of Numerical Experiments for Mammary Adenocarcinoma Cell Progression

Integral Methods in Science and Engineering, 2011

... The cells were harvested by trypsinization and counted on days 3, 6, and 9 ... has been devel... more ... The cells were harvested by trypsinization and counted on days 3, 6, and 9 ... has been developed in the framework of the kinetic theory for active particles [ArBeAnLa03, BeBe06 ... which is typical for non-equilibrium statistical mechanics and generalized kinetic theory, the unknown ...

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Research paper thumbnail of Upregulating CD59: a new strategy for protection of neurons from complement-mediated degeneration

The Pharmacogenomics Journal, 2010

An increasing number of studies have shown a critical role for the membrane attack complex, synth... more An increasing number of studies have shown a critical role for the membrane attack complex, synthesized on activation of the terminal pathway of the complement system, in causing demyelination and neuronal death in neurodegeneration. The aim of this study was to develop a strategy to increase the resistance of neurons to complement damage by modulating the expression of membrane complement regulatory protein CD59, the only inhibitor of the terminal pathway of the complement cascade. We exploited our recent finding that CD59 expression is regulated by the neural-restrictive silencer factor (REST) and designed a novel REST-derived peptide (REST5) containing the nuclear localization domain of the wild-type protein. The effect of REST5 and the mechanism by which it modulates CD59 expression were modelled in neuroblastoma cells transfected with expression constructs, and then confirmed in human neurons differentiated from neural progenitor cells. REST5 increased the expression of CD59 in neurons by fivefold and protected them from complement-mediated lysis spontaneously triggered by neurons. As a source of complement, we used either human serum or conditioned medium from primary human oligodendroglia. This study brings new insight into immunopharmacological research that may serve to inhibit neuronal death triggered by the terminal pathway of complement activation.

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Research paper thumbnail of Interplay between REST and nucleolin transcription factors: a key mechanism in the overexpression of genes upon increased phosphorylation

Nucleic Acids Research, 2014

Non-malignant cells can be transformed via the activation of kinases that control degradation of ... more Non-malignant cells can be transformed via the activation of kinases that control degradation of neural-restrictive silencer factor (REST). Here, we identify a mechanism that contributes to the activation of genes, expression of which is controlled by responsive elements containing overlapping binding sites for REST and nucleolin. We demonstrate that both phosphorylated and non-phosphorylated nucleolin-bound DNA; however, only phosphorylated nucleolin successfully competed with either full-length REST or a REST-derived DNA-binding peptide, REST68, for binding to the overlapping binding sites. We show that this interplay between the two transcription factors regulates the activation of cell survival and immunomodulatory genes in tumors and non-malignant cells with activated protein kinase C, which is accompanied with alterations in cell proliferation and apoptosis. We propose a model for the regulation of these genes, which brings a new insight into the molecular mechanisms that control cellular transformation driven by activation of protein kinases.

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Research paper thumbnail of Nonlinear modeling with mammographic evidence of carcinoma

Nonlinear Analysis: Real World Applications, 2010

... Keywords: Breast tumor progression; Mammographic data; Kinetic theory; Active particles; Math... more ... Keywords: Breast tumor progression; Mammographic data; Kinetic theory; Active particles; Mathematical model; Nonlinear integro ... cancer cell populations have been the subject of active mathematical research. ... physicians) let us mention the successful application on patients by ...

