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Modelling combined virotherapy and immunotherapy: strengthening the antitumour immune response mediated by IL-12 and GM-CSF expression 模拟联合病毒治疗和免疫治疗:增强IL-12和GM-CSF表达介导的抗肿瘤免疫应答
Q3 Mathematics Pub Date : 2018-03-12 DOI: 10.1080/23737867.2018.1438216
A. Jenner, C. Yun, A. Yoon, A. Coster, P. Kim
Combined virotherapy and immunotherapy has been emerging as a promising and effective cancer treatment for some time. Intratumoural injections of an oncolytic virus instigate an immune reaction in the host, resulting in an influx of immune cells to the tumour site. Through combining an oncolytic viral vector with immunostimulatory cytokines an additional antitumour immune response can be initiated, whereby immune cells induce apoptosis in both uninfected and virus infected tumour cells. We develop a mathematical model to reproduce the experimental results for tumour growth under treatment with an oncolytic adenovirus co-expressing the immunostimulatory cytokines interleukin 12 (IL-12) and granulocyte-monocyte colony stimulating factor (GM-CSF). By exploring heterogeneity in the immune cell stimulation by the treatment, we find a subset of the parameter space for the immune cell induced apoptosis rate, in which the treatment will be less effective in a short time period. Therefore, we believe the bivariate nature of treatment outcome, whereby tumours are either completely eradicated or grow unbounded, can be explained by heterogeneity in this immune characteristic. Furthermore, the model highlights the apparent presence of negative feedback in the helper T cell and APC stimulation dynamics, when IL-12 and GM-CSF are co-expressed as opposed to individually expressed by the viral vector.
一段时间以来,联合病毒治疗和免疫疗法已成为一种有前途和有效的癌症治疗方法。瘤内注射溶瘤病毒在宿主中引发免疫反应,导致免疫细胞涌入肿瘤部位。通过将溶瘤病毒载体与免疫刺激性细胞因子结合,可以启动额外的抗肿瘤免疫反应,从而免疫细胞在未感染和病毒感染的肿瘤细胞中诱导细胞凋亡。我们开发了一个数学模型来重现在用共表达免疫刺激细胞因子白细胞介素12(IL-12)和粒细胞-单核细胞集落刺激因子(GM-CSF)的溶瘤腺病毒治疗下肿瘤生长的实验结果。通过探索治疗对免疫细胞刺激的异质性,我们找到了免疫细胞诱导的凋亡率的参数空间的子集,其中治疗在短时间内效果较差。因此,我们认为,治疗结果的双变量性质,即肿瘤要么被完全根除,要么无限生长,可以用这种免疫特征的异质性来解释。此外,该模型强调了当IL-12和GM-CSF共同表达而不是由病毒载体单独表达时,辅助T细胞和APC刺激动力学中明显存在负反馈。
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引用次数: 10
Treating cancerous cells with viruses: insights from a minimal model for oncolytic virotherapy 用病毒治疗癌细胞:从溶瘤病毒治疗的最小模型的见解
Q3 Mathematics Pub Date : 2018-03-09 DOI: 10.1080/23737867.2018.1440977
A. Jenner, A. Coster, P. Kim, Federico Frascoli
Abstract In recent years, interest in the capability of virus particles as a treatment for cancer has increased. In this work, we present a mathematical model embodying the interaction between tumour cells and virus particles engineered to infect and destroy cancerous tissue. To quantify the effectiveness of oncolytic virotherapy, we conduct a local stability analysis and bifurcation analysis of our model. In the absence of tumour growth or viral decay, the model predicts that oncolytic virotherapy will successfully eliminate the tumour cell population for a large proportion of initial conditions. In comparison, for growing tumours and decaying viral particles there are no stable equilibria in the model; however, oscillations emerge for certain regions in our parameter space. We investigate how the period and amplitude of oscillations depend on tumour growth and viral decay. We find that higher tumour replication rates result in longer periods between oscillations and lower amplitudes for uninfected tumour cells. From our analysis, we conclude that oncolytic viruses can reduce growing tumours into a stable oscillatory state, but are insufficient to completely eradicate them. We propose that it is only with the addition of other anti-cancer agents that tumour eradication may be achieved by oncolytic virus.
