2A18 Abstracts 2020 (eSynthesis)

Saif Alam and Jonathan Lai

Consultant: Dr. Ana Tomljenovic-Berube

The Use of Paclitaxel-Incorporated Nanoparticles in Breast Cancer Treatment

The emerging field of nanotechnology provides a promising new outlook in the field of breast cancer treatment (BCT). Modern drug treatments often suffer from many glaring issues including insolubility, instability within biological environments, subpar selectivity, and unwanted side effects that may create risks for patients. The application of nanoparticles to drug discovery has further advanced medical technology due to their flexible physical, chemical, and biological properties. These adaptable characteristics allow for nanoparticles to perform their desired tasks at higher rates of efficacy, while removing the undesired toxic side effects that exist with current methods of BCT. The objective of this literature review is to examine the use of nanostructured lipid carriers and albumin-based nanoparticles as novel therapies in the treatment of breast cancer. Albumin nanoparticles have proven themselves to be versatile protein carriers for drug delivery, primarily due to their high binding capacity to paclitaxel. Similarly, lipid-based nanoparticles can increase the therapeutic index of the drug while limiting the adverse effects caused by the administration of existing anticancer drugs. This review will search MEDLINE for primary studies between the years 2000-2020 and present a comparative overview of the two selected types of nanoparticles, focusing on their method of synthesis, results from pre-clinical and clinical studies, toxicity effects towards mammalian cells and tissues, and site-specific drug targeting mechanisms. Existing literature has demonstrated that the use of these nanoparticles holds great potential, though further testing and research is required to find ways to optimize both technologies. 

Relevant Sources: (Harvard Anglia Ruskin)

Cortes, J. and Saura, C., 2010. Nanoparticle albumin-bound (nabTM)-paclitaxel: improving efficacy and tolerability by targeted drug delivery in metastatic breast cancer. European Journal of Cancer Supplements, 8(1), pp.1–10.

Cucinotto, I., Fiorillo, L., Gualtieri, S., Arbitrio, M., Ciliberto, D., Staropoli, N., Grimaldi, A., Luce, A., Tassone, P., Caraglia, M. and Tagliaferri, P., 2013. Nanoparticle Albumin Bound Paclitaxel in the Treatment of Human Cancer: Nanodelivery Reaches Prime-Time? Journal of Drug Delivery, [online] 2013. Available at: <https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3659516/> [Accessed 3 Mar. 2020].

Ge, L., You, X., Huang, J., Chen, Y., Chen, L., Zhu, Y., Zhang, Y., Liu, X., Wu, J. and Hai, Q., 2018. Human Albumin Fragments Nanoparticles as PTX Carrier for Improved Anti-cancer Efficacy. Frontiers in Pharmacology, [online] 9. Available at: <https://www.frontiersin.org/articles/10.3389/fphar.2018.00582/full> [Accessed 4 Mar. 2020].

Harries, M., Ellis, P. and Harper, P., 2005. Nanoparticle Albumin–Bound Paclitaxel for Metastatic Breast Cancer. Journal of Clinical Oncology, 23(31), pp.7768–7771.

Lohmann, A.E., Speers, C.H. and Chia, S.K., 2013. Evaluation of the clinical benefits of nanoparticle albumin-bound paclitaxel in women with metastatic breast cancer in British Columbia. Current Oncology, 20(2), pp.97–103.

Matsui, A., Tatibana, A., Suzuki, N., Hirata, M., Oishi, Y., Hamaguchi, Y., Murata, Y., Nagayama, A., Iwata, Y. and Okamoto, Y., 2017. Evaluation of Efficacy and Safety of Upfront Weekly Nanoparticle Albumin-bound Paclitaxel for HER2-negative Breast Cancer. Anticancer Research, 37(11), pp.6481–6488.

McArthur, H., Rugo, H., Nulsen, B. and Hawks, L., 2020. A Feasibility Study of Bevacizumab plus Dose-Dense Doxorubicin–Cyclophosphamide (AC) Followed by Nanoparticle Albumin–Bound Paclitaxel in Early-Stage Breast Cancer | Clinical Cancer Research. [online] Available at: <https://clincancerres-aacrjournals-org.libaccess.lib.mcmaster.ca/content/17/10/3398> [Accessed 3 Mar. 2020].

