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- Creators: Barrett, The Honors College
- Status: Published
Description
Cooperative cellular phenotypes are universal across multicellular life. Division of labor, regulated proliferation, and controlled cell death are essential in the maintenance of a multicellular body. Breakdowns in these cooperative phenotypes are foundational in understanding the initiation and progression of neoplastic diseases, such as cancer. Cooperative cellular phenotypes are straightforward to characterize in extant species but the selective pressures that drove their emergence at the transition(s) to multicellularity have yet to be fully characterized. Here we seek to understand how a dynamic environment shaped the emergence of two mechanisms of regulated cell survival: apoptosis and senescence. We developed an agent-based model to test the time to extinction or stability in each of these phenotypes across three levels of stochastic environments.
ContributorsDanesh, Dafna (Author) / Maley, Carlo (Thesis director) / Aktipis, Athena (Committee member) / Compton, Zachary (Committee member) / Barrett, The Honors College (Contributor) / School of Life Sciences (Contributor)
Created2021-12
Description
Early detection of disease is essential for alleviating disease burden, increasing success rate and decreasing mortality rate especially for cancer. To improve disease diagnostics, many candidate biomarkers have been suggested using molecular biology or image analysis techniques over the past decade. The receiver operating characteristics (ROC) curve is a standard technique to evaluate a diagnostic accuracy of biomarkers, but it has some limitations especially for heterogeneous diseases. As an alternative of the ROC curve analysis, we suggest a jittered dot plot (JDP) and JDP-based evaluation measures, above mean difference (AMD) and averaged above mean difference (AAMD). We demonstrate how JDP and AMD or AAMD together better evaluate biomarkers than the standard ROC curve. We analyze real and heterogeneous basal-like breast cancer data.
ContributorsBrister, Danielle (Author) / Chung, Yunro (Thesis director) / Park, Jin (Committee member) / Barrett, The Honors College (Contributor) / School of Life Sciences (Contributor) / School of Molecular Sciences (Contributor) / School of International Letters and Cultures (Contributor) / School of Human Evolution & Social Change (Contributor)
Created2021-12
Description
Trichoplax adhaerens (Placozoa) is the simplest multicellular animal to be described. This organism lacks nervous tissue, muscle tissue and organs, and is composed of only five cell types organized into three layers. Placozoa are gaining popularity as a model organism due to their simple make-up and completely sequenced genome. The complete sequencing of this organism’s genome has revealed the presence of important genes in cancer such as TP53 and MDM2 genes. Along with the presence of these genes, there are also additional pathways commonly deregulated in cancer that are well conserved in this organism. T. adhaerens are able to survive exposure to 160Gy and even 240Gy of X-ray radiation. Though small dark bodies form within the main body, they tend to extrude those masses, and continue to reproduce afterwards. After exposure to both grades of radiation, there was a greater increase in the apparent population size of the treated population than the control population. There was also a greater decrease in surface area of the organisms exposed to 160Gy than the control organisms. This increase in population and decrease in surface area of the treated organisms could be due to the extruded bodies. We hypothesize that the observed extrusion is a novel cancer defense mechanism for ridding the animal of damaged or mutated cells. This hypothesis should be tested through longitudinal observation and genetic analysis of the extruded bodies.
ContributorsYi, Avalon (Author) / Fortunato, Angelo (Thesis director) / Maley, Carlo (Committee member) / School of Molecular Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2019-12
Description
Tumor-stroma interactions significantly influence cancer cell metastasis and disease progression. These interactions partly comprise crosstalk between tumor and stromal fibroblasts, but the key molecular mechanisms within the crosstalk governing cancer invasion are still unclear. Here we develop a 3D in vitro organotypic microfluidic to model tumor-stroma interaction by mimicking the spatial organization of the tumor microenvironment on a chip. We co-culture breast cancer and patient-derived fibroblast cells in 3D tumor and stroma regions respectively and combine functional assessments, including cancer cell migration, with transcriptome profiling to unveil the molecular influence of tumor-stroma crosstalk on invasion. This led to the observation that cancer associated fibroblasts enhanced invasion in 3D by inducing the expression of a novel gene of interest, GPNMB, in breast cancer cells resulting in increased migration speed. Importantly, knockdown of GPNMB blunted the influence of CAFs on enhancing cancer invasion. Overall, these results demonstrate the ability of our model to recapitulate patient specific tumor microenvironment to investigate cellular and molecular consequences of tumor-stroma interactions.
ContributorsBarrientos, Eric Salvador (Author) / Nikkhah, Mehdi (Thesis director) / Veldhuizen, Jaime (Committee member) / School of Molecular Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2019-05
Description
Stromal cells play an important role in facilitating disease progression of ductal carcinoma. Cancer associated fibroblasts (CAFs) are an important component of the extracellular matrix (ECM) which constitutes the microenvironment of breast tumor cells. They are known to participate in chemotherapeutic drug resistance by modulating various biochemical and biophysical factors that contribute to increased matrix stiffness and collagen I density of the tumor-adjacent stroma. To address these issues in terms of patient treatment, anti-cancer drug regimes have been assembled to incorporate both chemotherapeutic as well as anti-fibrotic drugs to both target tumor cells while also diminishing the elastic modulus of the microenvironment by targeting CAFs. The quantitative assessment of these drug regimes on tumor progression is missing in terms of CAFs role alone.