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Research paper thumbnail of Experimental versus numerical data for breast cancer progression

Nonlinear Analysis: Real World Applications, 2012

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Research paper thumbnail of C5L2-mediated signals control contraction of human Th1 responses

Molecular Immunology, 2013

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Research paper thumbnail of Evidence for intracellular complement activation vital to Th1 immunity

Molecular Immunology, 2013

ABSTRACT Eculizumab (Soliris), a humanized mAb against the complement protein C5 inhibits the gen... more ABSTRACT Eculizumab (Soliris), a humanized mAb against the complement protein C5 inhibits the generation of the proinflammatory pep-tide C5a and the formation of the membrane complement complex C5b-9, thereby preventing complement-mediated inflammatory tissue destruction. Beneficial effects of eculizumab treatment have already been demonstrated in patients with paroxysmal nocturnal hemoglobinuria and there is accumulating evidence that it is also effective in severe cases of aHUS, STEC-HUS, MPGN as well as in protecting high risk patients against humoral renal graft rejection. However, the response to Eculizumab treatment in those patients appears to be more variable than in cases of paroxysmal noctur-nal hemoglobinuria, due to disease stage and different therapeutic regimen. aHUS, STEC-HUS and MPGN patients under therapy were moni-tored by a newly established specific ELISA for Eculizumab in serum, plasma and urine and by haemolytic inhibition assays to assess the drug's inhibitory capacity. Complement activation under therapy was measured by analysis of C3, C3d, and SC5b-9, considered to reflect the inhibitory efficacy of the C5 inhibitor in vivo. Circulating serum/plasma levels of Eculizumab, partly exceeding 1500 ␮g/ml were measured, resembling up to 10–20-fold of the recommended serum concentration of 50–100 ␮g/ml, indicating an accumulation of the drug over time. In some patients (MPGN, aHUS, renal trans-plantation), renal elimination could be demonstrated by detecting urinary Eculizumab levels up to 11 ␮g/ml. Functional assays con-firmed full inhibitory activity of the drug in the patients' urine if co-incubated with normal human serum, correlating with drug concentration. Based on these findings we suggest to include in monitoring of complement activation the combined analysis of Eculizumab by ELISA and its inhibitory effect in serum and urine to allow a better adaptation and optimization of anti-complement therapy in severe cases of complement-mediated nephropathies, such as (a)HUS and MPGN. Introduction: We have previously reported that mice deficient of the LP effector component MASP-2 are significantly advantaged in models of ischaemic disease such as myocardial infarction and

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Research paper thumbnail of Mathematical model of tumor invasion along linear or tubular structures

Mathematical and Computer Modelling, 2005

We examine a mathematical model of a population of cells distributed over a linear or tubular str... more We examine a mathematical model of a population of cells distributed over a linear or tubular structure. Growth of cells is regulated by a growth factor, which can diffuse over the structure. Aside from this, production of cells and of the growth factor is governed by a pair of ordinary differential equations. We find conditions under which diffusion causes destabilization

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Research paper thumbnail of A mathematical model for single cell cancer—Immune system dynamics

Mathematical and Computer Modelling, 2005

In this paper, we propose and analyse the model of competition between a single cell cancer and t... more In this paper, we propose and analyse the model of competition between a single cell cancer and the immune system. The model is a system of integro-differential bilinear equations and it describes both very early stage of a solid tumor and all stages of leukemias.

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Research paper thumbnail of Polymorphisms in Mannan-Binding Lectin (MBL)-Associated Serine Protease 2 Affect Stability, Binding to MBL, and Enzymatic Activity

The Journal of Immunology, 2009

Mannan-binding lectin-associated serine protease 2 (MASP-2) is an enzyme of the innate immune sys... more Mannan-binding lectin-associated serine protease 2 (MASP-2) is an enzyme of the innate immune system. MASP-2 forms complexes with the pattern recognition molecules mannan-binding lectin (MBL), H-ficolin, L-ficolin, or M-ficolin, and is activated when one of these proteins recognizes microorganisms and subsequently cleaves complement factors C4 and C2, thus initiating the activation of the complement system. Missense polymorphisms of MASP-2 exist in different ethnic populations. To further characterize the nature of these, we have produced and characterized rMASP-2s representing the following naturally occurring polymorphisms: R99Q, D120G, P126L, H155R, 156_159dupCHNH (CHNHdup), V377A, and R439H. Only very low levels of CHNHdup were secreted from the cells, whereas quantities similar to wild-type MASP-2 were found intracellularly, indicating that this mutation results in a misfolded protein. We found that D120G and CHNHdup could not associate with MBL, whereas R99Q, P126L, H155R, V377A, R439H, and wild-type MASP-2 bound equally well to MBL. Accordingly, when D120G and CHNHdup were mixed with MBL, no activation of complement factor C4 was observed, whereas R99Q, P126L, and V377A cleaved C4 with an activity comparable to wild-type MASP-2 and H155R slightly better. In contrast, the R439H variant was deficient in this process despite its normal binding to MBL. This variant was also not able to autoactivate in the presence of MBL and mannan. We find the R439H variant is common in Sub-Saharan Africans with a gene frequency of 10%. Our results indicate that individuals with different types of MASP-2 defects may be identified through genotyping.