Tang, X., Loc, W.S., Dong, C., Matters, G.L., Butler, P.J., Kester, M., Meyers, C., Jiang, Y. and Adair, J.H., 2017. The use of nanoparticulates to treat breast cancer. Nanomedicine, 12(19), pp.2367–2388.

Yeh, T.K., Lu, Z., Wientjes, M.G. and Au, J.L.-S., 2005. Formulating Paclitaxel in Nanoparticles Alters Its Disposition. Pharmaceutical Research, 22(6), pp.867–874.

Zong, Y., Wu, J. and Shen, K., 2017. Nanoparticle albumin-bound paclitaxel as neoadjuvant chemotherapy of breast cancer: a systematic review and meta-analysis. Oncotarget, 8(10), pp.17360–17372.

Spencer Arshinoff and Cohen Bolliger

Consultant: Dr. Sarah Symons

Historical Trends of Keyword Use in Evolutionary Psychology Publications

With millions of papers being published each year and this number continuing to rise, it is now more important than ever to examine the underlying trends and invisible forces which drive scientific study. Research examining these factors allows for the accurate interpretation and context of controversial theories. One controversial field is evolutionary psychology, a recent and rapidly growing field which continues to be rife with controversy and debate. The authors hope to shed light on the development of the field of evolutionary psychology by examining trends in published works through a historical framework. This paper will gather data regarding keyword use in article titles and abstracts to generate a quantitative analysis of any trends present. Data will be obtained from articles published on the PsycINFO database in both evolutionary psychology journals and the larger realm of general psychology. These trends will then be analyzed and discussed with historical context to provide a holistic exploration of evolutionary psychology. This should allow for the determination of any factors influencing work in the field as well as perceptions of the field in a larger academic context. While the paper hopes to focus on evolutionary psychology, it will be used as a tool to better understand the hidden influences which guide the way that science is performed, written, and studied. As such, the results of this study will serve as a case study for academics from any field who wish to better understand the inner workings of scientific publishing.

Christina Brinza, Olivia Di Biase, and Ashlyn Roy

Consultant: Dr. George Dragomir

Modelling the COVID-19 outbreak using SIR disease models

The COVID-19 epidemic continues to attract international media attention. The novel coronavirus was first identified in Wuhan, China, and is thought to have originated in bats. It has since spread to six continents and infected over five hundred thousand individuals. The aim of this study is to identify how the reproduction number of COVID-19 differs between countries with varying population densities, demographics, and treatment methods.

The structure of the zoonotic virus, mechanism of action, symptoms, and treatment strategies for COVID-19 are compared to other coronaviruses to explore the impact of the disease at the individual level. The reproduction number of COVID-19 is calculated for the epidemic in China and several other infected countries using Susceptible-Infected-Recovered (SIR) models of disease spread. Measures taken to slow the spread of the disease, such as quarantine and personal protective equipment, are incorporated into the models and analysis. In addition, an age-stratified model, which accounts for the primarily elderly victims of this illness, is created for Italy. Finally, we propose a model for the mortality and transmission of a COVID-19 outbreak in Ontario based on recent epidemiological data. Epidemiological models can inform policy making by predicting the optimal course of action during an outbreak. As the COVID-19 pandemic evolves, quantifying the effect of protective measures like quarantine may influence public perception and help steer the outbreak towards a resolution.

Shannon Buck and Mya Sharma

Consultant: Russ Ellis

Optimizing Methodology for the Extraction of Limonene from Oranges by Steam Distillation

