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Supply and demand in kidney transplantation: innovations to improve the equation
Get PDFDetailed formal protocol with illustrations and extensive bibliography.A recording of the protocol presentation is available on UT Southwestern's Mediasite. Note: Access to the video is restricted to authorized UT Southwestern users only.UT Southwestern--Internal Medicin
Examining Moral Injury in Legal Involved Veterans
Get PDFBACKGROUND: Legal-involved Veterans (LIV) currently comprise approximately 8% of the incarcerated U.S. population, with over 180,000 veterans estimated to be in prisons or jails and a far greater number currently on parole or probation. Furthermore, LIV appear to experience heightened risk for negative sequelae such as homelessness, suicide, unemployment and psychiatric diagnoses. While various factors may contribute to these negative outcomes, the potential for exposure to potentially morally injurious experiences (PMIEs) during legal involvement and the resulting expression of moral injury as contributors have not yet been examined in this population. As a result, we adapted measures of moral injury to assess moral injury in the legal context.
HYPOTHESES: 1. LIV will report exposure to PMIEs and moral injury during their legal involvement. 2. The adapted moral injury measures will demonstrate adequate psychometric strength. 3. Exposure to PMIEs and the expression of moral injury will be associated with suicidal ideation and suicide attempts.
METHOD: Study participants (N=100) were recruited from the VA North Texas Health Care System. Participants were adults (age 18+) who are veterans of the U.S. armed forces and have at least one felony conviction resulting in incarceration. Patients were administered a battery of measures including the Moral Injury Events Scale (MIES) the Expressions of Moral Injury Scale (EMIS) as well as adapted versions of each measure to assess legal-related moral injury (Moral Injury Events Scale-Legal Involved Persons [MIES-LIP]; Expressions of Moral Injury Scale-Legal Involved Persons [EMIS-LIP]). Measures also included assessments of depressive symptoms (PHQ-9), PTSD symptoms (PCL-5) and suicidality (SITBI-R). We examined the psychometric properties of the adapted measures by evaluating their reliability, validity, and factor structure. We utilized multinomial logistic regression to evaluate the relationship between moral injury and suicide risk.
RESULTS: The vast majority of our sample endorsed witnessing a potentially morally injurious event while in involved with the legal system and in the military. Furthermore, the majority of our sample endorsed engaging in morally injurious behavior in the legal context and in the military. Both adapted scales of moral injury (MIES-LIP & EMIS-LIP) demonstrated psychometric strength as evidence by good reliability, as well as convergent and discriminant validity with other study measures. Furthermore, the EMIS-LIP scale significantly differentiated those with a prior suicide attempt from those with no prior suicidal ideation.
DISCUSSION: Legal-related moral injury appears to be a salient factor affecting many legal-involved veterans, and our adapted measures of moral injury demonstrated good reliability and validity. Furthermore, legal-related moral injury as measured by the EMIS-LIP was significantly associated with lifetime suicide attempt in LIV. Future studies should examine drivers of legal-related moral injury in LIV, which may inform future assessment and treatment
The Role of Insulin-Like Growth Factor Binding Protein 3 in Mitochondrial Homeostasis
Get PDFPages 15-102 are misnumbered as pages 14-101, pages 103-155 are misnumbered as pages 100-152, and pages 156-192 are misnumbered as pages 151-187.The insulin-like growth factor (IGF) family includes three extracellular ligands and their cognate receptors, along with six IGF-binding proteins (IGFBPs 1-6). Of these, Insulin-like growth factor binding protein-3 (IGFBP-3) is expressed in corneal epithelial cells (CECs) and is present in human tear fluid. IGFBP-3 is a highly glycosylated secretory protein with known roles in growth and survival. In circulation, IGFBP-3 binds IGF-1 to inhibit activation of the IGF-1 receptor, thereby extending the half-life of IGF-1. IGFBP-3 also plays key roles in apoptosis, DNA repair, cell cycle control, the induction of autophagy, angiogenesis, hypoxia, and insulin resistance. However, the exact function of IGFBP-3 is cell and context-dependent. Prior