摘要近年来,人们对病毒颗粒治疗癌症的能力越来越感兴趣。在这项工作中,我们提出了一个数学模型,体现了肿瘤细胞和病毒颗粒之间的相互作用,病毒颗粒被设计成感染和破坏癌组织。为了量化溶瘤病毒治疗的有效性,我们对我们的模型进行了局部稳定性分析和分叉分析。在没有肿瘤生长或病毒衰变的情况下,该模型预测溶瘤病毒治疗将在很大一部分初始条件下成功消除肿瘤细胞群。相比之下,对于生长中的肿瘤和腐烂的病毒颗粒,模型中没有稳定的平衡;然而,在我们的参数空间中,某些区域会出现振荡。我们研究了振荡的周期和幅度如何取决于肿瘤生长和病毒衰变。我们发现,对于未感染的肿瘤细胞,较高的肿瘤复制率导致振荡之间的时间较长,振幅较低。根据我们的分析,我们得出结论,溶瘤病毒可以将生长中的肿瘤减少到稳定的振荡状态,但不足以完全根除它们。我们提出,只有在添加其他抗癌药物的情况下,才能通过溶瘤病毒实现肿瘤根除。
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引用次数: 22
A model for cross-institutional collaboration: how the intercollegiate biomathematics alliance is pioneering a new paradigm in response to diminishing resources in academia 跨机构合作的模式:校际生物数学联盟如何在学术界资源减少的情况下开创一种新的模式
Q3 Mathematics Pub Date : 2018-03-08 DOI: 10.1080/23737867.2018.1445044
Olcay Akman, Megan O. Powell
Abstract We present an emerging model of shared academic, intellectual and infrastructure resources that addresses the need for institutions to sustain their educational and scholarship missions under ever-declining funding. The (IBA) was created in 2014 by Illinois State University for this purpose, eventually growing to a state-recognized ‘Center for Collaborative Studies’ in 2017. As the impact of the IBA continues to expand, it is on its way to become a new education paradigm in response to diminishing resources, and it can serve as a model to foster collaboration for other fields of mathematics.
我们提出了一种新兴的共享学术、智力和基础设施资源的模式,解决了机构在资金不断减少的情况下维持其教育和奖学金使命的需求。该(IBA)于2014年由伊利诺伊州立大学为此目的创建,最终在2017年发展成为国家认可的“合作研究中心”。随着IBA的影响不断扩大,它正在成为一种新的教育范式,以应对资源的减少,它可以作为促进其他数学领域合作的典范。
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引用次数: 1
An extensible mathematical model of glucose metabolism. Part I: the basic glucose-insulin-glucagon model, basal conditions and basic dynamics 葡萄糖代谢的可扩展数学模型。第一部分:葡萄糖-胰岛素-胰高血糖素基本模型,基本条件和基本动态
Q3 Mathematics Pub Date : 2018-03-07 DOI: 10.1080/23737867.2018.1429332
Caleb L. Adams, D. G. Lasseigne
Abstract A basic model highlighting the counter-regulatory roles of insulin and glucagon is proposed to start a series of models designed to explore continuous rein control and major aspects of glucose metabolism. The three-by-three dynamical system uses black boxes to model unit processes such as the dependencies of insulin secretion rate and the glucagon secretion rate on blood glucose concentration. The dependency of basal conditions on insulin resistance and any defects in insulin or glucagon secretion are shown. Since over-production of hepatic glucose exists early in the history of diabetes, it is important that mathematical models should account for this effect by inclusion of the dynamical equation governing glucagon concentration as this illustrative model does. All solutions are consistent with gross features of the metabolic process. The model is examined for explicit and implicit assumptions affecting its validity which determines that the first extension to the model should account for glucose storage and the release of stored glucose.
