Theoretical Biology and Medical Modelling最新文献

{"title":"A patient-specific treatment model for Graves' hyperthyroidism.","authors":"Balamurugan Pandiyan,&nbsp;Stephen J Merrill,&nbsp;Flavia Di Bari,&nbsp;Alessandro Antonelli,&nbsp;Salvatore Benvenga","doi":"10.1186/s12976-017-0073-6","DOIUrl":"https://doi.org/10.1186/s12976-017-0073-6","url":null,"abstract":"<p><strong>Background: </strong>Graves' is disease an autoimmune disorder of the thyroid gland caused by circulating anti-thyroid receptor antibodies (TRAb) in the serum. TRAb mimics the action of thyroid stimulating hormone (TSH) and stimulates the thyroid hormone receptor (TSHR), which results in hyperthyroidism (overactive thyroid gland) and goiter. Methimazole (MMI) is used for hyperthyroidism treatment for patients with Graves' disease.</p><p><strong>Methods: </strong>We have developed a model using a system of ordinary differential equations for hyperthyroidism treatment with MMI. The model has four state variables, namely concentration of MMI (in mg/L), concentration of free thyroxine - FT4 (in pg/mL), and concentration of TRAb (in U/mL) and the functional size of the thyroid gland (in mL) with thirteen parameters. With a treatment parameter, we simulate the time-course of patients' progression from hyperthyroidism to euthyroidism (normal condition). We validated the model predictions with data from four patients.</p><p><strong>Results: </strong>When there is no MMI treatment, there is a unique asymptotically stable hyperthyroid state. After the initiation of MMI treatment, the hyperthyroid state moves towards subclinical hyperthyroidism and then euthyroidism.</p><p><strong>Conclusion: </strong>We can use the model to describe or test and predict patient treatment schedules. More specifically, we can fit the model to individual patients' data including loading and maintenance doses and describe the mechanism, hyperthyroidism→euthyroidism. The model can be used to predict when to discontinue the treatment based on FT4 levels within the physiological range, which in turn help maintain the remittance of euthyroidism and avoid relapses of hyperthyroidism. Basically, the model can guide with decision-making on oral intake of MMI based on FT4 levels.</p>","PeriodicalId":51195,"journal":{"name":"Theoretical Biology and Medical Modelling","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2018-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/s12976-017-0073-6","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35716429","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"On the utility of a compartmental population kinetics model of intestinal epithelial stem cell proliferation and differentiation.","authors":"Erik R Barthel","doi":"10.1186/s12976-017-0071-8","DOIUrl":"https://doi.org/10.1186/s12976-017-0071-8","url":null,"abstract":"<p><strong>Background: </strong>The small intestinal epithelium is a dynamic system with specialized cell types. The various cell populations of this tissue are continually renewed and replenished from stem cells that reside in the small intestinal crypt. The cell types and their locations in the crypt and villus are well known, but the details of the kinetics of stem cell division, and precursor cell proliferation and differentiation into mature enterocytes and secretory cells are still being studied. These proliferation and differentiation events have been extensively modeled with a variety of computational approaches in the past.</p><p><strong>Methods: </strong>A compartmental population kinetics model, incorporating experimentally measured proliferation rates for various intestinal epithelial cell types, is implemented for a previously reported scheme for the intestinal cell dynamics. A sensitivity analysis is performed to determine the effect that varying the model parameters has upon the model outputs, the steady-state cell populations.</p><p><strong>Results: </strong>The model is unable to reproduce the experimentally known timescale of renewal of the intestinal epithelium if literature values for the proliferation rates of stem cells and transit amplifying cells are employed. Unphysically large rates of proliferation result when these parameters are allowed to vary to reproduce this timescale and the steady-state populations of terminally differentiated intestinal epithelial cells. Sensitivity analysis reveals that the strongest contributor to the steady-state populations is the transit amplifying cell proliferation rate when literature values are used, but that the differentiation rate of transit amplifying cells to secretory progenitor cells dominates when all parameters are allowed to vary.