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Research paper thumbnail of Retraction: Targeting Neural-Restrictive Silencer Factor Sensitizes Tumor Cells to Antibody-Based Cancer Immunotherapy In Vitro via Multiple Mechanisms

The Journal of Immunology, 2011

Tumor cells escape clearance by complement by abundantly expressing CD59 and other membrane compl... more Tumor cells escape clearance by complement by abundantly expressing CD59 and other membrane complement regulators. Recently, we designed a peptide derived from the neural-restrictive silencer factor (REST), REST68, which we showed to inhibit expression of CD59 in tumors lacking the full-length REST and proposed a detailed model for regulation of CD59 expression via interplay between REST and nucleolin (NCL) transcription factors. In this paper, we study in detail the mechanisms for sensitization of malignant cells to Ab-based cancer immunotherapy by the REST68 peptide and the implications of the REST/NCL model for the design of treatment resulting in higher tumor susceptibility. REST68 inhibited CD59 expression in malignant cells expressing either truncated or full-length REST, but not in nonmalignant cells. However, activation of protein kinase C (PKC) in nonmalignant cells, a process that contributes to cellular transformation, phosphorylated NCL and enabled suppression of CD59 expression by the REST68. Combined treatment of different tumor types with REST68 and PKC inhibitor synergized to further suppress CD59 expression and reduce resistance to complement lysis. The combined treatment also increased susceptibility of tumors expressing either of the REST isoforms to PBMC-mediated killing, which, at least in part, accounted for the strong promotion of apoptosis by the REST68/PKC inhibitor. These data demonstrate that REST68 sensitizes tumors to Ab-based cancer immunotherapy via multiple mechanisms. Furthermore, the REST/NCL interplay model for regulation of expression of cd59 and other genes involved in cell survival enables the design of treatments for different tumor types to achieve more efficient tumor clearance.

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Research paper thumbnail of Neuronal death in Alzheimer’s disease and therapeutic opportunities

Journal of Cellular and Molecular Medicine, 2009

Alzheimer's disease (AD) ... more Alzheimer's disease (AD) is an age-related neurodegenerative disease that affects approximately 24 million people worldwide. A number of different risk factors have been implicated in AD; however, neuritic (amyloid) plaques are considered as one of the defining risk factors and pathological hallmarks of the disease. In the past decade, enormous efforts have been devoted to understand the genetics and molecular pathogenesis leading to neuronal death in AD, which has been transferred into extensive experimental approaches aimed at reversing disease progression. Modern medicine is facing an increasing number of treatments available for vascular and neurodegenerative brain diseases, but no causal or neuroprotective treatment has yet been established. Almost all neurological conditions are characterized by progressive neuronal dysfunction, which, regardless of the pathogenetic mechanism, finally leads to neuronal death. The particular emphasis of this review is on risk factors and mechanisms resulting in neuronal loss in AD and current and prospective opportunities for therapeutic interventions. This review discusses these issues with a view to inspiring the development of new agents that could be useful for the treatment of AD.

