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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
1

Mathematical Modelling of Cancer Cell Population Dynamics

Daukšte, Liene January 2012 (has links)
Mathematical models, that depict the dynamics of a cancer cell population growing out of the human body (in vitro) in unconstrained microenvironment conditions, are considered in this thesis. Cancer cells in vitro grow and divide much faster than cancer cells in the human body, therefore, the effects of various cancer treatments applied to them can be identified much faster. These cell populations, when not exposed to any cancer treatment, exhibit exponential growth that we refer to as the balanced exponential growth (BEG) state. This observation has led to several effective methods of estimating parameters that thereafter are not required to be determined experimentally. We present derivation of the age-structured model and its theoretical analysis of the existence of the solution. Furthermore, we have obtained the condition for BEG existence using the Perron- Frobenius theorem. Amathematical description of the cell-cycle control is shown for one-compartment and two-compartment populations, where a compartment refers to a cell population consisting of cells that exhibit similar kinetic properties. We have incorporated into our mathematical model the required growing/aging times in each phase of the cell cycle for the biological viability. Moreover, we have derived analytical formulae for vital parameters in cancer research, such as population doubling time, the average cell-cycle age, and the average removal age from all phases, which we argue is the average cell-cycle time of the population. An estimate of the average cell-cycle time is of a particular interest for biologists and clinicians, and for patient survival prognoses as it is considered that short cell-cycle times correlate with poor survival prognoses for patients. Applications of our mathematical model to experimental data have been shown. First, we have derived algebraic expressions to determine the population doubling time from single experimental observation as an alternative to empirically constructed growth curve. This result is applicable to various types of cancer cell lines. One option to extend this model would be to derive the cellcycle time from a single experimental measurement. Second, we have applied our mathematical model to interpret and derive dynamic-depicting parameters of five melanoma cell lines exposed to radiotherapy. The mathematical result suggests there are shortcomings in the experimental methods and provides an insight into the cancer cell population dynamics during post radiotherapy. Finally, a mathematical model depicting a theoretical cancer cell population that comprises two sub-populations with different kinetic properties is presented to describe the transition of a primary culture to a cell line cell population.
2

Impact of a Constitutive 16p11.2 Microdeletion on Tumor Progression, Angiogenesis, and Pro-Oncogenic Transcriptional Networks

Haebe, Joshua 15 September 2022 (has links)
Colorectal cancers (CRCs) rely heavily on host-derived structures to support tumour development and maintain growth. The tumour microenvironment (TME) includes contributions from underlying vascular endothelial cells to maintain nutrient and oxygen availability, as well as a delicate interplay with effector and suppressor immune cells to ensure effective immune evasion. Despite previous attempts to target these TME components through direct, individual therapeutic interventions targeting pro-angiogenic signaling and blocking immune suppression, in many cases the CRC TME remains supportive of tumour growth. Here, I have identified a loci-specific Autism Spectrum Disorder-linked 16p11.2 microdeletion, that demonstrates a negative impact on tumour growth. Initially, I show that a constitutive 16p11.2 deficiency (16p11.2df) alters tumour growth, although has no impact on tumourigenesis. Moreover, I demonstrate that a 16p11.2df in host- derived structures of the TME but not tumour cells is sufficient to slow tumour growth. Further, I demonstrate that vascular networks are altered in tumours derived from a 16p11.2df TME. While I present systemic alterations to the immunological landscape of 16p11.2df individuals at the transcriptional level, there is no detectable alteration in cytotoxic immune cell infiltration into 16p11.2df-derived tumours despite increased expression of T cell activating cytokines. In addition to altered growth characteristics, tumours derived from 16p11.2df mice show an enrichment in apoptosis of tumour cells, despite no change in proliferation. These findings suggest the potential for a 16p11.2df-mediated induction of tumour dormancy, through which volumetric tumour growth is slowed. Together, this study demonstrates the need for further investigation of the 16p11.2 microdeletion as a critical regulator of tumour growth.
3

Investigating the Role of FGL2 in Tumour Progression and Surgical Stress-Induced Immunosuppression

