Immune editing and surveillance in cancer evolution

Cancer is an evolutionary disease, reliant on genetic diversity and sculpted by selective forces from the immune microenvironment. Here, I use genomics data to decipher the tumor’s evolutionary trajectory and corresponding shifts in the immune contexture to elucidate the events governing tumor immunogenicity and the immune evasive mechanisms evolved by the tumor. To better understand the mutational processes contributing to intratumor heterogeneity in individual tumors, a method to quantify the activity of mutational processes in a single tumor sample was developed and applied to temporally dissected mutations. The clinical relevance of intratumor heterogeneity was examined in the context of immune recognition and modulation. Increased clonal neoantigen burden and minimal neoantigen intratumor heterogeneity were found to associate with improved patient outcome, both in the treatment-naïve and immunotherapy-treated setting. The identification of T-cells recognizing clonal neoantigens further supported the clinical importance of targeting neoantigens present in every cancer cell. Mechanisms of immune evasion were considered through the development of a method to identify loss-of-heterozygosity at the HLA locus, overcoming the challenges posed by the polymorphic nature of the locus. HLA loss-of-heterozygosity was found to be a frequent subclonal event in NSCLC, under strong selective pressure and associated with increased subclonal neoantigen burden. Finally, the immune microenvironment was examined through multi-region RNAseq, permitting the quantification of immune infiltration and allowing for the identification of heterogeneously immune infiltrated tumors. Supporting the interplay between genetic events and the immune contexture, a relationship between the genomic features of the tumor and immune infiltration was observed, with HLA loss-of-heterozygosity specifically identified as occurring within a highly active immune microenvironment. This thesis shows how an improved understanding of the relationship between the tumor and the immune system can illuminate features dictating immune recognition and evasion and how that knowledge may inform the development and implementation of successful immunotherapy

The Effect of Television Watching and Portion Size on Intake During a Meal

Background: Several investigations have examined the influence of television and portion size on intake. Results have found that watching television while eating or being provided larger portions increases intake. However, no investigation has examined the combined effect of these variables on food intake, when these factors are combined they may enhance consumption. Methods: To test the influence of television and portion size on intake during a meal in healthy weight adults, a 4X2X2 mixed factorial design was used, with a between-subject factor of order of conditions and within-subject factors of television (TV vs. NO TV) and portion size (SMALL vs. LARGE). Seventeen women and three men (21.6 + 2.3 kg/m2, 22.3 + 3.7 years), who were predominately white (80%), and non-Hispanic (95%), were randomized to one of four orders of conditions. For TV conditions, participants viewed a 30-minute show (no commercials or food cues), for NO TV conditions participants sat for 30 minutes. Participants received 500g macaroni and cheese (998 kcal) and 150g salad with dressing (85 kcal), providing a total of 1083 kcal in SMALL conditions; while LARGE conditions were provided with portions 200% of SMALL conditions. Dependent variables were grams and energy consumed during the meal. Results: Factorial ANOVA revealed a significant main effect of portion size on grams and energy consumed of the total meal. Participants consumed more grams (577.9 + 150.5g vs. 453.1 + 96.6g; p\u3c0.046) and more energy (903.9 + 270.4 kcal vs. 734.6 + 187.1 kcal; p\u3c0.049) when provided a larger portion size. Factorial ANOVA revealed a significant main effect of food type for grams and energy consumed. Participants consumed more grams (368.9 + 114.1g vs. 146.7 + 44.7g; p\u3c0.006) and more energy (736.2 + 227.8 kcal vs. 83.0 + 25.3 kcal; p\u3c0.000) of macaroni and cheese as compared to salad with dressing. A significant main effect of television viewing or interaction of television viewing x portion size was not found. Conclusion: Watching television did not increase intake during a meal. Greater gram and energy intake occurred when larger portion sizes were provided. To assist with reducing intake, smaller portion sizes should be implemented

Trial Advocacy - Final Trial Materials: 2016-17

Course Number 5270https://digitalcommons.osgoode.yorku.ca/casebooks/1062/thumbnail.jp

Trial Advocacy - Student Materials: 2018-19

Course code: 5270.4https://digitalcommons.osgoode.yorku.ca/casebooks/1094/thumbnail.jp

Engineering Flow States with Localized Forcing in a Thin, Marangoni-Driven Inclined Film

Numerical simulations of lubrication models provide clues for experimentalists about the development of wave structures in thin liquid films. We analyze numerical simulations of a lubrication model for an inclined thin liquid film modified by Marangoni forces due to a thermal gradient and additional localized forcing heating the substrate. Numerical results can be explained through connections to theory for hyperbolic conservation laws predicting wave fronts from Marangoni-driven thin films without forcing. We demonstrate how a variety of forcing profiles, such as Gaussian, rectangular, and triangular, affect the formation of downstream transient structures, including an N wave not commonly discussed in the context of thin films. Simulations employing a controlled approximation of a compressive-undercompressive wave pair demonstrate possibilities for applications of localized forcing as microfluidic valve. In the simulations, localized forcing provides a control parameter that can be used to determine mass flux and film profiles

Evaluating Nanoshells and a Potent Biladiene Photosensitizer for Dual Photothermal and Photodynamic Therapy of Triple Negative Breast Cancer Cells.