Techniques for the extraction of the natural product limonene were explored in this project. Limonene is used in a variety of food and household products for its flavour and aroma. Existing protocols were modified based on prior laboratory experience and literature research to optimize the experimental protocol. This study used steam distillation to extract the compound limonene

from orange peels and then used a variety of techniques to confirm the presence and purity of the product. Once the orange peels were distilled, liquid-liquid extraction was used to remove the polar phase from the organic phase. Thin-layer chromatography, using iodine staining to visualize compounds, was used to determine the identity and purity of the extracted compounds. Comparison of experimental retention factors to literature values aided in determining the compounds present. Once the extract was purified, mass spectrometry was performed on the sample to establish the chemical structure. The antimicrobial properties of the purified limonene were then tested against E. coli, B. subtilis, and M. luteus to elucidate its mechanism of action. An important aspect of this experiment was troubleshooting problems

that arose throughout, while combining techniques in novel ways. This improved laboratory skills and increased knowledge of experimental design and methodology. The extraction of organic compounds from natural sources is applicable to drug discovery and development, which are key components to the advancement of medicine.

Grace Burgess and Julia Singer

Consultant: Russ Ellis

Franken-stain: Modifying Masson’s Trichrome Stain

Research labs often operate with tight budgets, as a result, creative solutions must be undergone to ensure the most efficient use of funds. Histology is technique driven, requiring meticulous staining methods for subsequent slide analysis. This project will focus on modifying an existing histological stain—Masson’s Trichrome— within the material constraints imposed by an undergraduate laboratory and assessing the success of our stain using artificial intelligence (AI) morphometric and colorimetric analysis. Our goal is to create a novel “Franken-stain” version of Masson’s Trichrome utilizing dyes that are not typically included in pre-made staining kits. We will quantify the level of success of our stain by employing an AI cell classifier tool that will use cell shape and colour intensity to differentiate cellular and tissue components. We propose to acquire fresh tissue specimens and prepare them for histological staining. Our novel stain method will utilize Biebrich scarlet, hematoxylin, and Brilliant Blue dyes. We will use QuPath software to analyze our stain and compare it against control slides stained professionally. We hypothesize that our stain will produce similar results to a conventional Masson’s Trichrome stain, as demonstrated through the use of our AI cell classifier. If the classifier can detect equivalent cellular structures in the professionally stained slides, this would indicate that our stain was successful. If an unconventional stain can produce comparable results to an established stain such as Masson’s Trichrome, this has practical applications in circumventing material and financial restrictions that may constrain histological or research facilities.

Bonny Chong and Maya Rajasingham

Consultant: Dr. George Dragomir

Application of Probability and Permutation in Amida-Kuji 

A ladder lottery, also known as Amida-kuji in Japan and Sadaritagi in Korea, is a very popular method of lottery in Asia used to assign roles and distribute prizes fairly to a group of individuals. As the name would suggest, the lottery visually looks like a ladder, with players picking a given location at the top and prizes at the bottom. This lottery system is designed to create random pairings between two sets of elements, thus illustrating the basic application of permutation operators. In this paper, we explore the mathematics behind Amida-kuji as well as how it can be played as a game. We provide a method to find the optimal permutation of a ladder. We outline two tendencies that occur after repeatedly playing this game, and how these tendencies affect its fairness. Given an Amida-kuji with varying n vertical lines (each representing a player) and a fixed number of b horizontal bars, we analyze how the probability

of each player obtaining a given outcome changes with an increasing number of players. Using python, we create a simulation to see this lottery technique in action. By manipulating different aspects of the game board, such as varying and changing the placements of b, the probability of a given outcome is said to change. Using the simulation, data pertaining to changing n was collected. This study shows the potential of how mathematical concepts behind Amida-kuji

can be implemented into the fairness of the game.

Dia Martinez Gracey and Sarah Watson

Consultant: Dr. Adam Hitchcock

Investigation of Carbon Capture and Disposal

Climate change is a pressing issue of the 21st century and there is a significant need to reduce carbon emissions in an effort to prevent damage to human communities and ecosystems throughout the world. Carbon dioxide makes up a mere 0.04% of atmospheric gases by volume but nevertheless has a staggering impact on global temperature, sea levels and ocean acidification. Through the research completed we hope to propose a plausible solution to the global climate crisis.