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Research paper thumbnail of Intracellular Complement Activation Sustains T Cell Homeostasis and Mediates Effector Differentiation

Immunity, 2013

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Research paper thumbnail of Correlation between Animal and Mathematical Models for Prostate Cancer Progression

Computational and Mathematical Methods in Medicine, 2009

Page 1. Correlation between animal and mathematical models for prostate cancer progression Z. Jac... more Page 1. Correlation between animal and mathematical models for prostate cancer progression Z. Jackiewicza1, CL Jorcykb2, M. Kolevc3 and B. Zubik-Kowald4* aDepartment of Mathematics and Statistics, Arizona State University ...

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Research paper thumbnail of Numerical Solutions for a Model of Tissue Invasion and Migration of Tumour Cells

Computational and Mathematical Methods in Medicine, 2011

ABSTRACT The goal of this paper is to construct a new algorithm for the numerical simulations of ... more ABSTRACT The goal of this paper is to construct a new algorithm for the numerical simulations of the evolution of tumour invasion and metastasis. By means of mathematical model equations and their numerical solutions we investigate how cancer cells can produce and secrete matrix degradative enzymes, degrade extracellular matrix, and invade due to diffusion and haptotactic migration. For the numerical simulations of the interactions between the tumour cells and the surrounding tissue, we apply numerical approximations, which are spectrally accurate and based on small amounts of grid-points. Our numerical experiments illustrate the metastatic ability of tumour cells.

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Research paper thumbnail of Existence of Different but Overlapping IgG- and IgM-Binding Sites on the Globular Domain of Human C1q †

Biochemistry, 2006

C1q is the first subcomponent of the classical complement pathway that binds antigen-bound IgG or... more C1q is the first subcomponent of the classical complement pathway that binds antigen-bound IgG or IgM and initiates complement activation via association of serine proteases C1r and C1s. The globular domain of C1q (gC1q), which is the ligand-recognition domain, is a heterotrimeric structure composed of the C-terminal regions of A (ghA), B (ghB), and C (ghC) chains. The expression and functional characterization of ghA, ghB, and ghC modules have revealed that each chain has some structural and functional autonomy. Although a number of studies have tried to identify IgG-binding sites on the gC1q domain, no such attempt has been made to localize IgM-binding site. On the basis of the information available via the gC1q crystal structure, molecular modeling, mutational studies, and bioinformatics, we have generated a series of substitution mutants of ghA, ghB, and ghC and examined their interactions with IgM. The comparative analysis of IgM- and IgG-binding abilities of the mutants suggests that the IgG- and IgM-binding sites within the gC1q domain are different but may overlap. Whereas Arg(B108), Arg (B109), and Tyr(B175) mainly constitute the IgM-binding site, the residues Arg(B114), Arg(B129), Arg(B163), and His(B117) that have been shown to be central to IgG binding are not important for the C1q-IgM interaction. Given the location of Arg(B108), Arg (B109), and Tyr(B175) in the gC1q crystal structure, it is likely that C1q interacts with IgM via the top of the gC1q domain.

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Research paper thumbnail of Mathematical modelling of the competition between tumors and immune system considering the role of the antibodies

Mathematical and Computer Modelling, 2003

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Research paper thumbnail of A mathematical model of cellular immune response to leukemia

Mathematical and Computer Modelling, 2005

ABSTRACT The cell-mediated immune response is a very important part of the defence mechanism agai... more ABSTRACT The cell-mediated immune response is a very important part of the defence mechanism against cancer. In this paper, we present a model of the cellular immune response to leukemia. The model is developed with statistical methods analogous to those of kinetic theory. The cells of the interacting populations are characterized by a microscopic functional state variable. The development of the concept of inner functional state is considered. A new possibility for definition of the activation state, suitable for experimental evaluation, for three particular cell populations is proposed. The presented simulations are related to the modelling of three types of vaccinations.

