Parallelization of a Three-Dimensional Full Multigrid Algorithm to Simulate Tumor Growth

We present the performance gains of an openMP implementation of a fully adaptive nonlinear full multigrid (FMG) algorithm to simulate three-dimensional multispecies desmoplastic tumor growth on computer systems of varying processing capabilities. The FMG algorithm is applied to solve a recently published thermodynamic mixture model that uses a diffuse interface approach with fourth-order reaction-advection-diffusion PDEs (Cahn-Hilliard-type equations) that are coupled, nonlinear, and numerically stiff. The model includes multiple cell species and extracellular matrix (ECM), with adhesive and elastic energy contributions in chemical potential terms, as well as including blood and lymphatic vessels represented as continuous vasculatures. Advection-reaction-diffusion PDEs are employed for the cell-ECM components, whereas reaction-diffusion/advection-reaction-diffusion PDEs are used for the cell substrate and vessel species. This desmoplastic tumor model exhibits an extracellular matrix rich tumor microenvironment and may be beneficial when applied to studying fibrotic tumors such as pancreatic adenocarcinoma. After adding openMP to the FMG code, the program was run for a single time step on a i 7-4600U processor in single core and dual code configurations. Timing macros were used to determine how effective openMP improved the performance of the program from the single core to dual code execution. The model was then timed on a “FAT Node” of the Cardinal Research Cluster (CRC) for 1, 2, 4, 6, 8, 16, and 32 cores. The resulting data indicate that, relative to a single core system, openMP applied to the FMG algorithm renders the initial time step 1. 7 times faster on a dual core system and approximately 3 times faster on a quad core system. However, overhead between processing cores overtakes the benefits of using openMP on CPUs with more than 8 cores. Although using openMP demonstrates modest improvement in performance, this study indicates that further parallelization is required to achieve model performance that will yield practical benefit

Toiminimen kirjanpito

Opinnäytetyön tavoitteena oli selvittää mitä osaamista tarvitaan toiminimen kirjanpidon toteuttamiseen. Työn toimeksiantajana toimi tamperelainen hyvinvointialan yrittäjä, joka ei ole toiminnastaan alv-velvollinen. Työn tarkoituksena oli kouluttaa tekijä peruskirjanpidon hoitamiseen. Tarkoituksena oli, että toimeksiantajan kirjanpito sekä veroilmoituksen täyttäminen ovat vuodesta 2017 eteenpäin opinnäytetyön tekijän vastuulla. Työn teoriaosuudessa keskityttiin kirjanpidollisiin peruskäsitteisiin toimeksiantajan elinkeinotoiminnan luonne huomioiden. Verotuksen osuudessa keskityttiin yritystulon verottamiseen yleensä ja esiteltiin ammatinharjoittajan veroilmoitus siltä osin, kun se toimeksiantajan yritystoiminta huomioiden oli tarpeellista. Sen lisäksi, että tekijä perehdytti itsensä alusta alkaen kirjanpidon maailmaan, teki työstä työlään erityisesti edellisvuosien kirjanpitomateriaaliin tutustuminen, sopivan kirjanpito-ohjelman etsiminen ja juoksevan kirjanpidon suorittaminen. Opinnäyteyön tavoite toteutui, sillä työn tekijällä on nyt tarvittava osaaminen kirjanpito-ohjelman käyttämiseen sekä juoksevan kirjanpidon hoitamiseen. Kirjanpidollisiin perusasioihin keskittyminen oli työn tavoitteen toteutumisen kannalta tärkeää, sillä perustietoja kirjanpidosta tekijällä ei juurikaan ennestään ollut. Toimeksiantajan kirjanpito on tällä hetkellä toteutettuna Tappio kirjanpito-ohjelmaa käyttäen elokuun 2017 loppuun asti. Opinnäytetyön liitteenä on Tappio-ohjelmasta poimitut tuloslaskelma ja tase. Kirjaukset perustavat tapahtumiin, jotka ovat muodostuneet 31.8.2017 mennessä. Opinnäytetyötä varten lukuja on muunnettu. Työ ei suinkaan lopu raportin palauttamiseen. Juoksevaa kirjanpitoa jatketaan loppuvuoden osalta ja tilinpäätös tulee toteuttaa vuoden 2018 alussa todellisia tilikauden lukuja käyttäen. Toimeksiantaja on myös ulkoistanut veroilmoituksen täyttämisen tämän työn tekijälle. Prosessin myötä tekijän osaaminen toiminimen kirjanpidon hoitamiseen on kohonnut ammattimaiselle tasolle, joten kirjanpitopalvelua voi jatkossa tarjota myös muille toiminimiyrittäjille. Tekijä jatkaa osaamisen kartoitusta tutustumalla alv-kirjauksiin.The purpose of this thesis was to find out what skills are required to perform the accounting for a sole trader. The commissioner was a welfare entrepreneur who practices business in Tampere. The business is not liable to pay value added tax. The aim of the thesis was to give the author the capability to perform the commissioner´s accounting independently in the future. The theoretical part of the thesis focused on the basic bookkeeping concepts considering the nature of the commissioner´s business. The taxation section focused on the business income, and the tax return was presented, as it is necessary for the commissioner´s business. An essential part of the work process was to familiarize with the accounting material of the previous years, to find a suitable accounting program, and to perform the current bookkeeping. The author is now capable of using the accounting program and keeping the accounts until preparing the income statement and balance sheet. Thus the goal of the thesis was reached. The routine bookkeeping continues and the financial statements will be prepared at the end of the year. The author will also complete the tax return for the financial year of 2017. Because of the professional development, the author can provide bookkeeping services to other welfare entrepreneurs, too

