Design, assessment, and in vivo evaluation of a computational model illustrating the role of CAV1 in CD4+ T-lymphocytes

Caveolin-1 (CAV1) is a vital scaffold protein heterogeneously expressed in both healthy and malignant tissue. We focus on the role of CAV1 when overexpressed in T-cell leukemia. Previously, we have shown that CAV1 is involved in cell-to-cell communication, cellular proliferation, and immune synapse formation; however, the molecular mechanisms have not been elucidated. We hypothesize that the role of CAV1 in immune synapse formation contributes to immune regulation during leukemic progression, thereby warranting studies of the role of CAV1 in CD4+ T-cells in relation to antigen-presenting cells. To address this need, we developed a computational model of a CD4+ immune effector T-cell to mimic cellular dynamics and molecular signaling under healthy and immunocompromised conditions (i.e., leukemic conditions). Using the Cell Collective computational modeling software, the CD4+ T-cell model was constructed and simulated under CAV1+/+, CAV1+/−, and CAV1−/− conditions to produce a hypothetical immune response. This model allowed us to predict and examine the heterogeneous effects and mechanisms of CAV1 in silico. Experimental results indicate a signature of molecules involved in cellular proliferation, cell survival, and cytoskeletal rearrangement that were highly affected by CAV1 knock out. With this comprehensive model of a CD4+ T-cell, we then validated in vivo protein expression levels. Based on this study, we modeled a CD4+ T-cell, manipulated gene expression in immunocompromised versus competent settings, validated these manipulations in an in vivo murine model, and corroborated acute T-cell leukemia gene expression profiles in human beings. Moreover, we can model an immunocompetent versus an immunocompromised microenvironment to better understand how signaling is regulated in patients with leukemia

A Mathematical Study Of Two Retroviruses, Hiv And Htlv-i

In this thesis, we examine epidemiological models of two different retroviruses, which infect the human body. The two viruses under study are HIV or the human immunodefiency virus and HTLV-I, which is the human T lymphotropic virus type I. A retrovirus is a virus, which injects its RNA into the host, rather than it\u27s DNA. We will study each of the different mathematical models for each of the viruses separately. Then we use MATLAB-SIMULINK to analyze the models by studying the reproductive numbers in each case and the disease progression by examining the graphs. In Chapter 1, we mention basic ideas associated with HIV and HTLV-I. In Chapter 2 some of the basic mathematical model of epidemiology is presented. Chapter 3 is devoted to a model describing the intra-host dynamics of HIV. Here, we take into account how HIV infects and replicates in the CD4+ T cells. The model studied in this thesis examines the difference between cells, which are susceptible to the virus, and cells, which are not susceptible. Through the graphs associated with this model, we are able to see how this difference affects disease progression. In Chapter 4, we examine the effect of HTLV-I virus on human body. The HTLV-I virus causes a chronic infection in humans and may eventually lead to other diseases. In particular, the development of Adult T-cell Leukemia or ATL is studied in this thesis. The T-cell dynamics and progression to ATL is described using a mathematical model with coupled differential equations. Using mathematical analysis and SIMULINK, we obtain results on stability, asymptotic stability and the manner of progression of the disease. In Chapter 5 and appendices, we mention our inference and the MATLAB-SIMULINK codes used in this thesis, so that a reader can verify the details of the work carried out in this thesis

Translational Research in Cancer

Translational research in oncology benefits from an abundance of knowledge resulting from genome-scale studies concerning the molecular pathways involved in tumorigenesis. Translational oncology represents a bridge between basic research and clinical practice in cancer medicine. The vast majority of cancer cases are due to environmental risk factors. Many of these environmental factors are controllable lifestyle choices. Experimental cancer treatments are studied in clinical trials to compare the proposed treatment to the best existing treatment through translational research. The key features of the book include: 1) New screening for the development of radioprotectors: radioprotection and anti-cancer effect of β-Glucan (Enterococcus faecalis) 2) Translational perspective on hepatocellular carcinoma 3) Brachytherapy for endometrial cancer 4) Discovery of small molecule inhibitors for histone methyltransferases in cance

