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Open Access Publications from the University of California

Scholarly Works (8 results)

  • Thesis
  • Peer Reviewed
UCLA Electronic Theses and Dissertations (2019)

CD8+ cytotoxic T lymphocytes (CTL) play an important role in HIV-1 infection. However, in most persons the HIV-1-specific CTL become dysfunctional. It has been suggested that anergy, a mechanism of T cell tolerance, may play a role in HIV-1-specific CTL dysfunction. Since HIV-1 is known to escape CTL recognition through mutation of epitopes to produce weak agonist altered peptide ligands (APL)—and anergy is thought to occur through suboptimal recognition—we hypothesized that weakly-recognized epitope variants may suboptimally stimulate the T-cell receptor (TCR) and trigger aberrant TCR signaling, leading to CTL anergy and enhanced viral persistence. We investigated weak agonist APL-mediated anergy as a potential mechanism of dysfunction in three HIV-1-specific CTL clones targeting three different epitopes. Clones were exposed to weakly-recognized epitope variants and screened for cytokine secretion, gene expression of markers of anergy and other forms of T cell dysfunction, and subsequent capacity to kill index peptide-presenting target cells in secondary challenge. Under those conditions, although suboptimal stimulation dampened cytokine secretion, we observed no patterns in gene expression profile consistent with anergy. Additionally, pre-exposure of CTL to weak agonist epitope variants had no discernable effect on their subsequent capacity to kill index epitope-bearing target cells. These data suggest that while weak agonist epitope variants evade CTL pressure through reduced recognition, their weak agonism does not appear to drive dysfunction of HIV-1-specific CTL, arguing against a role of APL-induced anergy in HIV-1-specific CTL dysfunction. However, under different experimental conditions, one HIV-1-specific CTL clone appeared to demonstrate varying degrees of reduced recognition of index epitope after pre-treatment with weak agonist APL stimulation. To try to reconcile these seemingly contradictory results, additional literature on the role of costimulation in both anergy and CD28- effector CTL is incorporated into the discussion. In Chapter 7, I propose a speculative model of how HIV-1-derived weak agonist APL, in conjunction with blockade of CD28-independent costimulatory pathways, may be able to cause HIV-1-specific CTL anergy in vivo. In Chapter 8, alternative approaches are suggested for possible future studies to resolve the confounding issues that still surround the field of APL-induced T cell anergy.

    Cover page: An Investigation of Anergy As a Potential Mechanism of Human Immunodeficiency Virus Type 1 Escape from Control by Cytotoxic T Lymphocytes
    • Article
    • Peer Reviewed
    UCLA Previously Published Works (2019)

    Objective

    To assess whether weakly recognized epitope variants induce anergy in HIV-1-specific CD8 T lymphocyte (CTL) clones as a mechanism of dysfunction.

    Design

    HIV-1-specific CTL clones were exposed to suboptimally recognized epitope variants, and screened for anergy and other T-cell dysfunction markers, and subsequent capability to kill target cells bearing index epitope.

    Methods

    In addition to the optimally recognized index epitope, two suboptimally recognized epitope variants were selected based on titration curves for killing of peptide-labeled target cells by three HIV-1-specific CTL clones targeting the epitopes SLYNTVATL (Gag 77-85, A02-restricted), RPAEPVPLQL (Rev 66-75, B07-restricted), and KRWIIMGLNK (Gag 263-272, B27-restricted). Consequences of suboptimal stimulation were assessed by cytokine secretion, gene expression, and capacity to kill index epitope-labeled target cells upon rechallenge.

    Results

    Suboptimal recognition of epitope variants reduced cytokine production by CTL similarly to reduction in killing of target cells. Gene expression profiles after suboptimal stimulation demonstrated no patterns consistent with T-cell dysfunction due to anergy, exhaustion, or apoptosis. Preexposure of CTL to epitope variants had no discernable impact on their subsequent capacity to kill index epitope-bearing target cells.

