Mathematical modeling of cancer cell migration - from in vitro to in vivo

Tumors has been the object of computational model studies for nearly five decades. The early models considered simple tumor growth based on nutrients, whereas models now can simulate from microscale gene expressions in cells to the larger scale tissue, and even a combination of micro and macroscale models in hybrid models. In this thesis we apply a continuum model to capture different mechanisms that cause tumor cells to move. More precisely, the interaction between different cells and the flowing fluid in tissue through forces are investigated upon. The first versions of the model attempt to capture behavior found in experimental work performed in controlled environments, and evolves to better align with how a realistic tumor may act. The first paper (Paper I) in this thesis formulates a two-phase model consisting of a tumor cell and interstitial fluid phase. It relies upon the experience gained from creeping flow in petroleum reservoirs with regards to the interaction forces and how fluid flow is described. The model in Paper 1 is motivated by the experimental work by Shields et al. 2007 that identifies a tumor cell migration mechanism called autologous chemotaxis. This means that due to interstitial fluid flow, tumor cells creates a chemical gradient in the flow direction of its own fruition, letting cancer cells migrate downstream. The second part of this thesis (Paper II & III) extends the two-phase model in Paper I to include a new mechanism. Paper II maintains autologous chemotaxis as a migration mechanism and introduces a new one, rheotaxis. Rheotaxis is considered a competing mechanism to chemotaxis in the study by Polacheck et al. 2011, where fluid flow imposes a stress on the cancer cells and causes them to migrate in the upstream direction. These two competing mechanisms are explored in a computational context in Paper II. After in-depth investigation into the different parameters in the model in Paper II, the model is extended to a two-dimensional domain. This allows for better visualization, while at the same time illustrating the potential of the model as a tool to explore how tumor cells may escape from the primary tumor to metastasize. In the next part (Paper IV & V) a new phase in introduced, resulting in a three-phase model. The new phase is a common component of both normal and cancerous tissue, namely fibroblast cells. In our model we look at tumor-associated fibroblasts (TAFs) which behave differently from their normal counterpart. Motivated by the experimental work by Gaggioli et al. 2007; Labernadie et al. 2017; Shieh et al. 2011, we investigate two different methods TAFs use to enhance tumor cell migration, in the presence of interstitial fluid flow (Paper IV). In Paper V the model is used in a 2D setting, showing that fibroblasts may lead cancer cells in a collective manner towards draining lymphatics as a means for metastasis. It is also suggested targeting fibroblast-cancer cell interaction as a method to decrease metastasis. In the last part (Paper VI) the three-phase model is used to elucidate that ECM structures within the tumor can cause heterogeneous interstitial fluid pressure based on preclinical data from xenograft models in Hansem et al. 2019. One important aspect of the computational model is to achieve a realistic interstitial fluid pressure and fluid velocity, which is measured in the experimental data. We achieve similar results with regards to the pressure under the various circumstances explored in Hansem et al. 2019, and give rise to heterogeneous migration pattern with possibility for formation of isolated islands of tumor cells

Internal Myxosporidian Infections of Some Fishes of the Okoboji Region

Protozoa of the order Myxosporidia are primarily parasites of fishes, and no major group of fishes is entirely free from infection. Apparently most species of Myxosporidia do not produce serious pathological changes. However, some of the most destructive diseases of fish, such as the wormy halibut of the Pacific coast of North America; the boil disease of barbel in European waters; and the twist disease of salmonoid fish, are caused by myxosporidian infection. These infections are often fatal and sometimes occur in epidemic form. The life history of the myxosporidia has been discussed by Kudo (1920, 1939). The present paper is primarily a report of a survey of myxosporidian parasites which occur in the internal organs of fishes of the Okoboji region

In silico investigations of intratumoral heterogeneous interstitial fluid pressure