Bookmarks Related papers MentionsView impact

Research paper thumbnail of Anticancer activity of spin-labeled nitrosoureas as a function of the LUMO energy

2008 Conference on Human System Interactions, 2008

Full geometry optimization of spin-labeled nitrosoureas has been performed using the B3LYP functi... more Full geometry optimization of spin-labeled nitrosoureas has been performed using the B3LYP functional at the density functional level of theory (DFT). A significant linear correlation has been found between the energy of the lowest unoccupied molecular orbital (LUMO) and the anti-cancer activity against P388 murine lymphotic leukemia. The correlation is explained with the high compound-receptor interaction capabilities of active compounds having low LUMO energy.

Bookmarks Related papers MentionsView impact

Research paper thumbnail of CD46 co-stimulation is crucial for the induction of the key metabolic switch that drives Th1 lineage differentiation

Bookmarks Related papers MentionsView impact

Research paper thumbnail of Numerical Experiments for Mammary Adenocarcinoma Cell Progression

Integral Methods in Science and Engineering, 2011

... The cells were harvested by trypsinization and counted on days 3, 6, and 9 ... has been devel... more ... The cells were harvested by trypsinization and counted on days 3, 6, and 9 ... has been developed in the framework of the kinetic theory for active particles [ArBeAnLa03, BeBe06 ... which is typical for non-equilibrium statistical mechanics and generalized kinetic theory, the unknown ...

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Research paper thumbnail of Upregulating CD59: a new strategy for protection of neurons from complement-mediated degeneration

The Pharmacogenomics Journal, 2010

An increasing number of studies have shown a critical role for the membrane attack complex, synth... more An increasing number of studies have shown a critical role for the membrane attack complex, synthesized on activation of the terminal pathway of the complement system, in causing demyelination and neuronal death in neurodegeneration. The aim of this study was to develop a strategy to increase the resistance of neurons to complement damage by modulating the expression of membrane complement regulatory protein CD59, the only inhibitor of the terminal pathway of the complement cascade. We exploited our recent finding that CD59 expression is regulated by the neural-restrictive silencer factor (REST) and designed a novel REST-derived peptide (REST5) containing the nuclear localization domain of the wild-type protein. The effect of REST5 and the mechanism by which it modulates CD59 expression were modelled in neuroblastoma cells transfected with expression constructs, and then confirmed in human neurons differentiated from neural progenitor cells. REST5 increased the expression of CD59 in neurons by fivefold and protected them from complement-mediated lysis spontaneously triggered by neurons. As a source of complement, we used either human serum or conditioned medium from primary human oligodendroglia. This study brings new insight into immunopharmacological research that may serve to inhibit neuronal death triggered by the terminal pathway of complement activation.

Bookmarks Related papers MentionsView impact

Research paper thumbnail of Interplay between REST and nucleolin transcription factors: a key mechanism in the overexpression of genes upon increased phosphorylation

Nucleic Acids Research, 2014

Non-malignant cells can be transformed via the activation of kinases that control degradation of ... more Non-malignant cells can be transformed via the activation of kinases that control degradation of neural-restrictive silencer factor (REST). Here, we identify a mechanism that contributes to the activation of genes, expression of which is controlled by responsive elements containing overlapping binding sites for REST and nucleolin. We demonstrate that both phosphorylated and non-phosphorylated nucleolin-bound DNA; however, only phosphorylated nucleolin successfully competed with either full-length REST or a REST-derived DNA-binding peptide, REST68, for binding to the overlapping binding sites. We show that this interplay between the two transcription factors regulates the activation of cell survival and immunomodulatory genes in tumors and non-malignant cells with activated protein kinase C, which is accompanied with alterations in cell proliferation and apoptosis. We propose a model for the regulation of these genes, which brings a new insight into the molecular mechanisms that control cellular transformation driven by activation of protein kinases.

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Research paper thumbnail of Nonlinear modeling with mammographic evidence of carcinoma

Nonlinear Analysis: Real World Applications, 2010

... Keywords: Breast tumor progression; Mammographic data; Kinetic theory; Active particles; Math... more ... Keywords: Breast tumor progression; Mammographic data; Kinetic theory; Active particles; Mathematical model; Nonlinear integro ... cancer cell populations have been the subject of active mathematical research. ... physicians) let us mention the successful application on patients by ...