studies in our lab have demonstrated that expression of IGFBP-3 is increased in response to hyperglycemia and hypoxia, suggesting a potential role for IGFBP-3 in the corneal epithelial stress response. Using a combination of contemporary cellular, molecular, and biochemical approaches, we now provide new data showing that IGFBP-3 stabilizes mitochondria in CECs through alterations in mitochondrial morphology and mitophagy. This occurs through activation of the mechanistic target of the rapamycin (mTOR) signaling pathway. Taken together, these data highlight a new role for IGFBP-3 in the regulation of mitochondrial and metabolic homeostasis in the corneal epithelium. We next explored the pathophysiological role of IGFBP-3 in mitochondrial respiration, homeostasis, and mitophagy in CECs subject to hyperosmolar stress, as seen in Dry Eye Disease. Unlike hyperglycemia, hyperosmolar stress due to an increase in levels of salt downregulates IGFBP-3 in vitro. The loss of IGFBP-3 in response to hyperosmolar stress is associated with a shift towards a more respiratory phenotype and an increase in mitochondrial fission. In contrast, co-treatment with recombinant human IGFBP-3 induced robust mitochondrial fusion and maintained metabolic activity. The decrease in intracellular IGFBP-3 in response to hyperosmolarity was further confirmed in the mouse corneal epithelium in vivo using an aqueous-deficient dry eye model. These data confirm a novel role for IGFBP-3 in metabolic and mitochondrial homeostasis
Investigating the Role of Complex I Loss in Thyroid Tumorigenesis
Get PDFChanges in cellular metabolism are considered one of the hallmarks of cancer. In 1924, Otto Warburg initially posited that defects in cellular respiration drive tumorigenesis after observing that tumor cells often perform aerobic glycolysis in culture. Since then, multiple studies have demonstrated that most tumors actually require intact cellular respiration for proliferation. However, cancers of the colon, kidney, and thyroid are enriched in loss-of-function mutations predicted to negatively impact respiration. A recent study has shown that a cohort of tall cell variant-papillary thyroid cancer (TCV-PTC) tumors demonstrate widespread loss of Complex I of the electron transport chain. TCV-PTC is a clinically aggressive form of papillary thyroid cancer, driven universally by the BRAF V600E activating mutation. I have developed a murine model of Braf-driven thyroid cancer to investigate the role of Complex I loss in both tumor initiation and progression
Beyond checkpoints: evolving management of advanced melanoma
Get PDFDetailed formal protocol with illustrations and extensive bibliography.A recording of the protocol presentation is available on UT Southwestern's Mediasite. Note: Access to the video is restricted to authorized UT Southwestern users only.UT Southwestern--Internal Medicin
The Contextual Roles of Isocitrate Dehydrogenase-1 and Isocitrate Dehydrogenase-2 in Electron Transport Chain Complex III Deficiency
Get PDFInborn errors of metabolism provide excellent opportunities in translational research, because individual clinical cases can stimulate insights that lead to a deeper understanding of human metabolism and sometimes inform personalized patient care. Our clinical genetics team identified a female patient who presented at age 3 with recurrent episodes of metabolic decompensation involving hypoglycemia and hyperlactatemia, but for whom conventional testing could not identify the underlying molecular defect. Whole exome sequencing identified compound heterozygosity for novel, putatively pathogenic variants in the gene encoding Ubiquinol-Cytochrome C Reductase Core Protein II (UQCRC2), a nuclear-encoded subunit of electron transport chain complex III (ETCIII). Only a handful of UQCRC2-deficient patients have been described worldwide, and none have been subjected to a detailed metabolic analysis to understand the impact of defects in this protein.
We used CRISPR-Cas9 gene editing to generate UQCRC2-deficient cells in order to model deficiency of this protein. Metabolomic profiling of the patient's plasma and UQCRC2 KO cell lines demonstrated strong overlap, including some abnormalities broadly characteristic of ETC defects and others that may be more specific for ETCIII defects. UQCRC2-deficient cells constitutively exhibit reductive glutamine metabolism catalyzed by reversible isoforms of isocitrate dehydrogenase (IDH1 and IDH2) and undergo rapid cell death when glucose becomes scarce.