Galpin, Kristianne 02 December 2022 (has links)
Fibrinogen-like protein 2 (FGL2) expression is associated with tumour progression and poor survival in a number of different cancers. In these cancers, FGL2 promotes tumour progression via an immunosuppression-mediated mechanism or by promoting angiogenesis. Querying single-cell RNA sequencing (scRNA-seq) human cancer data shows FGL2 is produced by immune and stromal cells in the tumour microenvironment (TME), while cancer cells have minimal expression of FGL2. We therefore studied the role of FGL2 produced by cells in the TME in tumour progression in two models of cancer in which the role of FGL2 has not been previously studied: epithelial ovarian cancer (EOC) and melanoma. EOC is the most lethal gynecologic cancer with an imperative need for new treatments. Before testing novel immunotherapies, we first characterized the TME of six syngeneic ovarian cancer models. ID8-p53-/- and ID8-C3 tumours were most highly infiltrated by T cells, whereas STOSE and MOE-PTEN/KRAS tumours were primarily infiltrated by tumour associated macrophages and were unique in MHC class I and II expression. This panel of well-defined murine EOC models can serve as a valuable resource for studies that aim to test immunotherapies. We next studied the role of FGL2 in tumour progression in melanoma and ovarian cancer models. Using wild-type and FGL2 knockout mice, we found that absence of FGL2 led to a more activated TME, including activated dendritic cells (DCs - CD86+, CD40+) and T cells (CD25+, TIGIT+), as well as demonstrating for the first time that the absence of FGL2 led to more activated Natural Killer (NK) cells (DNAM-1, NKG2D) in the TME. The absence of FGL2 prolonged survival in the B16F10 model of melanoma, and synergized with oncolytic virus to prolong survival in the ID8-p53-/-Brca2-/- model of ovarian cancer.
4

Tumour associated macrophages in Diffuse Large B cell lymphoma

Doig, Tamasin Naomi January 2016 (has links)
Tumour associated macrophages (TAMs) have been associated with prognosis in a wide variety of tumours with most studies showing a high number of macrophages equating with poor prognosis. This is postulated to be due to TAMs providing support to the tumour through a wide variety of mechanisms including suppression of the immune response, promotion of angiogenesis and provision of growth supporting signals. Previous work within the group has characterised some of the mechanisms by which Burkitt lymphoma cells attract macrophages to the tumour and some of the mechanisms by which these macrophages support tumour cell growth. This thesis extends some of the work carried out in Burkitt lymphoma to Diffuse Large B cell lymphoma (DLBCL) and examines TAMs in this tumour type. Diffuse Large B cell lymphoma is the commonest high grade lymphoma in the Western world. Like Burkitt lymphoma it is characterised by diffuse sheets of lymphoid blasts. In contrast to Burkitt lymphoma, it represents a less well-defined entity that encompasses tumours with variable morphology, genetic abnormalities and outcome. Rates of proliferation and apoptosis vary between individual tumours, and unlike Burkitt lymphoma not all cases are characterised by a prominent macrophage infiltrate. Previous work within the group has shown a relationship in Burkitt lymphoma between apoptosis, macrophage infiltration and proliferation suggesting that apoptosis recruits macrophages to provide support to the tumour cells. This relationship was studied here in a large cohort of patients with DLBCL and the same relationship shown to exist in this tumour also. Following this observation, a bioinformatic approach was taken to define a gene expression signature of the TAM in DLBCL in situ in an unbiased way. Using large publicly available human tumour gene expression datasets, a graph clustering approach using the tool Biolayout Express 3D was used to explore the transcriptome of DLCBL and other human tumours. Signatures of immune cells and stromal cells, functional pathways and tumour specific signatures were defined from individual tumour type transcriptomes by study of clusters of co-expressed genes. Further work used a novel graph clustering approach based on mean Pearson correlations to define a ‘core’ transcriptome signature shared across many unrelated tumour types and in which elements of the tumour stroma were prominent. To validate the TAM signature derived from the DLBCL dataset, protein expression of selected elements of the signature were analysed at the protein level by immunohistochemistry in an unrelated cohort of DLBCL. Selected markers from the DLBCL TAM signature were then assessed for relationship to outcome in a cohort of patients treated with CHOP chemotherapy. Of the proteins studied, a significant difference in outcome was demonstrated only for leukocyte associated immunoglobulin receptor 1 (LAIR1) expression by TAMs, where low intensity staining for LAIR1 in TAMs was associated with better overall survival. LAIR1 is a collagen-binding inhibitory receptor expressed only in cells of haemopoetic lineage whose role is little studied in macrophages. The final results chapter presents some preliminary data from co-culture experiments in which the expression of LAIR-1 on the ‘macrophage-like’ cell line THP-1 is studied in various polarisation states and the ability of these cells to support or constrain tumour cell growth studied in the presence or absence of collagen.
5