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Research paper thumbnail of Experimental versus numerical data for breast cancer progression

Nonlinear Analysis: Real World Applications, 2012

Bookmarks Related papers MentionsView impact

Research paper thumbnail of C5L2-mediated signals control contraction of human Th1 responses

Molecular Immunology, 2013

Bookmarks Related papers MentionsView impact

Research paper thumbnail of Evidence for intracellular complement activation vital to Th1 immunity

Molecular Immunology, 2013

ABSTRACT Eculizumab (Soliris), a humanized mAb against the complement protein C5 inhibits the gen... more ABSTRACT Eculizumab (Soliris), a humanized mAb against the complement protein C5 inhibits the generation of the proinflammatory pep-tide C5a and the formation of the membrane complement complex C5b-9, thereby preventing complement-mediated inflammatory tissue destruction. Beneficial effects of eculizumab treatment have already been demonstrated in patients with paroxysmal nocturnal hemoglobinuria and there is accumulating evidence that it is also effective in severe cases of aHUS, STEC-HUS, MPGN as well as in protecting high risk patients against humoral renal graft rejection. However, the response to Eculizumab treatment in those patients appears to be more variable than in cases of paroxysmal noctur-nal hemoglobinuria, due to disease stage and different therapeutic regimen. aHUS, STEC-HUS and MPGN patients under therapy were moni-tored by a newly established specific ELISA for Eculizumab in serum, plasma and urine and by haemolytic inhibition assays to assess the drug's inhibitory capacity. Complement activation under therapy was measured by analysis of C3, C3d, and SC5b-9, considered to reflect the inhibitory efficacy of the C5 inhibitor in vivo. Circulating serum/plasma levels of Eculizumab, partly exceeding 1500 ␮g/ml were measured, resembling up to 10–20-fold of the recommended serum concentration of 50–100 ␮g/ml, indicating an accumulation of the drug over time. In some patients (MPGN, aHUS, renal trans-plantation), renal elimination could be demonstrated by detecting urinary Eculizumab levels up to 11 ␮g/ml. Functional assays con-firmed full inhibitory activity of the drug in the patients' urine if co-incubated with normal human serum, correlating with drug concentration. Based on these findings we suggest to include in monitoring of complement activation the combined analysis of Eculizumab by ELISA and its inhibitory effect in serum and urine to allow a better adaptation and optimization of anti-complement therapy in severe cases of complement-mediated nephropathies, such as (a)HUS and MPGN. Introduction: We have previously reported that mice deficient of the LP effector component MASP-2 are significantly advantaged in models of ischaemic disease such as myocardial infarction and

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Research paper thumbnail of Mathematical model of tumor invasion along linear or tubular structures

Mathematical and Computer Modelling, 2005

We examine a mathematical model of a population of cells distributed over a linear or tubular str... more We examine a mathematical model of a population of cells distributed over a linear or tubular structure. Growth of cells is regulated by a growth factor, which can diffuse over the structure. Aside from this, production of cells and of the growth factor is governed by a pair of ordinary differential equations. We find conditions under which diffusion causes destabilization

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Research paper thumbnail of A mathematical model for single cell cancer—Immune system dynamics

Mathematical and Computer Modelling, 2005

In this paper, we propose and analyse the model of competition between a single cell cancer and t... more In this paper, we propose and analyse the model of competition between a single cell cancer and the immune system. The model is a system of integro-differential bilinear equations and it describes both very early stage of a solid tumor and all stages of leukemias.