Evidence Report: Risk of Acute Radiation Syndromes Due to Solar Particle Events

Crew health and performance may be impacted by a major solar particle event (SPE), multiple SPEs, or the cumulative effect of galactic cosmic rays (GCR) and SPEs. Beyond low-Earth orbit, the protection of the Earth's magnetosphere is no longer available, such that increased shielding and protective mechanisms are necessary in order to prevent acute radiation sickness and impacts to mission success or crew survival. While operational monitoring and shielding are expected to minimize radiation exposures, there are EVA scenarios outside of low-Earth orbit where the risk of prodromal effects, including nausea, vomiting, anorexia, and fatigue, as well as skin injury and depletion of the blood-forming organs (BFO), may occur. There is a reasonable concern that a compromised immune system due to high skin doses from a SPE or due to synergistic space flight factors (e.g., microgravity) may lead to increased risk to the BFO. The primary data available at present are derived from analyses of medical patients and persons accidentally exposed to acute, high doses of low-linear energy transfer (LET) (or terrestrial) radiation. Data more specific to the space flight environment must be compiled to quantify the magnitude of increase of this risk and to develop appropriate protection strategies. In particular, information addressing the distinct differences between solar proton exposures and terrestrial exposure scenarios, including radiation quality, dose-rate effects, and non-uniform dose distributions, is required for accurate risk estimation

Human and computational models of atopic dermatitis:A review and perspectives by an expert panel of the International Eczema Council

Atopic dermatitis (AD) is a prevalent disease worldwide and is associated with systemic comorbidities representing a significant burden on patients, their families, and society. Therapeutic options for AD remain limited, in part because of a lack of well-characterized animal models. There has been increasing interest in developing experimental approaches to study the pathogenesis of human AD in vivo, in vitro, and in silico to better define pathophysiologic mechanisms and identify novel therapeutic targets and biomarkers that predict therapeutic response. This review critically appraises a range of models, including genetic mutations relevant to AD, experimental challenge of human skin in vivo, tissue culture models, integration of “omics” data sets, and development of predictive computational models. Although no one individual model recapitulates the complex AD pathophysiology, our review highlights insights gained into key elements of cutaneous biology, molecular pathways, and therapeutic target identification through each approach. Recent developments in computational analysis, including application of machine learning and a systems approach to data integration and predictive modeling, highlight the applicability of these methods to AD subclassification (endotyping), therapy development, and precision medicine. Such predictive modeling will highlight knowledge gaps, further inform refinement of biological models, and support new experimental and systems approaches to AD

Mathematical Analysis of Tumor-Immune Interactions based on Michaelis-Menten Kinetics with CAR-T Immunotherapy

In this paper, we study the dynamics of tumor growth under immune system surveillance with a mathematical model based on Michaelis-Menten kinetics. In our three-component differential equation system, we accounted for the factor of immunotherapy, its effect on tumor population, and synergy with immune cells. CAR-T, or Chimeric Antigen Receptor T cell, therapy is chosen to be incorporated into the model as a form of immunotherapy due to its promising clinical applications. The stability of the steady-state equilibria of the system is analyzed with parameters from referred sources, and the various patterns of dynamics are demonstrated through numerical simulations. The analysis shows different outcomes of the tumor population given different parameters and initial values, which provides insights into the clinical practicability of CAR-T treatment. Earlier stages of tumor progression at which therapy begins, a critical time frame of therapeutic injection to prevent tumor relapse, and improvement of antigen affinity of the receptors are found to be factors that can enhance CAR-T efficiency and cancer patients' life span. For further analysis, we also propose an expanded system to investigate the potential off-target toxic effects of CAR-T cells on normal host cells. Our instability results and oscillating numerical patterns  suggest non-cooperation between the cell types, posing potential clinical challenges to the therapy

Hodgkin's Lymphoma

Hodgkin's Lymphoma is the book consisting of 11 chapters: Recent insights into the biology of Hodgkin's lymphoma, including historical aspects, epidemiology, pathophysiology, genetic defects, and prognostic indicators are explained in the intro chapters. After a translational chapter from tumor microenvironment to immunotherapeutic approach, treatment of early stage, advanced, and refractory Hodgkin's lymphoma are explained in the following chapters. MALT lymphoma and adverse effects of chemotherapy and radiotherapy in the affected patients are discussed in the subsequent chapters, while the final chapter is focused on survivorship in Hodgkin's lymphoma. The book is intended to present recent advances in the pathophysiology of Hodgkin's lymphoma as well as practical approach to diagnosis and management in clinical practice, which is hoped to be welcomed by the physicians, who wish to learn more about Hodgkin's lymphoma