Functional Remodelling of the Nucleolus by Long Noncoding RNA

Jacob, Mathieu January 2013 (has links)
The nucleolus is a plurifunctional organelle in which structure and function are intimately linked. Though it is primarily known as the site of ribosomal biogenesis, the nucleolus is also capable of orchestrating the immobilization of a broad range of proteins under specific environmental conditions. This process, known as nucleolar sequestration, contributes to cell viability under stress. Despite the importance of this post-translational regulatory pathway, very little is known about the mechanisms that govern it. Here, we show that heat shock and acidosis, two physiological stimuli associated with nucleolar sequestration, induce the expression of long noncoding RNA (lncRNA) from stimulus-specific loci of the ribosomal intergenic spacer (IGS). These lncRNAs, in turn, immobilize proteins encoding a nucleolar detention sequence (NoDS) within a compartment of the nucleolus termed the detention centre (DC). The DC is a spatially and dynamically distinct region, characterized by an 8-anilino-1-naphthalenesulfonate (ANS)-positive hydrophobic signature. Its formation is accompanied by a redistribution of nucleolar factors and an arrest in ribosomal biogenesis. Silencing of regulatory IGS lncRNA prevents the creation of this structure and allows the nucleolus to retain its tripartite organization and transcriptional activity. Signal termination causes a decrease in IGS transcript levels and a return to the active nucleolar conformation. We propose that the induction of IGS lncRNA, by environmental signals, operates as a molecular switch that regulates the structure and function of the nucleolus.
6

THE ROLES OF HEDGEHOG, PTEN, AND ETS2 SIGNALING IN THE REGULATION OF PANCREATIC TUMORIGENESIS BY STROMAL FIBROBLASTS

Pitarresi, Jason Robert 08 November 2016 (has links)
No description available.
7

Strategies for Overcoming Shortcomings of Thermal Ablations: A Comprehensive Study of Nanoparticle Transport During Photothermal Chemotherapy Treatments, and High Frequency Irreversible Electroporation

Dewitt, Matthew Ryan 09 November 2017 (has links)
Cancer continues to be a leading cause of death worldwide despite the increasing research advances into novel treatments. Thermal ablation of tumors is a relatively established method for the destruction of many tumor types, despite inherent shortcomings including incomplete tumor treatment and non-specific treatment. Novel therapies are currently studied including nanoparticle-based therapies to overcome these limitations. One field of research is focused on utilizing non-lethal hyperthermia to enhance carried chemotherapeutic drugs. Additionally a novel field of non-thermal ablations termed Irreversible Electroporation has recently been developed to treat tumors by irreversibly destroying cell membrane function through short electrical pulses. The goal of the present study is to research two novel potential treatments for cancer that do not require thermal destruction of tissue. Firstly, we developed and tested novel ways to load the antineoplastic agent Cisplatin into SWNHs to test the ability to thermally enhance carried drugs with non-lethal, mild hyperthermia. We attached the imaging agent Quantum Dots (QDs) to the particles to understand how hyperthermia affects cellular uptake, minimizing thermal enhancement. Results of this study highlight the need for better biomimetic in vitro models of the tumors to study how hyperthermia affects tissue level transport of nanoparticles. In the second aim we utilized a perfusable 3D collagen in vitro model of the tumor microenvironment, previously developed by our group to study tumor angiogenesis, to study nanoparticle transport. We demonstrated the ability of this model to study key mass transport obstacles nanoparticles face in the tumor including extravasation from a leaky, pro-angiogenic vasculature, diffusion in the extracellular matrix, and cellular uptake in a 3D environment. This model was then utilized in the third aim to study how mild hyperthermia affects transport of SWNHs. Results from this aim were valuable in showing the utility of the 3D in vitro model to controllably test the effects of external stimuli on transport of particles and shows how mild hyperthermia can selectively allow increased permeability of SWNHs in the tumor, increasing selectivity of nanoparticle transport to the targeted tissue. Lastly, we tested the non-thermal ablation, high-frequency irreversible electroporation (H-FIRE) in a 3D tumor platform and in an in vivo swine model to better understand the ability of H-FIRE to produce repeatable destruction of hepatocellular carcinoma, a disease state growing in incidence rate. We then used H-FIRE in an outpatient treatment for infiltrative skin tumors in equines, showcasing the ability to deliver high voltage, short duration pulses in a clinical setting without muscle contractions. Ultimately, the results of this study the engineering studies that must occur to optimize novel treatments utilizing non-lethal hyperthermia, or non-thermal death mechanism to treat cancer. The studies show the usefulness of more complex 3D in vitro models of tumors for early development of novel therapies and the utility of in vivo models to validate studies. / Ph. D.
8