Bookmarks Related papers MentionsView impact

Research paper thumbnail of Polymorphisms in Mannan-Binding Lectin (MBL)-Associated Serine Protease 2 Affect Stability, Binding to MBL, and Enzymatic Activity

The Journal of Immunology, 2009

Mannan-binding lectin-associated serine protease 2 (MASP-2) is an enzyme of the innate immune sys... more Mannan-binding lectin-associated serine protease 2 (MASP-2) is an enzyme of the innate immune system. MASP-2 forms complexes with the pattern recognition molecules mannan-binding lectin (MBL), H-ficolin, L-ficolin, or M-ficolin, and is activated when one of these proteins recognizes microorganisms and subsequently cleaves complement factors C4 and C2, thus initiating the activation of the complement system. Missense polymorphisms of MASP-2 exist in different ethnic populations. To further characterize the nature of these, we have produced and characterized rMASP-2s representing the following naturally occurring polymorphisms: R99Q, D120G, P126L, H155R, 156_159dupCHNH (CHNHdup), V377A, and R439H. Only very low levels of CHNHdup were secreted from the cells, whereas quantities similar to wild-type MASP-2 were found intracellularly, indicating that this mutation results in a misfolded protein. We found that D120G and CHNHdup could not associate with MBL, whereas R99Q, P126L, H155R, V377A, R439H, and wild-type MASP-2 bound equally well to MBL. Accordingly, when D120G and CHNHdup were mixed with MBL, no activation of complement factor C4 was observed, whereas R99Q, P126L, and V377A cleaved C4 with an activity comparable to wild-type MASP-2 and H155R slightly better. In contrast, the R439H variant was deficient in this process despite its normal binding to MBL. This variant was also not able to autoactivate in the presence of MBL and mannan. We find the R439H variant is common in Sub-Saharan Africans with a gene frequency of 10%. Our results indicate that individuals with different types of MASP-2 defects may be identified through genotyping.

Bookmarks Related papers MentionsView impact

Research paper thumbnail of Retraction: Targeting Neural-Restrictive Silencer Factor Sensitizes Tumor Cells to Antibody-Based Cancer Immunotherapy In Vitro via Multiple Mechanisms

The Journal of Immunology, 2011

Tumor cells escape clearance by complement by abundantly expressing CD59 and other membrane compl... more Tumor cells escape clearance by complement by abundantly expressing CD59 and other membrane complement regulators. Recently, we designed a peptide derived from the neural-restrictive silencer factor (REST), REST68, which we showed to inhibit expression of CD59 in tumors lacking the full-length REST and proposed a detailed model for regulation of CD59 expression via interplay between REST and nucleolin (NCL) transcription factors. In this paper, we study in detail the mechanisms for sensitization of malignant cells to Ab-based cancer immunotherapy by the REST68 peptide and the implications of the REST/NCL model for the design of treatment resulting in higher tumor susceptibility. REST68 inhibited CD59 expression in malignant cells expressing either truncated or full-length REST, but not in nonmalignant cells. However, activation of protein kinase C (PKC) in nonmalignant cells, a process that contributes to cellular transformation, phosphorylated NCL and enabled suppression of CD59 expression by the REST68. Combined treatment of different tumor types with REST68 and PKC inhibitor synergized to further suppress CD59 expression and reduce resistance to complement lysis. The combined treatment also increased susceptibility of tumors expressing either of the REST isoforms to PBMC-mediated killing, which, at least in part, accounted for the strong promotion of apoptosis by the REST68/PKC inhibitor. These data demonstrate that REST68 sensitizes tumors to Ab-based cancer immunotherapy via multiple mechanisms. Furthermore, the REST/NCL interplay model for regulation of expression of cd59 and other genes involved in cell survival enables the design of treatments for different tumor types to achieve more efficient tumor clearance.