</p><p><strong>Conclusions: </strong>A compartmental population kinetics model of proliferation and differentiation of cells of the intestinal epithelium can provide a simplifying means of understanding a complicated multistep process. However, when literature values for proliferation rates of the crypt based columnar and transit amplifying cell populations are employed in the model, it cannot reproduce the experimentally known timescale of intestinal epithelial renewal. Nevertheless, it remains a valuable conceptual tool, and its sensitivity analysis provides important clues for which events in the process are the most important in controlling the steady-state populations of specialized intestinal epithelial cells.</p>","PeriodicalId":51195,"journal":{"name":"Theoretical Biology and Medical Modelling","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2017-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/s12976-017-0071-8","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35668105","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effects of pathogen dependency in a multi-pathogen infectious disease system including population level heterogeneity - a simulation study.","authors":"Abhishek Bakuli,&nbsp;Frank Klawonn,&nbsp;André Karch,&nbsp;Rafael Mikolajczyk","doi":"10.1186/s12976-017-0072-7","DOIUrl":"https://doi.org/10.1186/s12976-017-0072-7","url":null,"abstract":"<p><strong>Background: </strong>Increased computational resources have made individual based models popular for modelling epidemics. They have the advantage of incorporating heterogeneous features, including realistic population structures (like e.g. households). Existing stochastic simulation studies of epidemics, however, have been developed mainly for incorporating single pathogen scenarios although the effect of different pathogens might directly or indirectly (e.g. via contact reductions) effect the spread of each pathogen. The goal of this work was to simulate a stochastic agent based system incorporating the effect of multiple pathogens, accounting for the household based transmission process and the dependency among pathogens.</p><p><strong>Methods: </strong>With the help of simulations from such a system, we observed the behaviour of the epidemics in different scenarios. The scenarios included different household size distributions, dependency versus independency of pathogens, and also the degree of dependency expressed through household isolation during symptomatic phase of individuals. Generalized additive models were used to model the association between the epidemiological parameters of interest on the variation in the parameter values from the simulation data. All the simulations and statistical analyses were performed using R 3.4.0.</p><p><strong>Results: </strong>We demonstrated the importance of considering pathogen dependency using two pathogens, and showing the difference when considered independent versus dependent. Additionally for the general scenario with more pathogens, the assumption of dependency among pathogens and the household size distribution in the population cohort was found to be effective in containing the epidemic process. Additionally, populations with larger household sizes reached the epidemic peak faster than societies with smaller household sizes but dependencies among pathogens did not affect this outcome significantly. Larger households had more infections in all population cohort examples considered in our simulations. Increase in household isolation coefficient for pathogen dependency also could control the epidemic process.</p><p><strong>Conclusion: </strong>Presence of multiple pathogens and their interaction can impact the behaviour of an epidemic across cohorts with different household size distributions. Future household cohort studies identifying multiple pathogens will provide useful data to verify the interaction processes in such an infectious disease system.</p>","PeriodicalId":51195,"journal":{"name":"Theoretical Biology and Medical Modelling","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2017-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/s12976-017-0072-7","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35653208","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A mathematical model for histamine synthesis, release, and control in varicosities.","authors":"Janet Best,&nbsp;H F Nijhout,&nbsp;Srimal Samaranayake,&nbsp;Parastoo Hashemi,&nbsp;Michael Reed","doi":"10.1186/s12976-017-0070-9","DOIUrl":"https://doi.org/10.1186/s12976-017-0070-9","url":null,"abstract":"<p><strong>Background: </strong>Histamine (HA), a small molecule that is synthesized from the amino acid histidine, plays an important role in the immune system where it is associated with allergies, inflammation, and T-cell regulation. In the