    Conclusion

    Our data explore the hypothesis that poorly recognized epitope variants not only facilitate HIV-1 evasion of CTL recognition, but also induce CTL dysfunction through suboptimal signaling causing anergy. However, the results do not suggest that suboptimal signaling induces anergy (or exhaustion or apoptosis), indicating that the major role of CTL epitope variation is likely viral escape.
      Cover page: Suboptimal stimulation by weak agonist epitope variants does not drive dysfunction of HIV-1-specific cytotoxic T lymphocyte clones.
      • Article
      • Peer Reviewed
      UC Riverside Previously Published Works (2017)
      The MYC oncoprotein regulates transcription of a large fraction of the genome as an obligatory heterodimer with the transcription factor MAX. The MYC:MAX heterodimer and MAX:MAX homodimer (hereafter MYC/MAX) bind Enhancer box (E-box) DNA elements (CANNTG) and have the greatest affinity for the canonical MYC E-box (CME) CACGTG. However, MYC:MAX also recognizes E-box variants and was reported to bind DNA in a "non-specific" fashion in vitro and in vivo. Here, in order to identify potential additional non-canonical binding sites for MYC/MAX, we employed high throughput in vitro protein-binding microarrays, along with electrophoretic mobility-shift assays and bioinformatic analyses of MYC-bound genomic loci in vivo. We identified all hexameric motifs preferentially bound by MYC/MAX in vitro, which include the low-affinity non-E-box sequence AACGTT, and found that the vast majority (87%) of MYC-bound genomic sites in a human B cell line contain at least one of the top 21 motifs bound by MYC:MAX in vitro. We further show that high MYC/MAX concentrations are needed for specific binding to the low-affinity sequence AACGTT in vitro and that elevated MYC levels in vivo more markedly increase the occupancy of AACGTT sites relative to CME sites, especially at distal intergenic and intragenic loci. Hence, MYC binds diverse DNA motifs with a broad range of affinities in a sequence-specific and dose-dependent manner, suggesting that MYC overexpression has more selective effects on the tumor transcriptome than previously thought.
        Cover page: Sequence-specific DNA binding by MYC/MAX to low-affinity non-E-box motifs
        • Article
        • Peer Reviewed
        UCLA Previously Published Works (2021)

        Background

        Depression causes significant morbidity, which impacts mental health, overall general health outcomes, everyday functioning and quality of life. This study aims to contribute to knowledge in the field through enhanced understanding of factors that influence depression response and remission, with consideration for design of treatment services to optimize depression outcomes within integrated care programs.

        Methods

        Using routine behavioral health screening and electronic health record data, we identified a retrospective cohort consisting of 615 adult patients receiving depression treatment within an integrated care program. Cohort member Patient Health Questionnaire (PHQ-9) data was analyzed for the 6 months following initiation of treatment. Multinomial regression models were estimated to identify factors associated with depression treatment response (PHQ-9 < 10) and remission (PHQ-9 < 5).

        Results

        At 6 months, 47% of patients demonstrated treatment response and 16% demonstrated remission. Baseline trauma symptoms and suicidal ideation were significantly associated with decreased odds of achieving remission (Odds Ratio (95% CI) [OR] = 0.45 (0.23, 0.88) and OR = 0.49 (0.29, 0.82), respectively). In fully adjusted models, baseline suicidal ideation remained significant (OR = 0.53 (0.31, 0.89)) and some evidence of an association persisted for baseline trauma symptoms (OR = 0.51 (0.25, 1.01)).

        Conclusions

        After controlling for baseline depression symptoms, the presence of suicidal ideation is associated with reduced likelihood of remission. Increased understanding of factors associated with depression treatment outcomes may be employed to help guide the delivery and design of clinical services. Alongside routine screening for co-morbid anxiety, suicidal ideation and traumatic stress should be assessed and considered when designing depression treatment services.
          Cover page: Factors associated with response and remission from depression at 6-months of treatment in a retrospective cohort treated within an integrated care program.
          • Article
          • Peer Reviewed
          UCLA Previously Published Works (2016)
          Patients with behavioral health disorders often have worse health outcomes and have higher health care utilization than patients with medical diseases alone. As such, people with behavioral health conditions are important populations for accountable care organizations (ACOs) seeking to improve the efficiency of their delivery systems. However, ACOs have historically faced numerous barriers in implementing behavioral health population-based programs, including acquiring reimbursement, recruiting providers, and integrating new services. We developed an evidence-based, all-payer collaborative care program called Behavioral Health Associates (BHA), operated as part of UCLA Health, an integrated academic medical center. Building BHA required several innovations, which included using our enterprise electronic medical record for behavioral health referrals and documentation; registering BHA providers with insurance plans' mental health carve-out products; and embedding BHA providers in primary care practices throughout the UCLA Health system. Since 2012 BHA has more than tripled the number of patients receiving behavioral health services through UCLA Health. After receiving BHA treatment, patients had a 13 percent reduction in emergency department use. Our efforts can serve as a model for other ACOs seeking to integrate behavioral health care into routine practice.
            Cover page: Delivering On Accountable Care: Lessons From A Behavioral Health Program To Improve Access And Outcomes
            • Article
            • Peer Reviewed
            UCLA Previously Published Works (2022)

            Background

            Access to primary care was hindered by the coronavirus disease 2019 (COVID-19) pandemic.

            Objective

            Evaluate changes in health screening rates before and during the pandemic.

            Design

            Retrospective analysis of health maintenance and disease management screening rates among primary care patients before and during the pandemic.

            Participants

            Over 150,000 patients of a large, academic health system.

            Main measures

            Six quality measures were analyzed: colon cancer, breast cancer, cervical cancer, diabetes Hgb A1C, diabetes eye, and diabetes nephropathy monitoring. Based on US Preventative Services Task Force screening guidelines, we determined which patients were due for at least one of the quality measures. We tracked completion rates during three time periods: pre-pandemic (January 1-March 3, 2020), stay-at-home (March 4-May 8, 2020), and phased reopening (May 9-July 8, 2020). Differences in quality measure completion rates were evaluated using mixed-effects logistic regression models.

