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Epigenetics, or the reversible and heritable marks of gene regulation not including DNA sequence, encompasses modifications on both the DNA and histones and is as important as the DNA sequence itself. Gene transcription, DNA repair, DNA replication, and the cell cycle are each impacted by the chromatin structure. A variety of enzymes modulate these modifications, and a suite of factors interacts with them to aid in promoting or inhibiting cellular functions. Many of these chromatin-modifying factors are deregulated in cancer, making them novel therapeutic targets. This dissertation describes the identification of an H3K9 histone methyltransferase, SUV39H1, as a suppressor of rhabdomyosarcoma formation in zebrafish. This suppressor is dependent on the methyltransferase domain of the enzyme, ruling out any scaffold effects since this enzyme is a part of a multiprotein complex. SUV39H1-overexpressing and control tumors share many of the same characteristics, including proliferation rate, muscle differentiation state, and tumor growth rate. The tumor suppressive phenotype cannot be rescued by alterations in the downstream muscle program alone. However, SUV39H1-overexpressing fish initiate fewer tumors, which results in the observed suppressive phenotype. This initiation defect occurs between 5 and 7 days of life in the zebrafish, likely by impacting cyclin B1 expression. This dissertation also describes the development of a novel F1 transgenic screening strategy in the zebrafish. This approach was utilized to screen a variety of chromatin-modifying factors for their effects on hematopoietic development. The developed strategy will have future applications as a zebrafish screening tool. Our data suggest that chromatin-modifying factors play an important role in rhabdomyosarcoma and illustrate the use of the zebrafish in discovering genes involved in tumorigenesis and hematopoiesis.

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Objective: To examine reasons why Multiple Sclerosis (MS) patients may not be adherent to disease-modifying therapies (DMTs). Also, to determine patient perceptions of MS as a disease and DMTs as a source of treatment, and compare these between patients with prior DMT experience and those who were DMT-naïve. Finally, to assess the level of MS symptoms reported in patients taking DMTs, and compare these between DMT users and non-users. Methods: Patients with MS who were affiliated with a regional health plan at any point between January 2005 and December 2010 were asked to fill out a survey, the Multiple Sclerosis Medication Questionnaire (MSMQ). For study purposes, non-adherence was defined as missing any doses in the previous 28 days by the patient. In addition, the MSMQ examined reasons why MS patients do not initiate or discontinue DMT use. For statistical analyses, chi-square tests were performed to detect differences and t-tests and Mann-Whitney U tests to confirm the results. Results: A total of 197 surveys were returned, of which 105 (53.3%) patients were currently on a DMT. Thirty-two (30.5%) of the DMT users were considered non-adherent. Of the non-adherent respondents, the most frequent reason for non-adherence that was at least moderately important was being "too busy" (n=13/29, 44.8%). Amongst patients who were not using a DMT, the most common barrier to DMT use was related to possible side effects of treatment (n=46/79, 58.2%). Analyzing the statements regarding barriers to DMTs revealed significant differences in the proportion of agreement regarding physician's lack of advocacy for DMT use between DMT-naïve patients and those who discontinued DMT use (44.7% vs. 17.1%, respectively, p[less than]0.01), as well as for dislike for using needles (24.3% vs. 46.3%, respectively, p=0.043). In terms of MS symptoms, patients using a DMT generally reported the symptoms posed less of a problem, although significant differences were not seen in chi-square analyses. Conclusion: The injectable nature of most DMTs seems to cause varying degrees of discomfort in MS patients, which may contribute to non-adherence. Reasons given by MS patients for DMT non-adherence in the MSMQ mirror the literature regarding this topic. MS patients who are not currently on DMT may not seek or remain on treatment for various reasons. It appears certain perceptions regarding MS and DMTs are associated with potential DMT use. / text

Objectives: Adherence to multiple sclerosis (MS) treatment is essential to optimize the likelihood of full treatment effect. This prospective, observational, single-center cohort study investigated adherence to fingolimod over the 2 years following treatment initiation. Two facets of adherence - implementation and persistence - were examined and compared between new and experienced users of disease-modifying treatments (DMTs). Materials and methods: Implementation rates were based on the proportion of days covered and calculated as percentages per half-yearly visits and over 2 years, captured through refill data, pill count, and self-report. Nonadherence was defined as taking less than 85.8% of prescribed pills. Implementation rates were classified as nonadherent (< 85.8%), suboptimally adherent (>= 85.8% but. 96.2%), and optimally adherent (>= 96.2%), including perfectly adherent (100%). Persistence, ie, time until discontinuation, was analyzed by Kaplan-Meier analysis. Reasons for discontinuation were recorded. Results: The cohort included 98 patients with relapsing MS, all of whom received a dedicated education session about their medication. Of these 80% were women, 31.6% had fingolimod as first DMT, and 68.4% had switched from other DMTs. The mean implementation rate over 2 years was 98.6% (IQR(1-3) 98.51%-98.7%) and did not change significantly over time; 89% of measurements were in the optimally adherent category, 45.6% in the perfectly adherent category. There was one single occurrence of nonadherence. New users of DMTs were 1.29 times more likely to be adherent than experienced users (OR 1.29, 95% CI 1.11-1.51; P < 0.001), but not more persistent. Nineteen of 98 patients discontinued fingolimod. Conclusion: The very high implementation rates displayed in this sample of MS patients suggest that facilitation by health care professionals in preserving adherence behavior may be sufficient for the majority of patients. Targeted interventions should focus on patients who are nonadherent or who stop treatment without intention to reinitiate.

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Rheumatoid arthritis (RA) is a progressive autoimmune disorder of joints that is associated with high health care costs and yet lacks guidance on how early to initiate biologic disease-modifying antirheumatic drugs (DMARDs), a class of medications that is the major cost driver in RA management. The main purpose of this study was to examine patient socio-demographics, medication use patterns, and clinical characteristics associated with initiation of biologic DMARDs. This was a retrospective study using Texas Medicaid prescription and medical claims database during the study period of July 1, 2003 – December 31, 2010. Patients (18 – 63 years) with an RA diagnosis (ICD-9-CM code 714.xx), no non-biologic DMARD or biologic DMARD use during the pre-index period, and a minimum of 2 prescription claims for the same non-biologic DMARD during the post-index period were included in the study. The primary study outcomes were time to initiation of biologic DMARDs and likelihood of initiating biologic DMARDs. There was a total of 2,714 subjects included in the study. The majority had claims for pain medications (92.4%), glucocorticoids (64.9%), and non-biologic DMARD monotherapy (86.4%); while 24.3% initiated on biologic DMARDs and 58.9% had a Charlson Comorbidity Index (CCI) score=1. Compared to time to initiation (days) of biologic DMARDs for methotrexate (539.7±276.9) users, it was longer for sulfasalazine (670.2±167.8) and hydroxychloroquine (680.2±158.7) users and similar to leflunomide users (541.6±286.5; p<0.0001). There were no significant differences in time to initiation between non-biologic DMARD mono vs. dual therapy. Younger age, glucocorticoid use, methotrexate user (vs. sulfasalazine, hydroxychloroquine users), and non-biologic DMARD monotherapy user (vs. dual therapy user) were significantly associated with higher likelihood to initiate biologic DMARDs. In conclusion, age, glucocorticoid use, non-biologic DMARD type and therapy were significant factors associated with initiation of biologic DMARDs. Healthcare providers and Texas Medicaid should recognize these potential driving factors and take efforts to achieve optimal therapy for RA patients through thorough RA medication evaluation, well-structured RA monitoring programs, and patient education. / text

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