Tumor-immune metaphenotypes orchestrate an evolutionary bottleneck that promotes metabolic transformation

Introduction: Metabolism plays a complex role in the evolution of cancerous tumors, including inducing a multifaceted effect on the immune system to aid immune escape. Immune escape is, by definition, a collective phenomenon by requiring the presence of two cell types interacting in close proximity: tumor and immune. The microenvironmental context of these interactions is influenced by the dynamic process of blood vessel growth and remodelling, creating heterogeneous patches of well-vascularized tumor or acidic niches. Methods: Here, we present a multiscale mathematical model that captures the phenotypic, vascular, microenvironmental, and spatial heterogeneity which shapes acid-mediated invasion and immune escape over a biologically-realistic time scale. The model explores several immune escape mechanisms such as i) acid inactivation of immune cells, ii) competition for glucose, and iii) inhibitory immune checkpoint receptor expression (PD-L1). We also explore the efficacy of anti-PD-L1 and sodium bicarbonate buffer agents for treatment. To aid in understanding immune escape as a collective cellular phenomenon, we define immune escape in the context of six collective phenotypes (termed “meta-phenotypes”): Self-Acidify, Mooch Acid, PD-L1 Attack, Mooch PD-L1, Proliferate Fast, and Starve Glucose. Results: Fomenting a stronger immune response leads to initial benefits (additional cytotoxicity), but this advantage is offset by increased cell turnover that leads to accelerated evolution and the emergence of aggressive phenotypes. This creates a bimodal therapy landscape: either the immune system should be maximized for complete cure, or kept in check to avoid rapid evolution of invasive cells. These constraints are dependent on heterogeneity in vascular context, microenvironmental acidification, and the strength of immune response. Discussion: This model helps to untangle the key constraints on evolutionary costs and benefits of three key phenotypic axes on tumor invasion and treatment: acid-resistance, glycolysis, and PD-L1 expression. The benefits of concomitant anti-PD-L1 and buffer treatments is a promising treatment strategy to limit the adverse effects of immune escape

Recombination Line vs. Forbidden Line Abundances in Planetary Nebulae

Recombination lines (RLs) of C II, N II, and O II in planetary nebulae (PNs) have been found to give abundances that are much larger in some cases than abundances from collisionally-excited forbidden lines (CELs). The origins of this abundance discrepancy are highly debated. We present new spectroscopic observations of O II and C II recombination lines for six planetary nebulae. With these data we compare the abundances derived from the optical recombination lines with those determined from collisionally-excited lines. Combining our new data with published results on RLs in other PNs, we examine the discrepancy in abundances derived from RLs and CELs. We find that there is a wide range in the measured abundance discrepancy Delta(O+2) = log O+2(RL) - log O+2(CEL), ranging from approximately 0.1 dex up to 1.4 dex. Most RLs yield similar abundances, with the notable exception of O II multiplet V15, known to arise primarily from dielectronic recombination, which gives abundances averaging 0.6 dex higher than other O II RLs. We compare Delta(O+2) against a variety of physical properties of the PNs to look for clues as to the mechanism responsible for the abundance discrepancy. The strongest correlations are found with the nebula diameter and the Balmer surface brightness. An inverse correlation of Delta(O+2) with nebular density is also seen. Similar results are found for carbon in comparing C II RL abundances with ultraviolet measurements of C III].Comment: 48 pages, 14 figures, accepted for publication in the Astrophysical Journal Supplemen

Immunosuppressive niche engineering at the onset of human colorectal cancer

The evolutionary dynamics of tumor initiation remain undetermined, and the interplay between neoplastic cells and the immune system is hypothesized to be critical in transformation. Colorectal cancer (CRC) presents a unique opportunity to study the transition to malignancy as pre-cancers (adenomas) and early-stage cancers are frequently resected. Here, we examine tumor-immune eco-evolutionary dynamics from pre-cancer to carcinoma using a computational model, ecological analysis of digital pathology data, and neoantigen prediction in 62 patient samples. Modeling predicted recruitment of immunosuppressive cells would be the most common driver of transformation. As predicted, ecological analysis reveals that progressed adenomas co-localized with immunosuppressive cells and cytokines, while benign adenomas co-localized with a mixed immune response. Carcinomas converge to a common immune “cold” ecology, relaxing selection against immunogenicity and high neoantigen burdens, with little evidence for PD-L1 overexpression driving tumor initiation. These findings suggest re-engineering the immunosuppressive niche may prove an effective immunotherapy in CRC