Reasoning that these cell lines could be used to address basic questions about the contextual roles of IDH1 and IDH2 in regulation of the reductive carboxylation pathway, they were used to create concomitant IDH1 and IDH2 knockout lines. Surprisingly, loss of either enzyme did not suppress cell growth or survival under nutrient-replete conditions. However, we identified differential effects on reductive metabolism and on cell survival under nutrient deprivation. Specifically, we find that IDH1 is primarily responsible for reductive glutamine metabolism in these models of ETCIII deficiency. When glucose and glutamine become scarce, IDH2 supports cell survival while IDH1 becomes detrimental. We speculate that chronic IDH1-dependent utilization of reducing equivalents limits cell survival under nutritional stress. These findings present the first report of a context where wild-type IDH1 activity is detrimental to cell survival
Exploring the Experiences of Caregivers of Black Autistic Children: Barriers and Underrepresentation in Care
Get PDFPage vi is misnumbered as page vii, and page viii is misnumbered as page vii.Approximately 1 in 54 children are diagnosed with autism spectrum disorder (ASD). Research suggests Black children are more likely to be diagnosed later and with more severe ASD than white children and Black families report being more dissatisfied with their child's autism-related care even when adjusting for socioeconomic status. Having an autistic child increases parental stress, and while studies have found support groups to be a helpful for this population, these studies tend be composed of exclusively white participants. To our knowledge, only one other study has examined the experiences of Black families who have an autistic child. Understanding the general experiences of these caregivers, with a special emphasis on coping with the stigma in the Black community is an important area of focus to increase the utilization and satisfaction of their care.
Study aims were to: 1) explore the experiences of caregivers of Black autistic children related to obtaining the diagnosis for their child, participating in care at the Center for Autism and Developmental Disabilities (CADD), and coping with the diagnosis to improve future services and 2) understand the barriers to accessing care at CADD to address the underrepresentation of Black children receiving psychological services in order to improve awareness of barriers and develop a plan to mitigate this by improving access to care. Participants included 12 caregivers of Black autistic children. Qualitative analyses were guided by constructivist grounded theory and utilized the constant comparative approach.
Guided by study aims, qualitative analysis generated four primary sections: Section I: Pre-Diagnosis Experiences; Section II: Post-Diagnosis Experiences; Section III: Autism in the Black Community; and Section IV: Center for Autism and Developmental Disabilities. Findings describe the experience of caregivers and further explore how their child's race has impacted their experiences. Results suggest caregivers find support in sharing their experiences and problems with their immediate family, with friends, particularly those who also have children with disabilities, and by learning and sharing information about ASD with loved ones. Study results also revealed barriers to treatment, identified treatment facilitators, and include recommendations for program improvement, specifically to increase access and utilization of care
Clinical Utility of the AJCC 8th Edition pT1 Subclassification and Impact on Practice Patterns in Stage I Seminoma
No full textThe general metadata -- e.g., title, author, abstract, subject headings, etc. -- is publicly available, but access to the submitted files is restricted to UT Southwestern campus access and/or authorized UT Southwestern users.BACKGROUND: The American Joint Committee on Cancer 8th edition staging guidelines for testicular cancer established a 3 cm cutoff to subclassify stage T1 seminomas (<3 cm = pT1a and ≥3 cm = pT1b). The efficacy of this cutoff in predicting metastatic disease and impact on treatment patterns have not been studied.
METHODS: We retrospectively reviewed patients with pT1 testicular seminoma in the National Cancer Database from 2004-2016. Receiver operating curves (ROC) were used to determine the efficacy of the 3 cm tumor cutoff in identifying metastatic disease, and multivariable regression was used to compute the effect of tumor size on the rate of adjuvant therapy among Stage I patients.
RESULTS: 10,134 patients with pT1 seminoma were evaluated. The current size cutoff of 3 cm for subclassification did not exhibit high discrimination in identifying metastatic disease (area under ROC: 0.546). Surveillance has grown as the preferred treatment after orchiectomy - 32.1% in 2004 to 81.2% in 2015. However, the rate of adjuvant therapy for pT1, Stage I seminomas associated positively with tumor size even with adjustment for year of diagnosis. For tumors above 3 cm, the odds ratio stabilized around 1.9. By using the 3cm cutoff to guide adjuvant therapy, up to 85% of T1b patients may be overtreated.
CONCLUSION: The 3 cm cutoff for subclassification of Stage I seminoma does not predict metastatic recurrence but is associated with increased receipt of adjuvant therapy. A 3 cm cutoff and the pT1a/b classification may therefore contribute to overtreatment in many young patients with a long life expectancy for whom minimizing adverse effects should be prioritized
Enabling Structural Studies of the Yeast Prion Protein Within a Cellular Environment
No full textMy motivation for the work in this thesis was to take steps towards bridging the gap in structural information between atomic models of metastable proteins in isolated and cellular environments. Most biophysical techniques are generally limited by either sample composition or resolution. One technique, Nuclear Magnetic Resonance (NMR) is not limited by sample composition and can provide atomic-level resolution. However, NMR is limited by sensitivity. Recent advancements in the field produced a sensitivity-enhanced solid-state NMR technique, namely Dynamic Nuclear Polarization (DNP) NMR. Using DNP NMR, I observed sensitivity enhancements of up to 90-fold increase in sensitivity, eliminating this barrier.