The effects of microenvironment on inflammation and disease

Curry, Jennifer M. 26 June 2009 (has links)
No description available.
9

ACUTE MYELOID LEUKEMIA AND THE BONE MARROW MICROENVIRONMENT / FRIENDS OR FOES? ACUTE MYELOID LEUKEMIA AND THE BONE MARROW MICROENVIRONMENT

Prabagaran, Pradhariny 11 1900 (has links)
Acute myeloid leukemia (AML) is an aggressive cancer of the blood and bone marrow, affecting 1,100 Canadians annually. Older patients make up 75% of cases yet have the lowest survival rates due to the lack of tolerable treatments. Recently, the combination of Venetoclax and Azacitidine (Ven/Aza) has shown great therapeutic promise, however, chemoresistance has become a growing concern. Current evidence points towards a chemoprotective role from the bone marrow (BM) microenvironment, specifically by BM-derived mesenchymal stromal cells (BMSCs) and adipocytes. AML cells can manipulate BMSCs and adipocytes to create a niche that supports its own growth and evades chemotherapy. However, the role of the microenvironment in Ven/Aza chemoresistance has yet to be studied. Our objective was to study the ability of the microenvironment cells to induce AML chemoresistance to Ven/Aza. We employed a 2-dimensional direct contact co-culture system between MOLM-13 AML cells and BMSCs or adipocytes in both the absence and presence of Ven/Aza to determine the effects on the AML cells. In the absence of Ven/Aza, adipocyte co-cultured AML cells showed a 47% reduction in proliferation, 10% reduction in viability, yet a 1.7-fold increase in Maximal respiration when compared to the monocultured cells. In the presence of Ven/Aza, adipocyte co-cultured AML cells showed a significant increase in both proliferation and viability. Preliminary work investigating the mechanism of action of this support points toward an anti-apoptotic mechanism mediated by the upregulation of MCL-1 upon co-culture with adipocytes. Combination of Venetoclax and Tapotoclax, an MCL-1 inhibitor, abrogated the chemoprotection provided by BMSCs and adipocytes. Overall, our data suggests a dual role of adipocytes, where their inhibition or support of AML is context dependent. Therapeutic targeting of mechanisms for adipocyte chemoprotection such as MCL-1 upregulation may re-sensitize AML cells to Ven/Aza, thereby improving patient outcomes. / Thesis / Master of Science (MSc) / Acute myeloid leukemia (AML) is an aggressive cancer of the blood and bone marrow, affecting 1,100 Canadians annually. Older patients make up 75% of cases yet have the lowest survival rates due to the lack of tolerable treatments. A novel combination of Venetoclax and Azacitidine (Ven/Aza) has shown great therapeutic promise, however, chemoresistance remains an important concern. Previous studies have implicated fat cells, or adipocytes, in AML chemoresistance, however, their role in Ven/Aza treatment has yet to be studied. Here, we show that adipocytes reduce growth of AML cells, yet enhance their metabolism. In the presence of Ven/Aza, adipocytes induce chemoresistance. We show preliminary data that this chemoprotection may be mediated by the upregulation of mitochondrial MCL-1 protein as inhibition of this protein neutralized the protection. By understanding the relationship between adipocytes and AML chemoresistance, we can target this and re-sensitize AML to Ven/Aza, thereby improving older patient outcomes.
10

Variação intra e interespecífica na escolha de microambientes e sua relevância para a manutenção do balanço hídrico em anuros / Intra- and interspecific variation in microhabitats selection and its relevance to the maintenance of water balance in anurans