The effect of interstitial pressure on therapeutic agent transport : coupling with the tumor blood and lymphatic vascular systems

Vascularized tumor growth is characterized by both abnormal interstitial fluid flow and the associated interstitial fluid pressure (IFP). Here, we study the effect that these conditions have on the transport of therapeutic agents during chemotherapy. We apply our recently developed vascular tumor growth model which couples a continuous growth component with a discrete angiogenesis model to show that hypertensive IFP is a physical barrier that may hinder vascular extravasation of agents through transvascular fluid flux convection, which drives the agents away from the tumor. This result is consistent with previous work using simpler models without blood flow or lymphatic drainage. We consider the vascular/interstitial/lymphatic fluid dynamics to show that tumors with larger lymphatic resistance increase the agent concentration more rapidly while also experiencing faster washout. In contrast, tumors with smaller lymphatic resistance accumulate less agents but are able to retain them for a longer time. The agent availability (area-under-the curve, or AUC) increases for less permeable agents as lymphatic resistance increases, and correspondingly decreases for more permeable agents. We also investigate the effect of vascular pathologies on agent transport. We show that elevated vascular hydraulic conductivity contributes to the highest AUC when the agent is less permeable, but to lower AUC when the agent is more permeable. We find that elevated interstitial hydraulic conductivity contributes to low AUC in general regardless of the transvascular agent transport capability. We also couple the agent transport with the tumor dynamics to simulate chemotherapy with the same vascularized tumor under different vascular pathologies. We show that tumors with an elevated interstitial hydraulic conductivity alone require the strongest dosage to shrink. We further show that tumors with elevated vascular hydraulic conductivity are more hypoxic during therapy and that the response slows down as the tumor shrinks due to the heterogeneity and low concentration of agents in the tumor interior compared with the cases where other pathological effects may combine to flatten the IFP and thus reduce the heterogeneity. We conclude that dual normalizations of the micronevironment ? both the vasculature and the interstitium ? are needed to maximize the effects of chemotherapy, while normalization of only one of these may be insufficient to overcome the physical resistance and may thus lead to sub-optimal outcomes.PostprintPeer reviewe

Development of Halofluorochromic Polymer Nanoassemblies for the Potential Detection of Liver Metastatic Colorectal Cancer Tumors Using Experimental and Computational Approaches

Purpose—To develop polymer nanoassemblies (PNAs) modified with halofluorochromic dyes to allow for the detection of liver metastatic colorectal cancer (CRC) to improve therapeutic outcomes. Methods—We combine experimental and computational approaches to evaluate macroscopic and microscopic PNA distributions in patient-derived xenograft primary and orthotropic liver metastatic CRC tumors. Halofluorochromic and non-halofluorochromic PNAs (hfPNAs and n-hfPNAs) were prepared from poly(ethylene glycol), fluorescent dyes (Nile blue, Alexa546, and IR820), and hydrophobic groups (palmitate), all of which were covalently tethered to a cationic polymer scaffold [poly(ethylene imine) or poly(lysine)] forming particles with an average diameter \u3c 30 nm. Results—Dye-conjugated PNAs showed no aggregation under opsonizing conditions for 24 h and displayed low tissue diffusion and cellular uptake. Both hfPNAs and n-hfPNAs accumulated in primary and liver metastatic CRC tumors within 12 h post intravenous injection. In comparison to n-hfPNAs, hfPNAs fluoresced strongly only in the acidic tumor microenvironment (pH \u3c 7.0) and distinguished small metastatic CRC tumors from healthy liver stroma. Computational simulations revealed that PNAs would steadily accumulate mainly in acidic (hypoxic) interstitium of metastatic tumors, independently of the vascularization degree of the tissue surrounding the lesions. Conclusion—The combined experimental and computational data confirms that hfPNAs detecting acidic tumor tissue can be used to identify small liver metastatic CRC tumors with improved accuracy