摘要提出了一个强调胰岛素和胰高血糖素反调节作用的基本模型,以启动一系列旨在探索连续控制和葡萄糖代谢主要方面的模型。三乘三动力系统使用黑匣子对单位过程进行建模,如胰岛素分泌速率和胰高血糖素分泌速率对血糖浓度的依赖性。显示了基础条件对胰岛素抵抗的依赖性以及胰岛素或胰高血糖素分泌的任何缺陷。由于肝葡萄糖的过量产生在糖尿病早期就存在,因此重要的是,数学模型应该像这个说明性模型一样,通过纳入控制胰高血糖素浓度的动力学方程来解释这种影响。所有的解决方案都符合代谢过程的总体特征。检查该模型是否存在影响其有效性的显式和隐式假设,从而确定该模型的第一次扩展应考虑葡萄糖储存和储存葡萄糖的释放。
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引用次数: 4
Tumour-associated macrophages and oncolytic virotherapies: a mathematical investigation into a complex dynamics 肿瘤相关巨噬细胞和溶瘤病毒治疗:一项复杂动力学的数学研究
Q3 Mathematics Pub Date : 2018-02-06 DOI: 10.1080/23737867.2018.1430518
R. Eftimie, G. Eftimie
Abstract Anti-cancer therapies based on oncolytic viruses are emerging as important approaches in cancer treatment. However, the effectiveness of these therapies depends significantly on the interactions between the oncolytic viruses and the host immune response. Macrophages are one of the most important cell types in the anti-viral immune responses, by acting as a first line of defence against infections. Here, we consider a mathematical approach to investigate the possible outcomes of the interactions between two extreme phenotypes of macrophages (M1 and M2 cells) and an oncolytic virus (VSV), in the context of B16F10 melanoma. We show that polarization towards either an M1 or M2 phenotype can enhance oncolytic virus therapy through either (i) anti-tumour immune activation, or (ii) enhanced oncolysis. Moreover, we show that tumour reduction and elimination does not depend only on the ratio of M1:M2 cells, but also on the number of tumour-infiltrating macrophages.
基于溶瘤病毒的抗癌治疗正在成为癌症治疗的重要途径。然而,这些疗法的有效性在很大程度上取决于溶瘤病毒与宿主免疫反应之间的相互作用。巨噬细胞是抗病毒免疫反应中最重要的细胞类型之一,作为抵抗感染的第一道防线。在这里,我们考虑了一种数学方法来研究巨噬细胞(M1和M2细胞)和溶瘤病毒(VSV)在B16F10黑色素瘤背景下两种极端表型之间相互作用的可能结果。我们发现,M1或M2表型的极化可以通过(i)抗肿瘤免疫激活或(ii)增强溶瘤病毒治疗。此外,我们发现肿瘤的减少和消除不仅取决于M1:M2细胞的比例,还取决于肿瘤浸润的巨噬细胞的数量。
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引用次数: 30
Modelling epidemics on d-cliqued graphs d-cliqued图流行病建模
Q3 Mathematics Pub Date : 2018-01-16 DOI: 10.1080/23737867.2017.1419080
L. Schaposnik, Anlin Zhang
Abstract Since social interactions have been shown to lead to symmetric clusters, we propose here that symmetries play a key role in epidemic modelling. Mathematical models on d-ary tree graphs were recently shown to be particularly effective for modelling epidemics in simple networks. To account for symmetric relations, we generalize this to a new type of networks modelled on d-cliqued tree graphs, which are obtained by adding edges to regular d-trees to form d-cliques. This setting gives a more realistic model for epidemic outbreaks originating within a family or classroom and which could reach a population by transmission via children in schools. Specifically, we quantify how an infection starting in a clique (e.g. family) can reach other cliques through the body of the graph (e.g. public places). Moreover, we propose and study the notion of a safe zone, a subset that has a negligible probability of infection.