A systems genetics approach to the characterization of differential low dose radiation responses in BXD recombinant inbred mice

High doses of radiation (HDR) are clearly detrimental to human health, but relatively little is known about the health consequences following exposure to low doses of radiation (LDR, \u3c10cGy). Understanding the risks associated with LDR is of great importance to the general public due to the recent dramatic increase in diagnostic radiological imaging. While HDR clearly suppress immune function, there is evidence that LDR can be immunostimulatory. Within the organism, defining the consequences of LDR is further complicated by the impact of genetic background, particularly in systems such as the immune system for which both radiosensitivity and genetic effects are profound. We addressed the issue of genetic susceptibility to LDR using the immune system as a target system and treated the LDR response as a complex trait analyzed using a systems genetics framework. Using the BXD recombinant inbred strain mouse panel as a genetic reference population allowed us to address the radiation response within the context of natural genetic variation. Our overarching hypothesis is that, within a population, the immunological effects of LDR exposure depend in part on the individual’s baseline immunoprofile and gene expression which are ultimately dependent upon genetic background. We began by establishing the immunophenotypic variation (i.e., T:B cell ratio, CD4:CD8 ratio) within the BXD panel and used baseline spleen transcriptome profiling to identify putative candidate genes controlling these traits, specifically Acp1 and Ptprk for CD4:CD8 ratio. The same set of BXD strains was exposed to LDR (10cGy gamma radiation) to determine effects on immune function and oxidative stress. LDR significantly enhanced neutrophil phagocytosis in a manner that was independent of genetic background. In contrast, genetic background significantly impacted LDR-induced changes in spleen superoxide dismutase activity. By integrating these results with our previous analyses of BXD RI strains, we have demonstrated that baseline expression of Sod2 correlates with LDR-induced SOD activity, and baseline CD4:CD8 ratio is inversely correlated with LDR-induced neutrophil phagocytosis. In addition, spleen transcriptomic data from the BXD parental strains further highlighted the impact of genetic background on LDR responses. These data provide the groundwork for predicting LDR responses using baseline expression, immunophenotypes, and/or genotype

Development and Clinical Implementation of Next-Generation CAR-T cell Manufacture Methodology

Chimeric Antigen Receptor (CAR) T-cell therapies for haematological malignancy have revolutionised the treatment of patients with relapsed/refractory B-cell cancers. The scope of these therapies in other haematological and even solid cancers holds much promise for the future. However, there are several major bottlenecks for delivery of these novel therapies: availability of academic clinical trials for CAR T-cell therapies is limited in the UK and in particular, the paucity of manufacturing slots means that the majority of potentially eligible patients cannot access these therapies. Streamlining the manufacturing process and pipeline to enhance manufacturing capability and scalability would begin to address this challenging issue. Secondly, a large proportion of patients referred for consideration of autologous CAR T-cell therapy are heavily pre-treated with chemotherapy and their T-cell populations for harvest are often numerically (and in some cases functionally) compromised. Referring patients early, prior to several lines of toxic chemotherapy would be optimal, but this is logistically challenging. Another approach would be to review apheresis practice and work to enhance T-cell collection at the front end. Lastly, these new therapies are associated with a constellation of unique potential side effects. The clinical delivery of bespoke gene-modified T-cell therapies in routine Haemato-Oncology Units requires a paradigm shift in medical, nursing, pharmacy and stem cell lab care pathways. This project undertakes to address these issues through the initiation and delivery of an academic study of autologous CD19 CAR T-cells for relapsed/refractory acute lymphoblastic leukaemia (B-ALL). This project will (1) investigate and establish a streamlined manufacturing platform for CAR T-cell manufacture for the UCL CAR T-cell programme; (2) explore the single-centre apheresis practice at UCLH to define a model/guideline for successful CAR T-cell apheresis and (3) to begin to establish the clinical infrastructure required to deliver these therapies ‘routinely’ at a large central London teaching hospital