Light-activated therapies are ideal for treating cancer because they are non-invasive and highly specific to the area of light application. Photothermal therapy (PTT) and photodynamic therapy (PDT) are two types of light-activated therapies that show great promise for treating solid tumors. In PTT, nanoparticles embedded within tumors emit heat in response to laser light that induces cancer cell death. In PDT, photosensitizers introduced to the diseased tissue transfer the absorbed light energy to nearby ground state molecular oxygen to produce singlet oxygen, which is a potent reactive oxygen species (ROS) that is toxic to cancer cells. Although PTT and PDT have been extensively evaluated as independent therapeutic strategies, they each face limitations that hinder their overall success. To overcome these limitations, we evaluated a dual PTT/PDT strategy for treatment of triple negative breast cancer (TNBC) cells mediated by a powerful combination of silica core/gold shell nanoshells (NSs) and palladium 10,10-dimethyl-5,15-bis(pentafluorophenyl)biladiene-based (Pd[DMBil1]-PE

Performance on a Virtual Reality Angled Laparoscope Task Correlates with Spatial Ability of Trainees

The aim of the present study was to investigate whether trainees' performance on a virtual reality angled laparoscope navigation task correlates with scores obtained on a validated conventional test of spatial ability. 56 participants of a surgery workshop performed an angled laparoscope navigation task on the Xitact LS 500 virtual reality Simulator. Performance parameters were correlated with the score of a validated paper-and-pencil test of spatial ability. Performance at the conventional spatial ability test significantly correlated with performance at the virtual reality task for overall task score (p < 0.001), task completion time (p < 0.001) and economy of movement (p = 0.035), not for endoscope travel speed (p = 0.947). In conclusion, trainees' performance in a standardized virtual reality camera navigation task correlates with their innate spatial ability. This VR session holds potential to serve as an assessment tool for trainee

Personality traits and virtual reality performance

Background: Surgeons' personalities have been described as different from those of the general population, but this was based on small descriptive studies limited by the choice of evaluation instrument. Furthermore, although the importance of the human factor in team performance has been recognized, the effect of personality traits on technical performance is unknown. This study aimed to compare surgical residents' personality traits with those of the general population and to evaluate whether an association exists between their personality traits and technical performance using a virtual reality (VR) laparoscopy simulator. Methods: In this study, 95 participants (54 residents with basic, 29 with intermediate laparoscopic experience, and 12 students) underwent personality assessment using the NEO-Five Factor Inventory and performed five VR tasks of the Lap Mentor™ basic tasks module. The residents' personality traits were compared with those of the general population, and the association between VR performance and personality traits was investigated. Results: Surgical residents showed personality traits different from those of the general population, demonstrating lower neuroticism, higher extraversion and conscientiousness, and male residents showed greater openness. In the multivariable analysis, adjusted for gender and surgical experience, none of the personality traits was found to be an independent predictor of technical performance. Conclusions: Surgical residents present distinct personality traits that differ from those of the general population. These traits were not found to be associated with technical performance in a virtual environment. The traits may, however, play an important role in team performance, which in turn is highly relevant for optimal surgical performanc

Association between Participation in a Multiplayer Medical Home Intervention and Changes in Quality, Utilization, and Costs of Care

Importance Interventions to transform primary care practices into medical homes are increasingly common, but their effectiveness in improving quality and containing costs is unclear. Objective To measure associations between participation in the Southeastern Pennsylvania Chronic Care Initiative, one of the earliest and largest multipayer medical home pilots conducted in the United States, and changes in the quality, utilization, and costs of care. Design, Setting, and Participants Thirty-two volunteering primary care practices participated in the pilot (conducted from June 1, 2008, to May 31, 2011). We surveyed pilot practices to compare their structural capabilities at the pilot’s beginning and end. Using claims data from 4 participating health plans, we compared changes (in each year, relative to before the intervention) in the quality, utilization, and costs of care delivered to 64 243 patients who were attributed to pilot practices and 55 959 patients attributed to 29 comparison practices (selected for size, specialty, and location similar to pilot practices) using a difference-in-differences design. Exposures Pilot practices received disease registries and technical assistance and could earn bonus payments for achieving patient-centered medical home recognition by the National Committee for Quality Assurance (NCQA). Main Outcomes and Measures Practice structural capabilities; performance on 11 quality measures for diabetes, asthma, and preventive care; utilization of hospital, emergency department, and ambulatory care; standardized costs of care. Results Pilot practices successfully achieved NCQA recognition and adopted new structural capabilities such as registries to identify patients overdue for chronic disease services. Pilot participation was associated with statistically significantly greater performance improvement, relative to comparison practices, on 1 of 11 investigated quality measures: nephropathy screening in diabetes (adjusted performance of 82.7% vs 71.7% by year 3, P \u3c .001). Pilot participation was not associated with statistically significant changes in utilization or costs of care. Pilot practices accumulated average bonuses of $92 000 per primary care physician during the 3-year intervention. Conclusions and Relevance A multipayer medical home pilot, in which participating practices adopted new structural capabilities and received NCQA certification, was associated with limited improvements in quality and was not associated with reductions in utilization of hospital, emergency department, or ambulatory care services or total costs over 3 years. These findings suggest that medical home interventions may need further refinement