Recent preclinical studies have shown that interstitial fluid pressure (IFP) within tumors can be heterogeneous Andersen et al. (2019). In that study tumors of two xenograft models, respectively, HL-16 cervical carcinoma and Panc-1 pancreatic carcinoma, were investigated. Significant heterogeneity in IFP was reported and it was proposed that this was associated with division of tissue into compartments separated by thick connective tissue bands for the HL-16 tumors and with dense collagen-rich extracellular matrix for the Panc-1 tumors. The purpose of the current work is to explore these experimental observations by using in silico generated tumor models. We consider a mathematical multiphase model which accounts for tumor cells, fibroblasts and interstitial fluid. The model has been trained to comply with experimental in vitro results reported in Shieh et al. (2011) which has identified autologous chemotaxis, ECM remodeling, and cell-fibroblast interaction as drivers for invasive tumor cell behavior. The in silico model is informed with parameters that characterize the leaky intratumoral vascular network, the peritumoral lymphatics which collect the fluid, and the density of ECM as represented through the hydraulic conductivity of the interstitial space. Heterogeneous distribution of solid stress may result in heterogeneous compression of blood vessels and, thus, heterogeneous vascular density inside the tumor. To mimic this we expose the in silico tumor to an intratumoral vasculature whose net effect of density of blood vesssels and vessel wall conductivity is varied through a 2D Gaussian variogram constrained such that the resulting IFPs lie within the range as reported from the preclinical study. The in silico cervical carcinoma model illustrates that sparse ECM was associated with uniform intratumoral IFP in spite of heterogeneous microvascular network, whereas compartment structures resulted in more heterogeneous IFP. Similarly, the in silico pancreatic model shows that heterogeneity in the microvascular network combined with dense ECM structure prevents IFP to even out and gives rise to heterogeneous IFP. The computer model illustrates how a heterogeneous invasive front might form where groups of tumor cells detach from the primary tumor and form isolated islands, a behavior which is natural to associate with metastatic propensity. However, unlike experimental studies, the current version of the in silico model does not show an association between metastatic propensity and elevated IFP.publishedVersio

Adaptive Laboratory Evolution of Antibiotic Resistance Using Different Selection Regimes Lead to Similar Phenotypes and Genotypes

Antibiotic resistance is a global threat to human health, wherefore it is crucial to study the mechanisms of antibiotic resistance as well as its emergence and dissemination. One way to analyze the acquisition of de novo mutations conferring antibiotic resistance is adaptive laboratory evolution. However, various evolution methods exist that utilize different population sizes, selection strengths, and bottlenecks. While evolution in increasing drug gradients guarantees high-level antibiotic resistance promising to identify the most potent resistance conferring mutations, other selection regimes are simpler to implement and therefore allow higher throughput. The specific regimen of adaptive evolution may have a profound impact on the adapted cell state. Indeed, substantial effects of the selection regime on the resulting geno- and phenotypes have been reported in the literature. In this study we compare the geno- and phenotypes of Escherichia coli after evolution to Amikacin, Piperacillin, and Tetracycline under four different selection regimes. Interestingly, key mutations that confer antibiotic resistance as well as phenotypic changes like collateral sensitivity and cross-resistance emerge independently of the selection regime. Yet, lineages that underwent evolution under mild selection displayed a growth advantage independently of the acquired level of antibiotic resistance compared to lineages adapted under maximal selection in a drug gradient. Our data suggests that even though different selection regimens result in subtle genotypic and phenotypic differences key adaptations appear independently of the selection regime

Future Perspectives in Spinal Cord Repair: Brain as Saviour? TSCI with Concurrent TBI: Pathophysiological Interaction and Impact on MSC Treatment

Traumatic spinal cord injury (TSCI), commonly caused by high energy trauma in young active patients, is frequently accompanied by traumatic brain injury (TBI). Although combined trauma results in inferior clinical outcomes and a higher mortality rate, the understanding of the pathophysiological interaction of co-occurring TSCI and TBI remains limited. This review provides a detailed overview of the local and systemic alterations due to TSCI and TBI, which severely affect the autonomic and sensory nervous system, immune response, the blood-brain and spinal cord barrier, local perfusion, endocrine homeostasis, posttraumatic metabolism, and circadian rhythm. Because currently developed mesenchymal stem cell (MSC)-based therapeutic strategies for TSCI provide only mild benefit, this review raises awareness of the impact of TSCI-TBI interaction on TSCI pathophysiology and MSC treatment. Therefore, we propose that unravelling the underlying pathophysiology of TSCI with concomitant TBI will reveal promising pharmacological targets and therapeutic strategies for regenerative therapies, further improving MSC therapy

Early and Differential Diagnosis of Dementia and Mild Cognitive Impairment Design and Cohort Baseline Characteristics of the German Dementia Competence Network