Bookmarks Related papers MentionsView impact

Research paper thumbnail of Neuronal death in Alzheimer’s disease and therapeutic opportunities

Journal of Cellular and Molecular Medicine, 2009

Alzheimer's disease (AD) ... more Alzheimer's disease (AD) is an age-related neurodegenerative disease that affects approximately 24 million people worldwide. A number of different risk factors have been implicated in AD; however, neuritic (amyloid) plaques are considered as one of the defining risk factors and pathological hallmarks of the disease. In the past decade, enormous efforts have been devoted to understand the genetics and molecular pathogenesis leading to neuronal death in AD, which has been transferred into extensive experimental approaches aimed at reversing disease progression. Modern medicine is facing an increasing number of treatments available for vascular and neurodegenerative brain diseases, but no causal or neuroprotective treatment has yet been established. Almost all neurological conditions are characterized by progressive neuronal dysfunction, which, regardless of the pathogenetic mechanism, finally leads to neuronal death. The particular emphasis of this review is on risk factors and mechanisms resulting in neuronal loss in AD and current and prospective opportunities for therapeutic interventions. This review discusses these issues with a view to inspiring the development of new agents that could be useful for the treatment of AD.

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Research paper thumbnail of Intracellular Complement Activation Sustains T Cell Homeostasis and Mediates Effector Differentiation

Immunity, 2013

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Research paper thumbnail of Correlation between Animal and Mathematical Models for Prostate Cancer Progression

Computational and Mathematical Methods in Medicine, 2009

Page 1. Correlation between animal and mathematical models for prostate cancer progression Z. Jac... more Page 1. Correlation between animal and mathematical models for prostate cancer progression Z. Jackiewicza1, CL Jorcykb2, M. Kolevc3 and B. Zubik-Kowald4* aDepartment of Mathematics and Statistics, Arizona State University ...

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Research paper thumbnail of Numerical Solutions for a Model of Tissue Invasion and Migration of Tumour Cells

Computational and Mathematical Methods in Medicine, 2011

ABSTRACT The goal of this paper is to construct a new algorithm for the numerical simulations of ... more ABSTRACT The goal of this paper is to construct a new algorithm for the numerical simulations of the evolution of tumour invasion and metastasis. By means of mathematical model equations and their numerical solutions we investigate how cancer cells can produce and secrete matrix degradative enzymes, degrade extracellular matrix, and invade due to diffusion and haptotactic migration. For the numerical simulations of the interactions between the tumour cells and the surrounding tissue, we apply numerical approximations, which are spectrally accurate and based on small amounts of grid-points. Our numerical experiments illustrate the metastatic ability of tumour cells.

Bookmarks Related papers MentionsView impact

Research paper thumbnail of Existence of Different but Overlapping IgG- and IgM-Binding Sites on the Globular Domain of Human C1q †

Biochemistry, 2006

C1q is the first subcomponent of the classical complement pathway that binds antigen-bound IgG or... more C1q is the first subcomponent of the classical complement pathway that binds antigen-bound IgG or IgM and initiates complement activation via association of serine proteases C1r and C1s. The globular domain of C1q (gC1q), which is the ligand-recognition domain, is a heterotrimeric structure composed of the C-terminal regions of A (ghA), B (ghB), and C (ghC) chains. The expression and functional characterization of ghA, ghB, and ghC modules have revealed that each chain has some structural and functional autonomy. Although a number of studies have tried to identify IgG-binding sites on the gC1q domain, no such attempt has been made to localize IgM-binding site. On the basis of the information available via the gC1q crystal structure, molecular modeling, mutational studies, and bioinformatics, we have generated a series of substitution mutants of ghA, ghB, and ghC and examined their interactions with IgM. The comparative analysis of IgM- and IgG-binding abilities of the mutants suggests that the IgG- and IgM-binding sites within the gC1q domain are different but may overlap. Whereas Arg(B108), Arg (B109), and Tyr(B175) mainly constitute the IgM-binding site, the residues Arg(B114), Arg(B129), Arg(B163), and His(B117) that have been shown to be central to IgG binding are not important for the C1q-IgM interaction. Given the location of Arg(B108), Arg (B109), and Tyr(B175) in the gC1q crystal structure, it is likely that C1q interacts with IgM via the top of the gC1q domain.

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