摘要由于社会互动已被证明会导致对称集群,我们在这里提出对称性在流行病建模中起着关键作用。最近,d元树图上的数学模型被证明在简单网络中对流行病建模特别有效。为了说明对称关系,我们将其推广到一种新的基于d群树图的网络,该网络是通过向正则d树添加边来形成d群而获得的。这种设置为源自家庭或教室的流行病疫情提供了一个更现实的模型,这些疫情可能通过学校的儿童传播给人群。具体来说,我们量化了从一个群体(如家庭)开始的感染如何通过图体(如公共场所)传播到其他群体。此外,我们提出并研究了安全区的概念,即感染概率可忽略不计的子集。
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引用次数: 1
Modelling acute myeloid leukaemia in a continuum of differentiation states. 模拟急性髓性白血病在连续分化状态。
Q3 Mathematics Pub Date : 2018-01-01 Epub Date: 2018-06-18 DOI: 10.1080/23737867.2018.1472532
H Cho, K Ayers, L DePills, Y-H Kuo, J Park, A Radunskaya, R Rockne

Here we present a mathematical model of movement in an abstract space representing states of cellular differentiation. We motivate this work with recent examples that demonstrate a continuum of cellular differentiation using single cell RNA sequencing data to characterize cellular states in a high-dimensional space, which is then mapped into 2 or 2 with dimension reduction techniques. We represent trajectories in the differentiation space as a graph, and model directed and random movement on the graph with partial differential equations. We hypothesize that flow in this space can be used to model normal and abnormal differentiation processes. We present a mathematical model of hematopoeisis parameterized with publicly available single cell RNA-Seq data and use it to simulate the pathogenesis of acute myeloid leukemia (AML). The model predicts the emergence of cells in novel intermediate states of differentiation consistent with immunophenotypic characterizations of a mouse model of AML.

在这里,我们提出了一个抽象空间中代表细胞分化状态的运动数学模型。我们用最近的例子来激励这项工作,这些例子展示了细胞分化的连续体,使用单细胞RNA测序数据来表征高维空间中的细胞状态,然后用降维技术将其映射到2或2中。我们将微分空间中的轨迹表示为一个图,并用偏微分方程对图上的有向和随机运动进行建模。我们假设这个空间的流动可以用来模拟正常和异常的分化过程。我们提出了一个用公开的单细胞RNA-Seq数据参数化造血的数学模型,并用它来模拟急性髓性白血病(AML)的发病机制。该模型预测细胞出现在新的中间分化状态,与AML小鼠模型的免疫表型特征一致。
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引用次数: 16
Modeling the Diet Dynamics of Children: the Roles of Socialization and the School Environment. 儿童饮食动态的建模:社会化和学校环境的作用。
Q3 Mathematics Pub Date : 2018-01-01 Epub Date: 2018-12-07 DOI: 10.1080/23737867.2018.1552543
Muntaser Safan, Anarina L Murillo, Devina Wadhera, Carlos Castillo-Chavez

Childhood obesity is a health emergency in many parts of the world including the U.S. and, consequently, identifying local, regional or national intervention models capable, of altering the dynamics of obesity at scales that make a difference remains a challenge. The fact that consumption of healthful foods among most youth has yet to meet recommended nutritional standards highlights a lack of effective policies aimed at addressing the epidemic of obesity. Mathematical models are used to evaluate the roles of socialization and school environment on the diet dynamics of children. Data suggest that standard nutrition education programs may have, at best, minimal impact in altering diet dynamics at the population-level. Inclusion of peer influence (model as contagion) reinforced by the use of culturally-sensitive school menus (environmental disruption) may prove capable of modifying obesity enhancing diet dynamics; altering the diets of a significant (critical) proportion of youngsters. A framework is introduced to explore the value of behavior-based interventions and policies that account for the sociocultural environments of at risk communities. These models capture carefully choreographed scenarios to account for the fact that when dealing with diet-dynamics systems, thinking additively is not enough as it cannot account for the power of nonlinear effects.