Computer simulation of glioma growth and morphology

Despite major advances in the study of glioma, the quantitative links between intra-tumor molecular/cellular properties, clinically observable properties such as morphology, and critical tumor behaviors such as growth and invasiveness remain unclear, hampering more effective coupling of tumor physical characteristics with implications for prognosis and therapy. Although molecular biology, histopathology, and radiological imaging are employed in this endeavor, studies are severely challenged by the multitude of different physical scales involved in tumor growth, i.e., from molecular nanoscale to cell microscale and finally to tissue centimeter scale. Consequently, it is often difficult to determine the underlying dynamics across dimensions. New techniques are needed to tackle these issues. Here, we address this multi-scalar problem by employing a novel predictive three-dimensional mathematical and computational model based on first-principle equations (conservation laws of physics) that describe mathematically the diffusion of cell substrates and other processes determining tumor mass growth and invasion. The model uses conserved variables to represent known determinants of glioma behavior, e.g., cell density and oxygen concentration, as well as biological functional relationships and parameters linking phenomena at different scales whose specific forms and values are hypothesized and calculated based on in vitro and in vivo experiments and from histopathology of tissue specimens from human gliomas. This model enables correlation of glioma morphology to tumor growth by quantifying interdependence of tumor mass on the microenvironment (e.g., hypoxia, tissue disruption) and on the cellular phenotypes (e.g., mitosis and apoptosis rates, cell adhesion strength). Once functional relationships between variables and associated parameter values have been informed, e.g., from histopathology or intra-operative analysis, this model can be used for disease diagnosis/prognosis, hypothesis testing, and to guide surgery and therapy. In particular, this tool identifies and quantifies the effects of vascularization and other cell-scale glioma morphological characteristics as predictors of tumor-scale growth and invasion

Predicting drug pharmacokinetics and effect in vascularized tumors using computer simulation

In this paper, we investigate the pharmacokinetics and effect of doxorubicin and cisplatin in vascularized tumors through two-dimensional simulations. We take into account especially vascular and morphological heterogeneity as well as cellular and lesion-level pharmacokinetic determinants like P-glycoprotein (Pgp) efflux and cell density. To do this we construct a multi-compartment PKPD model calibrated from published experimental data and simulate 2-h bolus administrations followed by 18-h drug washout. Our results show that lesion-scale drug and nutrient distribution may significantly impact therapeutic efficacy and should be considered as carefully as genetic determinants modulating, for example, the production of multidrug-resistance protein or topoisomerase II. We visualize and rigorously quantify distributions of nutrient, drug, and resulting cell inhibition. A main result is the existence of significant heterogeneity in all three, yielding poor inhibition in a large fraction of the lesion, and commensurately increased serum drug concentration necessary for an average 50% inhibition throughout the lesion (the IC50 concentration). For doxorubicin the effect of hypoxia and hypoglycemia (“nutrient effect”) is isolated and shown to further increase cell inhibition heterogeneity and double the IC50, both undesirable. We also show how the therapeutic effectiveness of doxorubicin penetration therapy depends upon other determinants affecting drug distribution, such as cellular efflux and density, offering some insight into the conditions under which otherwise promising therapies may fail and, more importantly, when they will succeed. Cisplatin is used as a contrast to doxorubicin since both published experimental data and our simulations indicate its lesion distribution is more uniform than that of doxorubicin. Because of this some of the complexity in predicting its therapeutic efficacy is mitigated. Using this advantage, we show results suggesting that in vitro monolayer assays using this drug may more accurately predict in vivo performance than for drugs like doxorubicin. The nonlinear interaction among various determinants representing cell and lesion phenotype as well as therapeutic strategies is a unifying theme of our results. Throughout it can be appreciated that macroscopic environmental conditions, notably drug and nutrient distributions, give rise to considerable variation in lesion response, hence clinical resistance. Moreover, the synergy or antagonism of combined therapeutic strategies depends heavily upon this environment

Simulation of Multispecies Desmoplastic Cancer Growth via a Fully Adaptive Non-linear Full Multigrid Algorithm

A fully adaptive non-linear full multigrid (FMG) algorithm is implemented to computationally simulate a model of multispecies desmoplastic tumor growth in three spatial dimensions. The algorithm solves a thermodynamic mixture model employing a diffuse interface approach with Cahn-Hilliard-type fourth-order equations that are coupled, non-linear, and numerically stiff. The tumor model includes extracellular matrix (ECM) as a major component with elastic energy contribution in its chemical potential term. Blood and lymphatic vasculatures are simulated via continuum representations. The model employs advection-reaction-diffusion partial differential equations (PDEs) for the cell, ECM, and vascular components, and reaction-diffusion PDEs for the elements diffusing from the vessels. This study provides the details of the numerical solution obtained by applying the fully adaptive non-linear FMG algorithm with finite difference method to solve this complex system of PDEs. The results indicate that this type of computational model can simulate the extracellular matrix-rich desmoplastic tumor microenvironment typical of fibrotic tumors, such as pancreatic adenocarcinoma