Mathematical Model of the Effect of Interstitial Fluid Pressure on Angiogenic Behavior in Solid Tumors

We present a mathematical model for the concentrations of proangiogenic and antiangiogenic growth factors, and their resulting balance/imbalance, in host and tumor tissue. In addition to production, diffusion, and degradation of these angiogenic growth factors (AGFs), we include interstitial convection to study the locally destabilizing effects of interstitial fluid pressure (IFP) on the activity of these factors. The molecular sizes of representative AGFs and the outward flow of interstitial fluid in tumors suggest that convection is a significant mode of transport for these molecules. The results of our modeling approach suggest that changes in the physiological parameters that determine interstitial fluid pressure have as profound an impact on tumor angiogenesis as those parameters controlling production, diffusion, and degradation of AGFs. This model has predictive potential for determining the angiogenic behavior of solid tumors and the effects of cytotoxic and antiangiogenic therapies on tumor angiogenesis

Marcinkiewicz interpolation theorems for Orlicz and Lorentz gamma spaces

This research was supported in part by NSERC grant A4021, an USRA grant from NSERC, grant MSM 0021620839 of the Czech Ministry of Education, grants 201/07/0388 and 201/08/0383 of the Grant Agency of the Czech Republic, NATO grant PST.CLG.978798, Leverhulme Trust Grant n.F/00407/E and by the Necas Center for Mathematical Modelling project no. LC06052 financed by the Czech Ministry of Education

Combination of Chemotherapy and Antiangiogenic Therapies: A Mathematical Modelling Approach

A brief introduction to cancer biology and treatment is presented with a focus on current clinical advances in the delivery of chemotherapy and antiangiogenic therapies. Mathematical oncology is then surveyed with summaries of various models of tumor growth, tumor angiogenesis and other relevant biological entities such as angiogenic growth factors. Both strictly time-dependent ordinary differential equation (ODE)-based and spatial partial differential equation (PDE)-based models are considered. These biological models are first developed into an ODE model where various treatment options can be compared including different combinations of drugs and dosage schedules. This model gives way to a PDE model that includes the spatially heterogeneous blood vessel distribution found in tumors, as well as angiogenic growth factor imbalances. This model is similarly analyzed and implications are summarized. Finally, including the effects of interstitial fluid pressure into an angiogenic activity model is performed. This model displays the importance of factor convection on the angiogenic behaviour of tumours

Mathematical models for angiogenic, metabolic and apoptotic processes in tumours

This doctoral thesis outlines a body of research within the field of mathematical oncology that focusses on the inclusion of microenvironmental factors in mathematical models for solid tumour behaviour. These models primarily address tumour angiogenesis signalling, tumour metabolism and inducing apoptosis via novel treatment combinations. After a brief introduction in Chapter 1, background material pertinent to cancer biology and treatment is provided in Chapter 2. This chapter details tumour angiogenesis, tumour metabolism and various cancer treatments. This is followed in Chapter 3 by a survey of mathematical models that directly influence my work including summaries of models for relevant tumour entities such as angiogenic growth factors, interstitial fluid pressure, tu- mour metabolism and acidosis. The progression of topics in these two preliminary chapters emulate the ordering of the original research presented in Chapters 4–6. Chapter 4 presents an angiogenic growth factor (AGF) model used to study the impact of transport processes on tumour angiogenic behaviour. The study focusses on a coupled system of diffusion-convection-reaction equations that establish the role of convection in determining relative concentrations of proangiogenic and antiangiogenic growth factors, and hence the angiogenic behaviour, in solid tumours. The effect of various cancer treat- ments, such as chemotherapy and antiangiogenic drugs, that can alter tumour properties are considered through parameter analyses. The angiogenesis that results from angiogenic stimulation provides tumours with an oxygen and nutrient supply required for metabolism. Chapter 5 quantifies the benefit of metabolic symbiosis on tumour ATP production. A diffusion-reaction model of cell metabolism in the hypoxic tissue surrounding a leaky tumour blood vessel is developed that includes both lactate and glucose fuelled respiration along with glycolysis. We can then study the energetic effects of cancer cells’ metabolic behaviour, such as the Warburg effect and metabolic symbiosis. A model coupling these metabolic behaviours with acidosis is also analyzed that includes the effects of extracel- lular buffers. These models can be used to investigate metabolic inhibitor treatments by knocking out specific model parameters and buffering therapies. While treatment effects are considered in the previous chapters via parameter alter- ation, Chapter 6 explicitly models concentrations of molecular inhibitors and chemotherapy nanoparticles. These treatments are coupled to a model for apoptotic protein expression to evaluate strategies for counteracting chemoresistance in triple-negative breast cancer. The protein model is then used to predict cell viability, which indicates the efficacy of schedules for treatment combinations. The model prediction of post-chemotherapy inhibitor outper- forming pre-chemotherapy and simultaneous application is verified by further experiments. Finally, a summary of the contributions to the field of mathematical oncology and suggested future directions are indicated in the final chapter

Use of Valacyclovir for the treatment of cytomegalovirus antigenemia after hematopoietic stem cell transplantation

