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An Rb-Ezh2 Complex Mediates Silencing Of Repetitive Dna Sequences, Charles A. Ishak, Aren E. Marshall, Daniel T. Passos, Carlee R. White, Seung J. Kim, Matthew J. Cecchini, Sara Ferwati, William A. Macdonald, Christopher J. Howlett, Ian D. Welch, Seth M. Rubin, Mellissa R.W. Mann, Frederick A. Dick

Paediatrics Publications

Repetitive genomic regions include tandem sequence repeats and interspersed repeats, such as endogenous retroviruses and LINE-1 elements. Repressive heterochromatin domains silence expression of these sequences through mechanisms that remain poorly understood. Here, we present evidence that the retinoblastoma protein (pRB) utilizes a cell-cycle-independent interaction with E2F1 to recruit enhancer of zeste homolog 2 (EZH2) to diverse repeat sequences. These include simple repeats, satellites, LINEs, and endogenous retroviruses as well as transposon fragments. We generated a mutant mouse strain carrying an F832A mutation in Rb1 that is defective for recruitment to repetitive sequences. Loss of pRB-EZH2 complexes from repeats disperses H3K27me3 …

Comprehensive Molecular Characterization Of Human Nodal, Scott D. Findlay

Electronic Thesis and Dissertation Repository

Nodal and related ligands are highly conserved members of the TGF-beta superfamily with well-established and essential roles in the early embryonic development of vertebrates, and in cell fate decisions in human embryonic stem (hES) cells. Aberrant NODAL signaling also generally promotes pro-tumourigenic phenotypes and the progression of a wide array of human cancers. Despite being pursued as a potential therapeutic target, many aspects of NODAL’s molecular biology remain poorly understood. This thesis provides a comprehensive characterization of gene expression from the human NODAL locus at multiple levels. First, an intronic NODAL SNP known as rs2231947 was found to be functional …

Dose-Related Sex Differences In The Establishment Of Conditioned Disgust (Anticipatory Nausea), And The Effect Of Peripubertal And Adult Immune System Stimulation With The Endotoxin Lipopolysaccharide (Lps) On Learning And Memory In The Rat, Caylen J. Cloutier

Electronic Thesis and Dissertation Repository

This thesis examined sex differences in the establishment of lithium chloride (LiCl) – induced conditioned disgust behavior (anticipatory nausea) to a distinct context, as well as, the establishment of conditioned place avoidance (CPA) using rodent models. Also examined were potential sex differences in response to treatment with the bacterial endotoxin, lipopolysaccharide (LPS), and its effect on learning and memory. In Chapter 2, male and female naïve Long-Evans rats were injected (intraperitoneally; i.p.) with either 200 µg/kg LPS or 0.9% (NaCl), 90 minutes prior to i.p. injections of either 128 mg/kg LiCl or 0.9% NaCl, and immediately placed into a distinctive …

Characterization Of The Catalytic Ck2 Subunits With Substitutions At Residues Involved In Inhibitor Binding, Paul Desormeaux

Electronic Thesis and Dissertation Repository

CK2 is a constitutively active, ubiquitously expressed and pleiotropic serine/threonine protein kinase that is implicated in many cellular functions including tumorigenesis. CK2 has two catalytic subunits, CK2a and CK2a’, that carry out its function in the cell. Previous studies have indicated that inhibitor-refractory mutants have been effective in recovering residual CK2 activity, in the presence of inhibitors, when compared to wild type CK2. Based on these observations, inhibitor-refractory mutants were created for both CK2a and CK2a’ and tested with various concentrations with two CK2-specific inhibitors, CX-4945 and inhibitor VIII. The CK2a triple mutant (V66A/I174A/H160D) was tested in inducible U2OS Flp-In …

Longitudinal Evaluation Of Patient Concerns After Surgery For Head And Neck Cancer, Isabel Wozniczka

Electronic Thesis and Dissertation Repository

The primary purpose of this study was to investigate and describe the longitudinal effects of shoulder and neck mobility, strength, and quality of life (QOL) following neck dissection (ND) surgery and identify the concerns of head and neck cancer (HNC) patients. ND is one of the standard procedures for treating HNC, which results in many complications and dysfunctions that can have an effect on a patient’s QOL.

The study had 27 eligible HNC participants who underwent ND, of which eight participated in the shoulder range of motion (ROM) and strength and 12 participated in the QOL patient-reported outcomes analysis. The …

Characterization Of Numb As A Regulator Of Anaplastic Lymphoma Kinase, Ran Wei

Electronic Thesis and Dissertation Repository

Cellular events rely on protein-protein interactions that are often mediated by modular domains which recognize particular sequence motifs in binding partners. The NUMB protein is the first described cell fate determinant and multifaceted adaptor that is involved in a wide variety of cellular events. NUMB mainly mediates protein interactions via its modular PTB domain. Here we present a systematic investigation of the NUMB-PTB interactome by employing an integrative strategy combining both protein and peptide arrays. We profiled NUMB-PTB binding specificity and interacting proteins genome-wide. The receptor tyrosine kinases (RTKs) are found highly enriched in the interactome, raising the possibility that …

A Novel Minimally Invasive Tumour Localization Device, Doran Avivi

Electronic Thesis and Dissertation Repository

Lung cancer is one of the leading causes of death, by cancer. The usual treatment is surgical resection of tumours. However, patients who are weak or have poor pulmonary function are deemed unfit for surgery. For these patients, a minimally-invasive approach is desired. A major problem associated with minimally-invasive approaches is tumour localization in real time and accurate measurement of tool--tissue forces.

This thesis describes the design, analysis, manufacturing and validation of a minimally-invasive instrument for tumour localization, named Palpatron. The instrument has an end effector that is able to support two previously designed jaws, one containing an ultrasound sensor …

Cost-Effectiveness Of Bevacizumab Concomitant With The Standard Of Therapy For Newly Diagnosed Glioblastoma, Aren Fischer

Electronic Thesis and Dissertation Repository

Glioblastoma Multiforme (GBM), a glioma – cancer of the brain’s glial cells – is the most common and deadly malignant primary central nervous system tumor in developed countries. Two recently completed clinical trials investigating the use of bevacizumab (BEV), a monoclonal antibody, to treat newly diagnosed GBM concomitant with the standard-of-care (SOC) showed mixed survival and quality of life outcomes. In this study, a cost utility study was conducted to investigate if BEV should be used to treat newly diagnosed GBM. A three stage time-dependent Markov model was built using survival estimates from the two clinical trials, costs from Ontario …

Recommendations For Genetic Testing To Reduce The Incidence Of Anthracycline-Induced Cardiotoxicity, Folefac Aminkeng, Colin J.D. Ross, Shahrad R. Rassekh, Soomi Hwang, Michael J. Rieder, Amit P. Bhavsar, Anne Smith, Shubhayan Sanatani, Karen A. Gelmon, Daniel Bernstein, Michael R. Hayden, Ursula Amstutz, Bruce C. Carleton

Paediatrics Publications

Aims: Anthracycline-induced cardiotoxicity (ACT) occurs in 57% of treated patients and remains an important limitation of anthracycline-based chemotherapy. In various genetic association studies, potential genetic risk markers for ACT have been identified. Therefore, we developed evidence-based clinical practice recommendations for pharmacogenomic testing to further individualize therapy based on ACT risk. Methods: We followed a standard guideline development process, including a systematic literature search, evidence synthesis and critical appraisal, and the development of clinical practice recommendations with an international expert group. Results: RARG rs2229774, SLC28A3 rs7853758 and UGT1A6 rs17863783 variants currently have the strongest and the most consistent evidence for association …