Mathematical Models of Tumor Growth and Therapy

A number of mathematical models of cancer growth and treatment are presented. The most significant model presented is of the interactions between a growing tumor and the immune system. The equations and parameters of the model are based on experimental and clinical results from published studies. The model includes the primary cell populations involved in effector-T-cell-mediated tumor killing: regulatory T cells, helper T cells, and dendritic cells. A key feature is the inclusion of multiple mechanisms of immunosuppression through the main cytokines and growth factors mediating the interactions between the cell populations. Decreased access of effector cells to the tumor interior with increasing tumor size is accounted for.The model is applied to tumors of different growth rates and antigenicities to gauge the relative importance of the various immunosuppressive mechanisms in a tumor. The results suggest that there is an optimum antigenicity for maximal immune system effect. The immunosuppressive effects of further increases in antigenicity outweigh the increase in tumor cell control due to larger populations of tumor-killing effector T cells. The model is applied to situations involving cytoreductive treatment, specifically chemotherapy and a number of immunotherapies. The results how that for some types of tumors, the immune system is able to remove any tumor cells remaining after the therapy is finished. In other cases, the immune system acts to prolong remission periods. A number of immunotherapies are found to be ineffective at removing a tumor burden alone, but offer significant improvement on therapeutic outcome when used in combination with chemotherapy.Two simplified classes of cancer models are also presented. A model of cellular metabolism is formulated. The goal of the model is to understand the differences between normal cell and tumor cell metabolism. Several theories explaining the Crabtree Effect, hereby tumor cells reduce their aerobic respiration in the presence of glucose, have been put forth in the literature; the models test some of these theories, and examine their plausibility.A model of elastic tissue mechanics for a cylindrical tumor growing within a ductal membrane is used to determine the buildup of residual stress due to growth. These results can have possible implications for tumor growth rates and morphology

Mathematical models of tumor growth and therapy

A number of mathematical models of cancer growth and treatment are presented. The most significant model presented is of the interactions between a growing tumor and the immune system. The equations and parameters of the model are based on experimental and clinical results from published studies. The model includes the primary cell populations involved in effector-T-cell-mediated tumor killing: regulatory T cells, helper T cells, and dendritic cells. A key feature is the inclusion of multiple mechanisms of immunosuppression through the main cytokines and growth factors mediating the interactions between the cell populations. Decreased access of effector cells to the tumor interior with increasing tumor size is accounted for. The model is applied to tumors of different growth rates and antigenicities to gauge the relative importance of the various immunosuppressive mechanisms in a tumor. The results suggest that there is an optimum antigenicity for maximal immune system effect. The immunosuppressive effects of further increases in antigenicity out-weigh the increase in tumor cell control due to larger populations of tumor-killing effector T cells. The model is applied to situations involving cytoreductive treatment, specifically chemotherapy and a number of immunotherapies. The results show that for some types of tumors, the immune system is able to remove any tumor cells remaining after the therapy is finished. In other cases, the immune system acts to prolong remission periods. A number of immunotherapies are found to be ineffective at removing a tumor burden alone, but offer significant improvement on therapeutic outcome when used in combination with chemotherapy. Two simplified classes of cancer models are also presented. A model of cellular metabolism is formulated. The goal of the model is to understand the differences between normal cell and tumor cell metabolism. Several theories explaining the Crabtree Effect, whereby tumor cells reduce their aerobic respiration in the presence of glucose, have been put forth in the literature; the models test some of these theories, and examine their plausibility. A model of elastic tissue mechanics for a cylindrical tumor growing within a ductal membrane is used to determine the buildup of residual stress due to growth. These results can have possible implications for tumor growth rates and morphology

Driven damped oscillator

Knowledge in basic physicsThis Demonstration shows the movement of a damped driven mass-spring system, as well as a plot of the solutionComponente Curricular::Educação Superior::Ciências Exatas e da Terra::FísicaComponente Curricular::Ensino Médio::Físic

Driven damped oscillator

Knowledge in basic physicsThis Demonstration shows the movement of a damped driven mass-spring system, as well as a plot of the solutionComponente Curricular::Educação Superior::Ciências Exatas e da Terra::FísicaComponente Curricular::Ensino Médio::Físic

Non-sinusoidal oscillation: a balloon on a string

Educação Superior::Ciências Exatas e da Terra::MatemáticaPicture a buoyant balloon trailing a string with some mass per unit length. As the balloon rises, more string is lifted off the floor and the weight of the balloon-string system increases. As the balloon sinks, string returns to the floor and the weight of the balloon-string system decreases. In effect, the mass of the system depends on its positio

The Vibrating String

Mechanics lawsUsing the locators, you can construct approximations to a polynomial of arbitrary degree or a piecewise continuous function on the interval 0 to π. The trigger starts the solution with no initial velocity and shows the evolution of the string as a function of time. This solution is built through the so-called d'Alembert solutions, which are a superposition of left and right traveling waves. The construction of these solutions can be explicitly demonstrated by only plotting right or left traveling waves (better seen on a larger interval). The evolving string is the superposition of both waves. The time evolutions of the first three Fourier modes of the solutions are shown on the left of the plotComponente Curricular::Educação Superior::Ciências Exatas e da Terra::Físic