brain, histamine is stored in mast cells and other non-neuronal cells and also acts as a neurotransmitter. The histamine neuron cell bodies are in the tuberomammillary (TM) nucleus of the hypothalamus and these neurons send projections throughout the central nervous system (CNS), in particular to the cerebral cortex, amygdala, basal ganglia, hippocampus, thalamus, retina, and spinal cord. HA neurons make few synapses, but release HA from the cell bodies and from varicosities when the neurons fire. Thus the HA neural system seems to modulate and control the HA concentration in projection regions. It is known that high HA levels in the extracellular space inhibit serotonin release, so HA may play a role in the etiology of depression.</p><p><strong>Results: </strong>We compare model predictions to classical physiological experiments on HA half-life, the concentration of brain HA after histidine loading, and brain HA after histidine is dramatically increased or decreased in the diet. The model predictions are also consistent with in vivo experiments in which extracellular HA is measured, using Fast Scan Cyclic Voltammetry, in the premammillary nucleus (PM) after a 2 s antidromic stimulation of the TM, both without and in the presence of the H ₃ autoreceptor antagonist thioperamide. We show that the model predicts well the temporal behavior of HA in the extracellular space over 30 s in both experiments.</p><p><strong>Conclusions: </strong>Our ability to measure in vivo histamine dynamics in the extracellular space after stimulation presents a real opportunity to understand brain function and control. The observed extracellular dynamics depends on synthesis, storage, neuronal firing, release, reuptake, glial cells, and control by autoreceptors, as well as the behavioral state of the animal (for example, depression) or the presence of neuroinflammation. In this complicated situation, the mathematical model will be useful for interpreting data and conducting in silico experiments to understand causal mechanisms. And, better understanding can suggest new therapeutic drug targets.</p>","PeriodicalId":51195,"journal":{"name":"Theoretical Biology and Medical Modelling","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2017-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/s12976-017-0070-9","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35241552","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Estimating the prevalence of infectious diseases from under-reported age-dependent compulsorily notification databases.","authors":"Marcos Amaku,&nbsp;Marcelo Nascimento Burattini,&nbsp;Eleazar Chaib,&nbsp;Francisco Antonio Bezerra Coutinho,&nbsp;David Greenhalgh,&nbsp;Luis Fernandez Lopez,&nbsp;Eduardo Massad","doi":"10.1186/s12976-017-0069-2","DOIUrl":"https://doi.org/10.1186/s12976-017-0069-2","url":null,"abstract":"<p><strong>Background: </strong>National or local laws, norms or regulations (sometimes and in some countries) require medical providers to report notifiable diseases to public health authorities. Reporting, however, is almost always incomplete. This is due to a variety of reasons, ranging from not recognizing the diseased to failures in the technical or administrative steps leading to the final official register in the disease notification system. The reported fraction varies from 9 to 99% and is strongly associated with the disease being reported.</p><p><strong>Methods: </strong>In this paper we propose a method to approximately estimate the full prevalence (and any other variable or parameter related to transmission intensity) of infectious diseases. The model assumes incomplete notification of incidence and allows the estimation of the non-notified number of infections and it is illustrated by the case of hepatitis C in Brazil. The method has the advantage that it can be corrected iteratively by comparing its findings with empirical results.</p><p><strong>Results: </strong>The application of the model for the case of hepatitis C in Brazil resulted in a prevalence of notified cases that varied between 163,902 and 169,382 cases; a prevalence of non-notified cases that varied between 1,433,638 and 1,446,771; and a total prevalence of infections that varied between 1,597,540 and 1,616,153 cases.</p><p><strong>Conclusions: </strong>We conclude that the model proposed can be useful for estimation of the actual magnitude of endemic states of infectious diseases, particularly for those where the number of notified cases is only the tip of the iceberg. In addition, the method can be applied to other situations, such as the well-known underreported incidence of criminality (for example rape), among others.