In conducting this study, we hope to construct a comparison between the use of artificial and natural trees in the carbon capture and reduction methodologies, through observing the process of photosynthesis as a thermodynamic cycle. In doing so, the efficiency of both systems can be determined and compared through the use of Sherwood’s Law. Another crucial component of the carbon capture process is determining how to correctly dispose of the net carbon waste. As such we plan to propose an efficient carbon capture process and a system of carbon emission disposal that is economically, environmentally and thermodynamically feasible. We expect to find that the solution to the current climate change crisis is dependent on a combination of several air capture techniques but that the use of natural trees will be of the most significant benefit. 

Through utilizing knowledge of thermodynamics and climate change conditions, the benefits and detriments of various forms of direct air capture can be proposed as a possible solution to the climate change crisis.

Relevant Sources:

Knox, R., 1969. Thermodynamics and the Primary Processes of Photosynthesis. Biophysical Journal, 9(11), pp. 1351-1362. https://doi.org/10.1016/S0006-3495(69)86457-X

Nabil Swedan, 2019. Photosynthesis as a thermodynamic cycle https://link.springer.com/article/10.1007%2Fs00231-019-02768-x

Pritchard, C., Yang, A., Holmes, P., Wilkinson, M., 2015. Thermodynamics, Economics, and System Thinking: What Role for Air Capture of CO2? Process Safety and Environmental Protection, 94 pp.188-195. https://doi.org/10.1016/j.psep.2014.06.011.

Grace Horseman, Helen MacDougall-Shackleton, and Jessica Wassens

Consultant: Dr. Chad Harvey

Beetle invaders on a fungal fast track: An ecological summary of symbiotic interaction in beetle-fungus complexes

Many invasive bark beetles form symbiotic relationships with various microorganisms, which ultimately improve beetle fitness and allow beetles to bypass phenolic chemical defenses in their host trees. The best-studied bark beetle symbionts are fungi, which vary widely in both the species involved and their effect on the beetles and other microbiota. The influences of other external factors, including environmental conditions and multitrophic interactions with other organisms such as mites, further increase the complexity of these interactions.

We performed a systematic review of bark beetle-symbiont systems, in order to construct an ecological summary of the interactions involved in these systems and to identify specific mechanisms of their invasions. We focused on the mountain pine beetle (MPB) and red turpentine beetle (RTB) systems, to investigate the effect of different levels of co-evolution with mutualist symbionts and how this may influence the invasion success of beetle complexes.

Using the Web of Science database, we performed a search limited to primary and review articles, targeting invasive bark beetles, associated symbionts, and their interactions. We quantitatively and qualitatively described the findings of 38 papers as they relate to the interactions involved in these complexes.

Studying these symbiotic interactions is a necessary step in understanding the invasive success of these beetle complexes, and in developing possible prevention strategies for similar microbe-facilitated invasions in future.

Khalil Husein and Michelle Kooleshova

Consultant: Dr. George Dragomir

Investigating the Role of the MPAK pathway in Development and Progression of Melanoma

Melanoma, a particularly aggressive brand of dermatological cancer, accounts for 80% of skin cancer related death, despite comprising only 4% of skin cancer cases. The malignancy of melanoma is partly attributed to its high cell plasticity potential. Cellular plasticity drives the progression of melanocytes into highly heterogeneous and invasive melanoma growth. In the Clark Model, a molecular model of melanoma progression, the initial stages of the skin carcinoma are marked with the activation of the mitogen-activated protein kinase (MAPK) signalling pathway, which could potentially induce dysplasia. Abnormal promotion of this signalling pathway is characteristic of numerous cancers and in melanoma the oncogene BRAF has been held responsible for over 50% of cases. By suppressing BRAF, cancer cell growth and proliferation is expected to be hindered.

In this study, we aim to explore the implications of the MAPK signalling pathway on the development of melanoma and how development of this cancer is altered when this pathway is inhibited during treatment. A mathematical model will be used to represent the varying expressions of the MAPK signalling pathway and the corresponding effect on melanoma cell growth and proliferation. According to literature, increasing activation of the MAPK signalling pathway will stimulate growth and differentiation of melanoma populations. By introducing the repression of MAPK, we expect restraint in further cell development and potentially destabilisation of cell processes, resulting in apoptosis or autophagy. The results of this model will review the effectiveness of MAPK inhibitors as a developing therapeutic technique in the treatment of melanoma.