Background: The German Dementia Competence Network (DCN) has established procedures for standardized multicenter acquisition of clinical, biological and imaging data, for centralized data management, and for the evaluation of new treatments. Methods: A longitudinal cohort study was set up for patients with mild cognitive impairment (MCI), patients with mild dementia and control subjects. The aims were to establish the diagnostic, differential diagnostic and prognostic power of a range of clinical, laboratory and imaging methods. Furthermore, 2 clinical trials were conducted with patients suffering from MCI and mild to moderate Alzheimer's Disease (AD). These trials aimed at evaluating the efficacy and safety of the combination of galantamine and memantine versus galantamine alone. Results: Here, we report on the scope and projects of the DCN, the methods that were employed, the composition and flow within the diverse groups of patients and control persons and on the clinical and neuropsychological baseline characteristics of the group of 2,113 subjects who participated in the observational and clinical trials. Conclusion: These data have an impact on the procedures for the early and differential clinical diagnosis of dementias, the current standard treatment of AD as well as on future clinical trials in AD. Copyright (C) 2009 S. Karger AG, Base

Validation of reference genes for expression analysis in a murine trauma model combining traumatic brain injury and femoral fracture

Systemic and local posttraumatic responses are often monitored on mRNA expression level using quantitative real-time PCR (qRT-PCR), which requires normalisation to adjust for confounding sources of variability. Normalisation requests reference (housekeeping) genes stable throughout time and divergent experimental conditions in the tissue of interest, which are crucial for a reliable and reproducible gene expression analysis. Although previous animal studies analysed reference genes following isolated trauma, this multiple-trauma gene expression analysis provides a notable study analysing reference genes in primarily affected (i.e. bone/fracture callus and hypothalamus) and secondarily affected organs (i.e. white adipose tissue, liver, muscle and spleen), following experimental long bone fracture and traumatic brain injury. We considered tissue-specific and commonly used top-ranked reference candidates from different functional groups that were evaluated applying the established expression stability analysis tools NormFinder, GeNorm, BestKeeper and RefFinder. In conclusion, reference gene expression in primary organs is highly time point as well as tissue-specific, and therefore requires careful evaluation for qRT-PCR analysis. Furthermore, the general application of Ppia, particularly in combination with a second reference gene, is strongly recommended for the analysis of systemic effects in the case of indirect trauma affecting secondary organs through local and systemic pathophysiological responses

Investigating the Direct Meltwater Effect in Terrestrial Oxygenâ Isotope Paleoclimate Records Using an Isotopeâ Enabled Earth System Model

Variations in terrestrial oxygenâ isotope reconstructions from ice cores and speleothems have been primarily attributed to climatic changes of surface air temperature, precipitation amount, or atmospheric circulation. Here we demonstrate with the fully coupled isotopeâ enabled Community Earth System Model an additional process contributing to the oxygenâ isotope variations during glacial meltwater events. This process, termed â the direct meltwater effect,â involves propagating large amounts of isotopically depleted meltwater throughout the hydrological cycle and is independent of climatic changes. We find that the direct meltwater effect can make up 15â 35% of the δ18O signals in precipitation over Greenland and eastern Brazil for large freshwater forcings (0.25â 0.50 sverdrup (106 m3/s)). Model simulations further demonstrate that the direct meltwater effect increases with the magnitude and duration of the freshwater forcing and is sensitive to both the location and shape of the meltwater. These new modeling results have important implications for past climate interpretations of δ18O.Key PointsA portion of the δ18O signal in landâ based paleoclimate proxies can be attributed to the direct meltwater effect instead of climatic changesThe direct meltwater effect can make up 15â 35% of the δ18O signals in precipitation in Greenland and eastern Brazil for large meltwater eventsThe direct meltwater effect increases with the magnitude and duration of the freshwater forcing and is sensitive to location and shape dependentPeer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141374/1/grl56782_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/141374/2/grl56782-sup-0001-Supporting_Information.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/141374/3/grl56782.pd

Hydroclimate footprint of pan-Asian monsoon water isotope during the last deglaciation

Oxygen isotope speleothem records exhibit coherent variability over the pan-Asian summer monsoon (AM) region. The hydroclimatic representation of these oxygen isotope records for the AM, however, has remained poorly understood. Here, combining an isotope-enabled Earth system model in transient experiments with proxy records, we show that the widespread AM delta O-18(c) signal during the last deglaciation (20 to 11 thousand years ago) is accompanied by a continental-scale, coherent hydroclimate footprint, with spatially opposite signs in rainfall. This footprint is generated as a dynamically coherent response of the AM system primarily to meltwater forcing and secondarily to insolation forcing and is further reinforced by atmospheric teleconnection. Hence, widespread delta O-18(p) depletion in the AM region is accompanied by a northward migration of the westerly jet and enhanced southwesterly monsoon wind, as well as increased rainfall from South Asia (India) to northern China but decreased rainfall in southeast China