A high density 3D tumor model was utilized to recapitulate the tumor microenvironment of ductal carcinoma in vitro. The tumor model consisted of MDA-MB-231 tumors seeded within micromolded collagen wells, chemically immobilized upon a surface treated PDMS substrate. CAFs were seeded within the greater collagen structure from which the microwells were formed. The combinatorial effect of anti-fibrotic drug (Tranilast) and chemotherapy drug (Doxorubicin) were studied within 3D co culture conditions. Specifically, the combinatorial effects of the drugs on tumor cell viability, proliferation, and invasion were examined dynamically upon coculture with CAFs using the microengineered model.
The results of the study showed that the combinatorial effects of Tranilast and Doxorubicin significantly decreased the proliferative ability of tumor cells, in addition to significantly decreasing the ability of tumor cells to remain viable and invade their surrounding stroma, compared to control conditions.
A high density 3D tumor model was utilized to recapitulate the tumor microenvironment of ductal carcinoma in vitro. The tumor model consisted of MDA-MB-231 tumors seeded within micromolded collagen wells, chemically immobilized upon a surface treated PDMS substrate. CAFs were seeded within the greater collagen structure from which the microwells were formed. The combinatorial effect of anti-fibrotic drug (Tranilast) and chemotherapy drug (Doxorubicin) were studied within 3D co culture conditions. Specifically, the combinatorial effects of the drugs on tumor cell viability, proliferation, and invasion were examined dynamically upon coculture with CAFs using the microengineered model.
The results of the study showed that the combinatorial effects of Tranilast and Doxorubicin significantly decreased the proliferative ability of tumor cells, in addition to significantly decreasing the ability of tumor cells to remain viable and invade their surrounding stroma, compared to control conditions.
ContributorsSilva, Casey Rudolph (Author) / Nikkhah, Mehdi (Thesis director) / Saini, Harpinder (Committee member) / Harrington Bioengineering Program (Contributor, Contributor) / Barrett, The Honors College (Contributor)
Created2019-05
Description
YAP/TAZ is the key effector in the Hippo pathway, but it is also involved in many other regulatory pathways to control tissue and organ size. To better understand its regulation and effects in tumorigenesis and degeneration, a preliminary feedback network was created with the species YAP/TAZ, phosphorylated YAP/TAZ, LATS, miR-130a, VGLL4, and β-catenin. From this network a set of ordinary differential equations were written and analyzed for parameter effects. A model showing the healthy, tumorigenic, and degenerative states was created and preliminary parameter analysis identified the effects of parameter modifications on the overall levels of YAP/TAZ. Further analysis is required and connections with the underlying biology should continue to be pursued to better understand how parameter modifications could improve disease treatments.
ContributorsSussex, Erin Nicole (Author) / Tian, Xiaojun (Thesis director) / Wang, Xiao (Committee member) / School of International Letters and Cultures (Contributor) / Harrington Bioengineering Program (Contributor) / Barrett, The Honors College (Contributor)
Created2019-05
Description
The purpose of this research project is to explore the healthy sibling’s response to the diagnosis and treatment of cancer. A cancer diagnosis is a life altering event that effects the ill child, the family, and more specifically sibling(s) if applicable. Over the past decade research on siblings of children with cancer has steadily increased and called for implementing the population into the pediatric oncology plan of care. A systematic literature review containing both qualitative and quantitative data was conducted in order to uncover common themes presented in existing sibling research that influence the sibling experience. A literature search was conducted utilizing EBSCOhost, SAGE journals, and CINAHL. Inclusion criteria used included English, full text, scholarly, peer reviewed, research articles, and systematic reviews, and the search was limited to publications between January 2014 to August 2019. Search results found 196 articles originally. The researcher removed duplicates and scanned the titles narrowing the literature to a total of thirteen articles. The articles included comprised literature reviews, interviews, group intervention studies, a cross-sectional study, and case-controlled design. From this systematic review, common themes that emerged included sibling demographics and characteristics, emotional/behavioral difficulties, a lost sense of self, altered family functioning, the effect of peer, family, and professional support systems, and lack of knowledge and communication. These themes can be interpreted as factors that may influence a sibling’s cancer experience. The results of this research project showed that the sibling’s experience to cancer is complex, multifaceted, and unique. These findings emphasize the need to provide siblings with adequate resources and support in an effort to mitigate the negative effects a diagnosis and treatment of cancer can bring. It is important that the entire healthcare team is competent in this care perspective so that appropriate referrals and interventions can be made, and siblings have the smoothest transition possible.