10.1186/s12878-015-0028-2BMC Hematology151

Reckoning up: sexual harassment and violence in the neoliberal university

This paper situates sexual harassment and violence in the neoliberal university. Using data from a ‘composite ethnography’ representing twelve years of research, I argue that institutional inaction on these issues reflects how they are ‘reckoned up’ in the context of gender and other structures. The impact of disclosure is projected in market terms: this produces institutional airbrushing which protects both the institution and those (usually privileged men) whose welfare is bound up with its success. Staff and students are differentiated by power/value relations, which interact with gender and intersecting categories. Survivors are often left with few alternatives to speaking out in the ‘outrage economy’ of the corporate media: however, this can support institutional airbrushing and bolster punitive technologies. I propose the method of Grounded Action Inquiry, implemented with attention to Lorde’s work on anger, as a parrhesiastic practice of ‘speaking in’ to the neoliberal institution

How are normal sleeping controls selected? A systematic review of cross-sectional insomnia studies, and a standardised method to select healthy controls for sleep research

There appears to be some inconsistency in how normal sleepers (controls) are selected and screened for participation in research studies for comparison with insomnia patients. The purpose of the current study is to assess and compare methods of identifying normal sleepers in insomnia studies, with reference to published standards. We systematically reviewed the literature on insomnia patients which included control subjects. The resulting 37 articles were systematically reviewed with reference to the five criteria for normal sleep specified by Edinger et al. (2004). In summary, these criteria are: evidence of sleep disruption; sleep scheduling; general health; substance/medication use; and other sleep disorders. We found sleep diaries, PSG, and clinical screening examinations to be widely used with both control subjects and insomnia participants. However, there are differences between research groups in the precise definitions applied to the components of normal sleep. We found that none of reviewed studies applied all of the Edinger et al. criteria, and 16% met four criteria. In general, screening is applied most rigorously at the level of a clinical disorder, whether physical, psychiatric, or sleep. While the Edinger et al. criteria seem to be applied in some form by most researchers, there is scope to improve standards and definitions in this area. Ideally, different methods such as sleep diaries and questionnaires would be used concurrently with objective measures to ensure normal sleepers are identified, and descriptive information for control subjects would be reported. Here, we have devised working criteria and methods to be used for assessment of normal sleepers. This would help clarify the nature of the control group, in contrast to insomnia subjects and other patient groups

Allogeneic haematopoietic cell transplantation for extranodal natural killer/Tâ cell lymphoma, nasal type: a CIBMTR analysis

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/146342/1/bjh14879.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/146342/2/bjh14879_am.pd

Proceedings of the third international molecular pathological epidemiology (MPE) meeting

Molecular pathological epidemiology (MPE) is a transdisciplinary and relatively new scientific discipline that integrates theory, methods and resources from epidemiology, pathology, biostatistics, bioinformatics and computational biology. The underlying objective of MPE research is to better understand the etiology and progression of complex and heterogeneous human diseases with the goal of informing prevention and treatment efforts in population health and clinical medicine. Although MPE research has been commonly applied to investigating breast, lung, and colorectal cancers, its methodology can be used to study most diseases. Recent successes in MPE studies include: 1) the development of new statistical methods to address etiologic heterogeneity; 2) the enhancement of causal inference; 3) the identification of previously unknown exposure-subtype disease associations; and 4) better understanding of the role of lifestyle/behavioral factors on modifying prognosis according to disease subtype. Central challenges to MPE include the relative lack of transdisciplinary experts, educational programs, and forums to discuss issues related to the advancement of the field. To address these challenges, highlight recent successes in the field, and identify new opportunities, a series of MPE meetings have been held at the Dana-Farber Cancer Institute in Boston, MA. Herein, we share the proceedings of the Third International MPE Meeting, held in May 2016 and attended by 150 scientists from 17 countries. Special topics included integration of MPE with immunology and health disparity research. This meeting series will continue to provide an impetus to foster further transdisciplinary integration of divergent scientific fields

Gene-based analysis of regulatory variants identifies 4 putative novel asthma risk genes related to nucleotide synthesis and signaling

Background Hundreds of genetic variants are thought to contribute to variation in asthma risk by modulating gene expression. Methods that increase the power of genome-wide association studies (GWASs) to identify risk-associated variants are needed. Objective We sought to develop a method that aggregates the evidence for association with disease risk across expression quantitative trait loci (eQTLs) of a gene and use this approach to identify asthma risk genes. Methods We developed a gene-based test and software package called EUGENE that (1) is applicable to GWAS summary statistics; (2) considers both cis- and trans-eQTLs; (3) incorporates eQTLs identified in different tissues; and (4) uses simulations to account for multiple testing. We applied this approach to 2 published asthma GWASs (combined n\ua0=\ua046,044) and used mouse studies to provide initial functional insights into 2 genes with novel genetic associations. Results We tested the association between asthma and 17,190 genes that were found to have cis- and/or trans-eQTLs across 16 published eQTL studies. At an empirical FDR of 5%, 48 genes were associated with asthma risk. Of these, for 37, the association was driven by eQTLs located in established risk loci for allergic disease, including 6 genes not previously implicated in disease cause (eg, LIMS1, TINF2, and SAFB). The remaining 11 significant genes represent potential novel genetic associations with asthma. The association with 4 of these replicated in an independent GWAS: B4GALT3, USMG5, P2RY13, and P2RY14, which are genes involved in nucleotide synthesis or nucleotide-dependent cell activation. In mouse studies, P2ry13 and P2ry14—purinergic receptors activated by adenosine 5-diphosphate and UDP-sugars, respectively—were upregulated after allergen challenge, notably in airway epithelial cells, eosinophils, and neutrophils. Intranasal exposure with receptor agonists induced the release of IL-33 and subsequent eosinophil infiltration into the lungs. Conclusion We identified novel associations between asthma and eQTLs for 4 genes related to nucleotide synthesis/signaling and demonstrated the power of gene-based analyses of GWASs