Maia, Maya Romano 15 July 2014 (has links)
Desde o início a ecofisiologia tenta entender como o comportamento dos animais tampona os desafios ambientais. Anfíbios perdem água através da pele em taxas elevadas e assumem riscos quando buscam por água. Testamos se cinco espécies de anfíbios arborícolas diferem em na adoção de estratégias na busca de água e se diferenças interespecíficas na fisiologia e no comportamento se correlacionam com distribuição temporal e escolha microhabitat na atividade reprodutiva. Estratégias de busca de água foram classificadas como direta ou energética errática de acordo com a atividade de busca de água dos indivíduos em um labirinto. Foram registradas, também, a atividade reprodutiva dos machos durante um ano e sua associação com condições microambientais e de distribuição temporal relacionadas com a disponibilidade de água em um mesmo charco. Observamos grandes diferenças interespecíficas na atividade de busca de água. As espécies do gênero Hypsiboas demonstraram uma clara tendência para a estratégia direta, levando mais tempo para encontrar a fonte de água, em contraposição foram mais precisas. A estratégia das espécies do gênero Scinax foi classificada como energética errática, pois costumavam encontrar a fonte de água mais rápido por meio de uma busca ativa e errática. A espécie Hypsiboas bandeirantes, no entanto, tem um comportamento generalista, exibindo ambas as estratégias. A análise discriminante indicou que a estratégia tinha maior poder discriminativo quando associado à distribuição temporal da atividade reprodutiva (96.24% de classificação correta, 100% de confiabilidade na validação cruzada), sendo que espécies tímidas são mais dependentes da temporada de chuva. Dentro de variáveis de microhábitat, a estratégia energética errática poderia ser diferenciadas por ocupar microhabitats com maior umidade relativa. Estes resultados sugerem que, embora as espécies de estratégia direta concentrem sua atividade no pico da estação chuvosa, elas são independentes das condições do microambiente. Por outro lado, espécies energéticas erráticas se reproduzem quando a umidade relativa é muito alta, independente da temporada. A variação interespecífica na variável fisiológica de resistência da pele à perda de água (RPA) também pode ser discriminada com base na distribuição temporal (89.4% de classificação correta, 94.5% de confiabilidade na validação cruzada). Os valores mais baixos de RPA (H. albopunctatus < S. crospedospilus < S. hayii) são diretamente proporcionais à dependência a estação chuvosa e parece refletir tanto a adaptação à disponibilidade de água no ambiente quanto a herança filogenética, particularmente em espécies caracterizadas por baixo RPAE que tende a vocalizar em períodos de alta disponibilidade de água. Testes em mais espécies serão necessários para confirmar esses padrões / A longstading question in ecophysiology is how behavior buffers environmental challenges in animals. Amphibians loose water at high rates through skin and assume risks when searching for water. We tested if five species of treefrogs differ in water search strategy and whether differences in physiology and in behavior would correlate with temporal distribution and microhabitat choice for reproductive activity. We classified strategies as direct or energetic erratic according to individuals\' activity finding water in a maze. Temporal distribution and microenvironmental conditions related to water availability were recorded associated to males reproductive activity during a year in a same pond. We observed high interspecific differences in treefrogs activity in search for water. Species from genus Hypsiboas demonstrated a clear trend towards direct strategy, taking longer to find water source but being more accurate. Species from Scinax genus were energetic erratic, finding water source sooner by an erratic-active search. Hypsibos bandeirantes, however, had a generalist behavior, exhibiting both strategies. Discriminant analysis indicated that water search strategies had higher discriminative power when associated to temporal distribution of reproductive activity (96.24% correct classification, 100% cross-validated results), with higher dependence of species from direct search strategy to wet season. Within microhabitat variables, energetic erratic strategies could be differentiated by occupying microhabitats with higher humidity. These results suggest that while species with the direct strategy concentrate activity at the wet season peak regardless of microenvironment conditions, energetic erratic species opportunistically call when UR% is very high, independent of the season. Interspecific variation in the physiological variable, the skin resistance to water loss (RWL), can also be discriminated on the basis on temporal distribution (89.4% correct classification, 94.5%. cross-validated results). The lower RWL values (H. albopunctatus < S. crospedospilus < S. hayii) are directly proportional to their dependence to wet season and seems to reflect both adaptation to environmental water availability and phylogenetic inheritance, particularly with species characterized by low RWL tending to call at periods of high water availability. Tests on more species are necessary to confirm this pattern

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