ContributorsHenrichsen, Meghan (Author) / Beals, Jacquelin (Thesis director) / Murphy, Ana (Committee member) / Edson College of Nursing and Health Innovation (Contributor) / Barrett, The Honors College (Contributor)
Created2019-12
Description
Cancer is a disease in which abnormal cells divide uncontrollably and destroy body tissue, and currently plagues today’s world. Carcinomas are cancers derived from epithelial cells and include breast and prostate cancer. Breast cancer is a type of carcinoma that forms in breast tissue cells. The tumor cells can be further categorized after testing the cells for the presence of certain molecules. Hormone receptor positive breast cancer includes the tumor cells with receptors that respond to the steroid hormones, estrogen and progesterone, or the peptide hormone, HER2. These forms of cancer respond well to chemotherapy and endocrine therapy. On the other hand, triple negative breast cancer (TNBC) is characterized by the lack of hormone receptor expression and tends to have a worse prognosis in women. Prostate cancer forms in the cells of the prostate gland and has been attributed to mutations in androgen receptor ligand specificity. In a subset of triple negative breast cancer, genetic expression profiling has found a luminal androgen receptor that is dependent on androgen signaling. TNBC has also been found to respond well to enzalutamide, a an androgen receptor inhibitor. As the gene of the androgen receptor, AR, is located on the X chromosome and expressed in a variety of tissues, the responsiveness of TNBC to androgen receptor inhibition could be due to the differential usage of isoforms - different gene mRNA transcripts that produce different proteins. Thus, this study analyzed differential gene expression and differential isoform usage between TNBC cancers – that do and do not express the androgen receptor – and prostate cancer in order to better understand the underlying mechanism behind the effectiveness of androgen receptor inhibition in TNBC. Through the analysis of differential gene expression between the TNBC AR+ and AR- conditions, it was found that seven genes are significantly differentially expressed between the two types of tissues. Genes of significance are AR and EN1, which was found to be a potential prognostic marker in a subtype of TNBC. While some genes are differentially expressed between the TNBC AR+ and AR- tissues, the differences in isoform expression between the two tissues do not reflect the difference in gene expression. We discovered 11 genes that exhibited significant isoform switching between AR+ and AR- TNBC and have been found to contribute to cancer characteristics. The genes CLIC1 and RGS5 have been found to help the rapid, uncontrolled growth of cancer cells. HSD11B2, IRAK1, and COL1Al have been found to contribute to general cancer characteristics and metastasis in breast cancer. PSMA7 has been found to play a role in androgen receptor activation. Finally, SIDT1 and GLYATL1 are both associated with breast and prostate cancers. Overall, through the analysis of differential isoform usage between AR+ and AR- samples, we uncovered differences that were not detected by a gene level differential expression analysis. Thus, future work will focus on analyzing differential gene and isoform expression across all types of breast cancer and prostate cancer to better understand the responsiveness of TNBC to androgen receptor inhibition.
ContributorsDeshpande, Anagha J (Author) / Wilson-Sayres, Melissa (Thesis director) / Buetow, Kenneth (Committee member) / Natri, Heini (Committee member) / School of Human Evolution & Social Change (Contributor) / School of Life Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2019-05
Description
Malignant Pleural Mesothelioma (MPM) is an aggressive deadly tumor that has few therapeutic options. Immunotherapies have shown great potential in alleviating MPM patient symptoms. Using patient data from the Cancer Genome Atlas (TCGA) we sought to identify mutations, regulators, and immune factors driving immune cell migration. We explored computational methods to define regulatory causal flows in order to make biological predictions. These predictions were verified by cross-referencing peer-reviewed articles. A disease-relevant inference model was developed to examine the chemokine IL-18’s effect on natural killer cell (NK cell) migration.
ContributorsWipper, Gabrielle Frances (Author) / Plaisier, Christopher (Thesis director) / Plaisier, Seema (Committee member) / Harrington Bioengineering Program (Contributor, Contributor) / Barrett, The Honors College (Contributor)
Created2020-05
Description
Malignant Pleural Mesothelioma is a type of lung cancer usually discovered at an advanced stage at which point there is no cure. Six primary MPM cell lines were used to conduct in vitro research to make conclusions about specific gene mutations associated with Mesothelioma. DNA exome sequencing, a time efficient and inexpensive technique, was used for identifying specific DNA mutations. Computational analysis of exome sequencing data was used to make conclusions about copy number variation among common MPM genes. Results show a CDKN2A gene heterozygous deletion in Meso24 cell line. This data is validated by a previous CRISPR-Cas9 outgrowth screen for Meso24 where the knocked-out gene caused increased Meso24 growth.
ContributorsKrdi, Ghena (Author) / Plaisier, Christopher (Thesis director) / Wilson, Melissa (Committee member) / School of Life Sciences (Contributor) / Hugh Downs School of Human Communication (Contributor) / Barrett, The Honors College (Contributor)
Created2020-05