Kate Jamieson and Brandon Nicholson

Consultant: Dr. George Dragomir

Review of Knotting in the Magnetic Field of the Solar Corona

The sun is a complex magnetohydrodynamic system that is not yet fully understood. The solar corona – the plasma surrounding the sun – is of particular interest; whereas the sun’s surface is approximately 5500 Celsius, the corona exceeds one million degrees Celsius. Recent research points to the knotting and braiding of magnetic fields to explain the phenomenon of how such high states of energy are dynamically maintained.

For several decades the applications of knots to magnetic fields has been known. Knots and loops are 3-dimensional closed objects which can be manipulated and untangled. Loops, which are involved in sun flares and sunspots, also release large amounts of heat when enormous stress from knotting is applied until a breaking, causing explosions of energy. This comprises a highly tangled dynamic system achieving an energetic equilibrium. Although the high degree of tangling presents a challenge in their visualization, their energies can be estimated through topological and geometric information obtained from magnetic imaging. 

This report will provide a comprehensive review of current ideas within this area of topological astronomy. To visualize this occurrence, a 3-dimensional model of magnetic loops will also be created using Python, and will further elucidate how magnetic loops, knots, and braids behave to achieve an energetic equilibrium.

Maria Pricop and Will Roderick

Consultant: Dr. Ana Tomljenovic-Berube

CaP Nanoparticles for the Delivery of Tazemetostat in Epithelioid Sarcomas

Epithelioid sarcoma (ES) is a rare, slow-growing form of soft-tissue cancer characterized by regional lymph node involvement, high recurrence, and distant metastases. Common late detection results in metastasis having already occurred, no option for surgery, and a one-year survival rate of <50%. Recently, a drug called Tazemetostat was approved for ES treatment, however twice daily oral delivery of the drug is subject to poor patient adherence and thus decreased therapeutic efficacy and increased treatment cost. Therefore, optimization of tazemetostat’s delivery and improvements for the mitigation of adverse events must still be made. Tazemetostat works by targeting the protein complex PRC2 involved in gene expression, causing changes in histone trimethylation. When delivered in combination, the drug has also been shown to significantly increase the efficacy of general chemotherapeutics. To improve drug delivery, we propose a calcium-phosphate nanoparticle (CaP-NP) delivery system for the achievement of longer drug half-life, increased target specificity, and combined delivery of both doxorubicin (DOX) and tazemetostat to soft-tissue sarcomas. The design employs a combination of DOX and tazemetostat-filled CaP nanorods, layered with a stabilizing chitosan layer and then PEGylated for protein adsorption inhibition. The potential of these CaP-NPs for treatment is analyzed and the design rationale is unfolded based on recent literature. A brief review of existing designs, methods for synthesis, and considerations is also included as a grounded basis for nonclinical and clinical research developments. Specific considerations include pH-sensitive targeting for drug release in the tumor microenvironment (pH≈5.5), oral delivery barriers, and fluorescent tagging for distribution imaging.

Relevant Sources: (Harvard Anglia Ruskin)

Agulnik, M., Tannir, N.M., Pressey, J.G., Gounder, M.M., Cote, G.M., Roche, M., Doleman, S., Blakemore, S.J., Clawson, A., Daigle, S., Tang, J., Ho, P.T.C. and Demetri, G.D., 2016. A phase II, multicenter study of the EZH2 inhibitor tazemetostat in adult subjects with INI1-negative tumors or relapsed/refractory synovial sarcoma. Journal of Clinical Oncology, 34(15_suppl), pp.TPS11071–TPS11071.

Knutson, S.K., Kawano, S., Minoshima, Y., Warholic, N.M., Huang, K.-C., Xiao, Y., Kadowaki, T., Uesugi, M., Kuznetsov, G., Kumar, N., Wigle, T.J., Klaus, C.R., Allain, C.J., Raimondi, A., Waters, N.J., Smith, J.J., Porter-Scott, M., Chesworth, R., Moyer, M.P., Copeland, R.A., Richon, V.M., Uenaka, T., Pollock, R.M., Kuntz, K.W., Yokoi, A. and Keilhack, H., 2014. Selective Inhibition of EZH2 by EPZ-6438 Leads to Potent Antitumor Activity in EZH2-Mutant Non-Hodgkin Lymphoma. Molecular Cancer Therapeutics, 13(4), pp.842–854.