儿童肥胖在包括美国在内的世界许多地方都是一个健康紧急情况,因此,确定能够大规模改变肥胖动态并产生影响的地方、区域或国家干预模式仍然是一项挑战。大多数年轻人对健康食品的消费尚未达到建议的营养标准,这一事实突显出缺乏旨在解决肥胖流行病的有效政策。利用数学模型来评价社会化和学校环境对儿童饮食动态的影响。数据显示,标准的营养教育项目在改变人群饮食动态方面最多只能产生最小的影响。通过使用对文化敏感的学校菜单(环境破坏)加强同伴影响(传染模型),可能证明能够改变肥胖,增强饮食动态;改变相当(临界)比例青少年的饮食。介绍了一个框架来探索基于行为的干预措施和政策的价值,这些干预措施和政策考虑了风险社区的社会文化环境。这些模型捕捉了精心设计的场景,以解释这样一个事实:当处理饮食动力学系统时,加法思维是不够的,因为它不能解释非线性效应的力量。
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引用次数: 5
Technology as a tool in teaching quantitative biology at the secondary and undergraduate levels: a review. 技术作为中学和大学阶段定量生物学教学的工具:综述。
Q3 Mathematics Pub Date : 2018-01-01 Epub Date: 2017-12-26 DOI: 10.1080/23737867.2017.1413432
Miranda M Chen, S M Scott, Jessica D Stevens

Since the publication of the National Research Councils Report BIO2010, e orts have increased to better integrate mathematics and biology in undergraduate education. Unfortunately, equivalent e orts to introduce these quantitative topics at the secondary level have been seldom. This could cause differential success of undergraduate students who come from diverse secondary science backgrounds. Undergraduate courses regularly use technology to integrate these two disciplines, and we believe that technology can similarly be used at the secondary level to prevent quantitative achievement mismatch in undergraduate biology programs. In this paper, we review the current uses of technology to teach quantitative biology at the secondary and undergraduate levels, propose needs for further implementation, and address potential barriers to integrating mathematics and biology using technology.

自从国家研究委员会发布BIO2010报告以来,在本科教育中更好地整合数学和生物学的努力有所增加。不幸的是,在中学阶段引入这些定量主题的同等努力很少。这可能会导致来自不同中学科学背景的本科生取得不同的成功。本科课程经常使用技术来整合这两个学科,我们相信技术可以类似地用于二级水平,以防止本科生物学课程的定量成就不匹配。在本文中,我们回顾了目前在中学和本科阶段使用技术教授定量生物学的情况,提出了进一步实施的需求,并解决了利用技术整合数学和生物学的潜在障碍。
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引用次数: 18
Mathematical modeling, analysis and simulation of the spread of Zika with influence of sexual transmission and preventive measures 性传播对寨卡病毒传播的影响及预防措施的数学建模、分析和模拟
Q3 Mathematics Pub Date : 2017-01-01 DOI: 10.1080/23737867.2017.1319746
P. Padmanabhan, P. Seshaiyer, C. Castillo-Chavez
Abstract The Zika arbovirus transmitted by the Aedes aegypti mosquitoes has been shown to be capable of infecting humans via two routes: the bites of infected vectors and through sexual contacts involving infected and non-infected persons. There is no treatment and current prevention or mitigating efforts rely on the use of the Centers for Disease Control and Prevention recommendations including the use of insecticide-treated bed nets (ITN) and indoor residual spraying (IRS). In this work, we investigate via a mathematical model, the role of ITN and IRS as methods for limiting the impact of Zika transmission. We introduce a model that builds on classical SEIR epidemiological single outbreak models. We compute the basic and control reproduction numbers and the final epidemic size in the presence of control measures ITN and IRS. We derive a gross estimate for the rate of sexual transmission, during the initial stages of the outbreak, in terms of prior estimates of the basic reproduction number from related albeit not sexually transmitted arboviral diseases.
摘要由埃及伊蚊传播的寨卡虫媒病毒已被证明能够通过两种途径感染人类:感染媒介的叮咬和通过感染者和未感染者的性接触。没有治疗方法,目前的预防或缓解工作依赖于使用疾病控制和预防中心的建议,包括使用杀虫剂处理的蚊帐(ITN)和室内残留喷洒(IRS)。在这项工作中,我们通过数学模型研究了ITN和IRS作为限制寨卡病毒传播影响的方法的作用。我们介绍了一个建立在经典SEIR流行病单次爆发模型基础上的模型。我们计算了在控制措施ITN和IRS存在的情况下的基本和控制繁殖数量以及最终流行病规模。我们根据先前对相关但非性传播的虫媒病毒疾病的基本繁殖数量的估计,得出了疫情暴发初期性传播率的粗略估计。
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引用次数: 34
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Letters in Biomathematics
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