</p>","PeriodicalId":51195,"journal":{"name":"Theoretical Biology and Medical Modelling","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2017-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/s12976-017-0069-2","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35637169","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Classification and sensitivity analysis of the transmission dynamic of hepatitis B.","authors":"Tahir Khan,&nbsp;Il Hyo Jung,&nbsp;Amir Khan,&nbsp;Gul Zaman","doi":"10.1186/s12976-017-0068-3","DOIUrl":"https://doi.org/10.1186/s12976-017-0068-3","url":null,"abstract":"<p><strong>Background: </strong>Hepatitis B infection caused by the hepatitis B virus is one of the most serious viral infections and a global health problem. In the transmission of hepatitis B infection, three different phases, i.e. acute infected, chronically infected, and carrier individuals, play important roles. Carrier individuals are especially significant, because they do not exhibit any symptoms and are able to transmit the infection. Here we assessed the transmissibility associated with different infection stages of hepatitis B and generated an epidemic model.</p><p><strong>Methods: </strong>To demonstrate the transmission dynamic of hepatitis B, we investigate an epidemic model by dividing the infectious class into three subclasses, namely acute infected, chronically infected, and carrier individuals with both horizontal and vertical transmission.</p><p><strong>Results: </strong>Numerical results and sensitivity analysis of some important parameters are presented to show that the proportion of births without successful vaccination, perinatally infected individuals, and direct contact rate are highest risk factors for the spread of hepatitis B in the community.</p><p><strong>Conclusion: </strong>Our work provides a coherent platform for studying the full dynamics of hepatitis B and an effective direction for theoretical work.</p>","PeriodicalId":51195,"journal":{"name":"Theoretical Biology and Medical Modelling","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2017-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/s12976-017-0068-3","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35614076","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Theoretically proposed optimal frequency for ultrasound induced cartilage restoration.","authors":"April D Miller,&nbsp;Anuradha Subramanian,&nbsp;Hendrik J Viljoen","doi":"10.1186/s12976-017-0067-4","DOIUrl":"https://doi.org/10.1186/s12976-017-0067-4","url":null,"abstract":"<p><strong>Background: </strong>Matching the frequency of the driving force to that of the system's natural frequency of vibration results in greater amplitude response. Thus we hypothesize that applying ultrasound at the chondrocyte's resonant frequency will result in greater deformation than applying similar ultrasound power at a frequency outside of the resonant bandwidth. Based on this resonant hypothesis, our group previously confirmed theoretically and experimentally that ultrasound stimulation of suspended chondrocytes at resonance (5 MHz) maximized gene expression of load inducible genes. However, this study was based on suspended chondrocytes. The resonant frequency of a chondrocyte does not only depend on the cell mass and intracellular stiffness, but also on the mechanical properties of the surrounding medium. An in vivo chondrocyte's environment differs whether it be a blood clot (following microfracture), a hydrogel or the pericellular and extracellular matrices of the natural cartilage. All have distinct structures and compositions leading to different resonant frequencies. In this study, we present two theoretical models, the first model to understand the effects of the resonant frequency on the cellular deformation and the second to identify the optimal frequency range for clinical applications of ultrasound to enhance cartilage restoration.</p><p><strong>Results: </strong>We showed that applying low-intensity ultrasound at the resonant frequency induced deformation equivalent to that experimentally calculated in previous studies at higher intensities and a 1 MHz frequency. Additionally, the resonant frequency of an in vivo chondrocyte in healthy conditions, osteoarthritic conditions, embedded in a blood clot and embedded in fibrin ranges from 3.5 - 4.8 MHz.</p><p><strong>Conclusion: </strong>The main finding of this study is the theoretically proposed optimal frequency for clinical applications of therapeutic ultrasound induced cartilage restoration is 3.5 - 4.8 MHz (the resonant frequencies of in vivo chondrocytes). Application of ultrasound in this frequency range will maximize desired bioeffects.