Recent work on a metastable protein, Sup35, assembled in cellular lysates using DNP NMR demonstrates that the biological environment has a dramatic effect on the Sup35 protein structure. In this thesis, I sought to harness sensitivity gains from DNP NMR to identify strategies for the specific detection of isotopically labeled proteins at within a cellular lysate for structural analysis. First I present theoretical calculations, validated by experimental results, for the expected signal of detection ratio of an isotopically labeled protein within a cellular lysate. These results concluded that DNP NMR can specifically detect a 30 kDa, uniformly isotopically labeled protein at low micromolar concentrations. However, sensitivity is still a barrier to specifically detect proteins with lower molecular weights or non-uniform isotopic labeling. Therefore, I optimized sample preparation for maximum sensitivity for DNP NMR on cellular lysates. DNP sensitivity enhancement depends on sample composition. DNP NMR is performed at 100 K, and requires sample glassing, polarizing agent, and protonation for optimal DNP enhancement. Some of the first DNP NMR experiments on purified protein samples were optimized for a matrix of 60:30:10, d8-glycerol:D2O:H2O with 10 mM biradical. These matrix conditions became standard in the field, known as "DNP Juice". However, I found that these matrix conditions are not optimal for DNP NMR cellular lysate samples. In the presence of cellular lysate, sensitivity is improved by addition of lower cryoprotectant (15%) and biradical concentrations (5 mM). I also found that deuteration was unnecessary. Finally, I investigated methods to simplify DNP NMR spectra through segmental labeling of proteins. The strategies in this thesis benefit future research of structural studies on environmentally sensitive proteins, such as alpha-synuclein or tau, within their native environment at physiological concentrations
The Migraine Disability Assessment (MIDAS) as an Indicator of Resilience in Patients with Headaches
No full textBACKGROUND: The Migraine Disability Assessment is a clinical tool to measure disability in migraine patients. However, Migraine Disability Assessment predicted disability does not always correlate with actual functional disability, with some high-scoring patients remaining high functioning, and some low-scoring patients having poor functional outcomes. Based on these observed discrepancies, we investigated whether the Migraine Disability Assessment was also an indicator of resilience. Our objectives were to correlate the degree of headache disability with measures of resilience, as quantified by the Conner Davidson Resilience Scale; determine whether the level of resilience modified the association between headache severity/frequency and disability; and assess the association between anxiety and depression with resilience in headache patients.
METHODS: We prospectively recruited patients with primary headache disorders seen in an academic, tertiary Headache Medicine program between 02/20/2018 and 08/02/2019 to participate in this study. Each participant completed 5 validated measures in the clinic: Migraine Disability Assessment, Conner Davidson Resilience Scale, Patient Health Questionnaire-9, General Anxiety Disorder-7 and WHO Well-Being Index.
RESULTS: Complete data were obtained and analyzed for 160 participants. Consistent with our hypothesis, the Conner Davidson Resilience Scale score was negatively correlated with total Migraine Disability Assessment score (r= -.0.21, p=0.0091), total General Anxiety Disorder-7 score (r= -0.56, p 21), logistical regression models showed negative associations between resilience and headache-related disability, anxiety and depression. A one point increase in the Conner Davidson Resilience Scale score decreased the odds of being severely disabled by 4% (OR = 0.96, p=0.001). After adjusting for resilience score and age, only the total General Anxiety Disorder-7 score was associated with severe disability, with a one-point increase in total General Anxiety Disorder-7 score increasing the odds of severe disability by 16% (OR=1.16, p<.001). Similarly, a one point increase in total Patient Health Questionnaire-9 score, increased the odds of being severely disabled by 24% (OR=1.24, p<.001).
CONCLUSION: A higher resilience score inversely correlated with headache-related disability in this cohort. In participants with severe disability as measured by Migraine Disability Assessment, higher levels of anxiety and depression were associated with increased levels of headache-related disability