Qi, W., Chan, H., Teng, L., Li, L., Chuai, S., Zhang, R., Zeng, J., Li, M., Fan, H., Lin, Y., Gu, J., Ardayfio, O., Zhang, J.-H., Yan, X., Fang, J., Mi, Y., Zhang, M., Zhou, T., Feng, G., Chen, Z., Li, G., Yang, T., Zhao, K., Liu, X., Yu, Z., Lu, C.X., Atadja, P. and Li, E., 2012. Selective inhibition of Ezh2 by a small molecule inhibitor blocks tumor cells proliferation. Proceedings of the National Academy of Sciences, 109(52), pp.21360–21365.

Sobanko, J.F., Meijer, L. and Nigra, T.P., 2009. Epithelioid Sarcoma. The Journal of Clinical and Aesthetic Dermatology, 2(5), pp.49–54.

Sokolova, V., Rotan, O., Klesing, J., Nalbant, P., Buer, J., Knuschke, T., Westendorf, A.M. and Epple, M., 2012. Calcium phosphate nanoparticles as versatile carrier for small and large molecules across cell membranes. Journal of Nanoparticle Research, 14(6), p.910.

Stacchiotti, S., Blay, J.-Y., Jones, R.L., Demetri, G.D.D., Mir, O., Italiano, A., Thomas, D., Chen, T.W.-W., Schöffski, P., Gil, T., Jahan, T., Cote, G., Ratan, R., Attia, S., Roche, M., Daigle, S., Sapir, I., Clawson, A. and Gounder, M., 2018. 1611PDA phase II, multicenter study of the EZH2 inhibitor tazemetostat in adults (INI1-negative tumors cohort) (NCT02601950). Annals of Oncology, [online] 29(suppl_8). Available at: <https://academic.oup.com/annonc/article/29/suppl_8/mdy299.010/5140277> [Accessed 1 Feb. 2020].

Susa, M., Milane, L., Amiji, M.M., Hornicek, F.J. and Duan, Z., 2011. Nanoparticles: A Promising Modality in the Treatment of Sarcomas. Pharmaceutical Research, 28(2), pp.260–272. 

Zhang, J., Zhang, H., Jiang, J., Cui, N., Xue, X., Wang, T., Wang, X., He, Y. and Wang, D., 2020. Doxorubicin-Loaded Carbon Dots Lipid-Coated Calcium Phosphate Nanoparticles for Visual Targeted Delivery and Therapy of Tumor. International Journal of Nanomedicine, 15, pp.433–444.

Samin Lu-Sullivan and Keshikaa Suthaaharan

Consultant: Dr. George Dragomir

Modelling Sepsis Progression: A Mathematical Model

Sepsis is typically caused by bacterial infection that causes overstimulation of the immune system, leading to organ and tissue damage. In the intensive care unit (ICU), contraction of sepsis can be a fatal condition. Sepsis typically progresses through three stages: sepsis, severe sepsis and septic shock. Early recognition of sepsis is crucial to efficient clinical management of the condition. However, the clinical manifestation of sepsis is heavily heterogeneous; therefore, a more dynamic treatment approaches is required to reflect the nature of this disease.

In our project, we discuss the clinical manifestation and pathogenesis of sepsis, particularly the interaction of Toll Like Receptor 4 (TLR4) with the immune system. We also discuss a pre-existing mathematical models of sepsis. We propose a simplified model that helps provide additional insight into the progression of sepsis through the interaction of TLR4. This mathematical model, models trafficking events between the endosomal recycling compartment (ERC) and trans Golgi network (TGN) to and from the cell surface and within the endosomes-endolysosome (EE) system. The proposed model can be effectively used to predict disease progression in sepsis patients, thus informing effective treatment strategies. This demonstrates the utility of mathematical models in clinical management of a diverse patient population, which is fundamental for a heterogeneous clinical disease such as sepsis.