</p>","PeriodicalId":51195,"journal":{"name":"Theoretical Biology and Medical Modelling","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2017-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/s12976-017-0067-4","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35601360","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Anistropically varying conductivity in irreversible electroporation simulations.","authors":"Nicholas Labarbera,&nbsp;Corina Drapaca","doi":"10.1186/s12976-017-0065-6","DOIUrl":"https://doi.org/10.1186/s12976-017-0065-6","url":null,"abstract":"<p><strong>Background: </strong>One recent area of cancer research is irreversible electroporation (IRE). Irreversible electroporation is a minimally invasive procedure where needle electrodes are inserted into the body to ablate tumor cells with electricity. The aim of this paper is to propose a mathematical model that incorporates a tissue's conductivity increasing more in the direction of the electrical field as this has been shown to occur in experiments.</p><p><strong>Method: </strong>It was necessary to mathematically derive a valid form of the conductivity tensor such that it is dependent on the electrical field direction and can be easily implemented into numerical software. The derivation of a conductivity tensor that can take arbitrary functions for the conductivity in the directions tangent and normal to the electrical field is the main contribution of this paper. Numerical simulations were performed for isotropic-varying and anisotropic-varying conductivities to evaluate the importance of including the electrical field's direction in the formulation for conductivity.</p><p><strong>Results: </strong>By starting from previously published experimental results, this paper derived a general formulation for an anistropic-varying tensor for implementation into irreversible electroporation modeling software. The anistropic-varying tensor formulation allows the conductivity to take into consideration both electrical field direction and magnitude, as opposed to previous published works that only took into account electrical field magnitude. The anisotropic formulation predicts roughly a five percent decrease in ablation size for the monopolar simulation and approximately a ten percent decrease in ablation size for the bipolar simulations. This is a positive result as previously reported results found the isotropic formulation to overpredict ablation size for both monopolar and bipolar simulations. Furthermore, it was also reported that the isotropic formulation overpredicts the ablation size more for the bipolar case than the monopolar case. Thus, our results are following the experimental trend by having a larger percentage change in volume for the bipolar case than the monopolar case.</p><p><strong>Conclusions: </strong>The predicted volume of ablated cells decreased, and could be a possible explanation for the slight over-prediction seen by isotropic-varying formulations.</p>","PeriodicalId":51195,"journal":{"name":"Theoretical Biology and Medical Modelling","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2017-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/s12976-017-0065-6","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35560281","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Theoretical Model of the Wnt Signaling Pathway in the Epithelial Mesenchymal Transition.","authors":"Kelsey Gasior,&nbsp;Marlene Hauck,&nbsp;Alyson Wilson,&nbsp;Sudin Bhattacharya","doi":"10.1186/s12976-017-0064-7","DOIUrl":"https://doi.org/10.1186/s12976-017-0064-7","url":null,"abstract":"<p><strong>Background: </strong>Following the formation of a primary carcinoma, neoplastic cells metastasize by undergoing the epithelial mesenchymal transition (EMT), which is triggered by cues from inflammatory and stromal cells in the microenvironment. EMT allows epithelial cells to lose their highly adhesive nature and instead adopt the spindle-like appearance, as well as the invasive and migratory behavior, of mesenchymal cells. We hypothesize that a bistable switch between the epithelial and mesenchymal phenotypes governs EMT, allowing the cell to maintain its mesenchymal phenotype even after it leaves the primary tumor microenvironment and EMT-inducing extracellular signal.