            Key results

            Compared to pre-pandemic rates, completion of all health screenings declined during the stay-at-home period: mammograms (OR: 0.34; 95% CI: 0.31-0.37), cervical cancer (OR: 0.83; 95% CI: 0.76-0.91), colorectal cancer (OR: 0.25; 95% CI: 0.23-0.28), diabetes eye (OR: 0.34; 95% CI: 0.29-0.41), diabetes Hgb A1c (OR: 0.41; 95% CI: 0.37-0.46), and diabetes nephropathy (OR: 0.46, 95% CI: 0.41-0.53). During phased reopening, completion of all quality measures increased compared to the stay-at-home period, except for cervical cancer screening (OR: 0.83; 95% CI: 0.76-0.92). There was a persistent reduction in completion of all quality measures, except for diabetic nephropathy monitoring (OR: 0.99; 95% CI: 0.89-1.09), during phased reopening compared to pre-pandemic.

            Conclusions

            Healthcare screening rates were reduced during the early part of the COVID-19 pandemic and did not fully recover to pre-pandemic rates by July 2020. Future research should aim to clarify the long-term impacts of delayed health screenings. New interventions should be considered for expanding remote preventative health services.
              Cover page: Impact of COVID-19 on Primary Care Quality Measures in an Academic Integrated Health System.
              • Article
              • Peer Reviewed
              UCLA Previously Published Works (2021)
              Given the high rates at which patients present with behavioural health (BH) concerns in primary care (PC), this setting has become the de facto mental health system. As a result, screening for depression and other BH conditions in PC has become a critical target for improving patient outcomes. However, integration of screening into busy PC workflows can be challenging due to barriers such as limited time and resources. A digital, cloud-based BH assessment tool, which included electronic health record enhancements, was developed and implemented in two urban PC practices as a prelude to a planned larger-scale implementation. The implementation strategies included a reorganisation of workflows within the PC setting, comprehensive training for staff and PC physicians, and institution of an incentive programme for PC clinic managers. To examine whether the introduction of the cloud-based BH assessment tool and associated implementation strategies was associated with increased screening rates, we compared rates of screening from January through June 2017 to rates of screening from January through June 2018 (subsequent to implementation). We also examined BH symptomatology reported by patients in PC. Following the implementation process, rate of BH screening with Patient Health Questionnaire-2 (PHQ-2) increased from 50.5% to 57% (p<0.00000000000000022) and rates of subsequent screening with PHQ-9, for those scoring at risk, defined as a score of ≥1, on PHQ-2, increased from 34.5% to 91.4% (p<0.00000000000000022). Additionally, high rates of 'moderate' and 'severe' symptoms of depression (40.3%), anxiety (42.6%) and substance use (26.7% alcohol; 31.2% other substance use) were observed among PC patients. Results suggest that a comprehensive implementation plan, including digitisation of BH assessment, reduced the burden of systematic screening. High rates of BH symptomatology underscore the need for comprehensive BH assessment and systems planning to address the high need for BH services among PC patients.
                Cover page: Using web-based technology to improve depression screening in primary care settings.
                • Article
                • Peer Reviewed
                UCLA Previously Published Works (2018)

                Introduction

                Colorectal cancer (CRC) is a common but largely preventable disease with suboptimal screening rates despite national guidelines to screen individuals age 50-75. Single-component interventions aimed to improve screening uptake only modestly improve rates; data suggest that multi-modal approaches may be more effective.

                Methods

                We designed, implemented, and evaluated the impact of a multi-modal intervention on CRC screening uptake among unscreened patients in a large managed care population. Patient-level components included a mailed letter with education about screening options and pre-colonoscopy telephone counseling. For providers, we facilitated communication of screening test results and work-flow for abnormal results. System-level modifications included establishment of a patient navigator, expedited work-up for abnormal results, and stream-lined colonoscopy scheduling. We measured the rate of screening uptake overall, screening uptake by modality, change in the proportion of the population screened, and positive fecal immunochemical test (FIT) follow-up rates in the 1-year study period.

                Results

                There were 5093 patients in the intervention cohort. Of these, 33.2% participated in FIT or colonoscopy screening within 1 year of the mailing. A total of 1078 (21.2%) participants completed a FIT and 611 (12.0%) completed a screening colonoscopy. The screening rate in the managed care population increased from 65.1 to 76.6%. Fifty-nine patients (5.5%) had a positive FIT, of which 30 (50.8%) completed a diagnostic colonoscopy.

                Conclusion

                Multi-modal interventions can result in substantial improvement in CRC screening uptake in large and diverse managed care populations.

                Translational impact

                Health systems should shift their focus from single-level to multi-level interventions when addressing barriers to CRC screening.
                  Cover page: A Multi-Level Fit-Based Quality Improvement Initiative to Improve Colorectal Cancer Screening in a Managed Care Population.
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