</p><p><strong>Results: </strong>This work presents a simple mathematical model of EMT, specifically the roles played by four key proteins in the Wnt signaling pathway: Dishevelled (Dvl), E-cadherin, β-catenin, and Slug. The model predicts that following activation of the Wnt pathway, an epithelial cell in the primary carcinoma must attain a threshold level of membrane-bound Dvl to convert to the mesenchymal-like phenotype and maintain that phenotype once it has migrated away from the primary tumor. Furthermore, sensitivity analysis of the model suggests that in both the epithelial and the mesenchymal states, the steady state behavior of E-cadherin and the transcription factor Slug are sensitive to changes in the degradation rate of Slug, while E-cadherin is also sensitive to the IC₅₀ (half-maximal) concentration of Slug necessary to inhibit E-cadherin production. The steady state behavior of Slug exhibits sensitivity to changes in the rate at which it is induced by β-catenin upon activation of the Wnt pathway. In the presence of sufficient amount of Wnt ligand, E-cadherin levels are sensitive to the ratio of the rate of Slug activation via β-catenin to the IC₅₀ concentration of Slug necessary to inhibit E-cadherin production.</p><p><strong>Conclusions: </strong>The sensitivity of E-cadherin to the degradation rate of Slug, as well as the IC₅₀ concentration of Slug necessary to inhibit E-cadherin production, shows how the adhesive nature of the cell depends on finely-tuned regulation of Slug. By highlighting the role of β-catenin in the activation of EMT and the relationship between E-cadherin and Slug, this model identifies critical parameters of therapeutic concern, such as the threshold level of Dvl necessary to inactivate the GSK-3β complex mediating β-catenin degradation, the rate at which β-catenin translocates to the nucleus, and the IC₅₀ concentration of Slug needed to inhibit E-cadherin production.</p>","PeriodicalId":51195,"journal":{"name":"Theoretical Biology and Medical Modelling","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2017-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/s12976-017-0064-7","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35488262","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Perspective on the dynamics of cancer.","authors":"Youcef Derbal","doi":"10.1186/s12976-017-0066-5","DOIUrl":"https://doi.org/10.1186/s12976-017-0066-5","url":null,"abstract":"<p><strong>Background: </strong>The genetic diversity of cancer and the dynamic interactions between heterogeneous tumor cells, the stroma and immune cells present daunting challenges to the development of effective cancer therapies. Although cancer biology is more understood than ever, this has not translated into therapies that overcome drug resistance, cancer recurrence and metastasis. The future development of effective therapies will require more understanding of the dynamics of homeostatic dysregulation that drives cancer growth and progression.</p><p><strong>Results: </strong>Cancer dynamics are explored using a model involving genes mediating the regulatory interactions between the signaling and metabolic pathways. The exploration is informed by a proposed genetic dysregulation measure of cellular processes. The analysis of the interaction dynamics between cancer cells, cancer associated fibroblasts, and tumor associate macrophages suggests that the mutual dependence of these cells promotes cancer growth and proliferation. In particular, MTOR and AMPK are hypothesized to be concurrently activated in cancer cells by amino acids recycled from the stroma. This leads to a proliferative growth supported by an upregulated glycolysis and a tricarboxylic acid cycle driven by glutamine sourced from the stroma. In other words, while genetic aberrations ignite carcinogenesis and lead to the dysregulation of key cellular processes, it is postulated that the dysregulation of metabolism locks cancer cells in a state of mutual dependence with the tumor microenvironment and deepens the tumor's inflammation and immunosuppressive state which perpetuates as a result the growth and proliferation dynamics of cancer.</p><p><strong>Conclusions: </strong>Cancer therapies should aim for a progressive disruption of the dynamics of interactions between cancer cells and the tumor microenvironment by targeting metabolic dysregulation and inflammation to partially restore tissue homeostasis and turn on the immune cancer kill switch. One potentially effective cancer therapeutic strategy is to induce the reduction of lactate and steer the tumor microenvironment to a state of reduced inflammation so as to enable an effective intervention of the immune system. The translation of this therapeutic approach into treatment regimens would however require more understanding of the adaptive complexity of cancer resulting from the interactions of cancer cells with the tumor microenvironment and the immune system.</p>","PeriodicalId":51195,"journal":{"name":"Theoretical Biology and Medical Modelling","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2017-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/s12976-017-0066-5","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35409298","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}