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Aging and the kidney: lessons for health?
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
Ethical issues at the end of life in Catholic bioethics
No full textTuesday, September 13, 2022; noon to 1 p.m. (Central Time); via Zoom. "Ethical Issues at the End of Life in Catholic Bioethics". Becket Gremmels, Ph.D.; System Vice President, Theology and Ethics; Mission Innovation, Theology and Ethics, CommonSpirit Health®Since over 20% of Americans are Catholic, and 1 in 7 patients in the U.S. is admitted to a Catholic hospital, Catholic moral theology has a significant impact on medical decisions at the end of life. In this talk, Dr. Gremmels will outline foundational principles and concepts in Catholic moral theology regarding end of life care. He will review the 1,800-year history of the development of these principles, discuss some recent developments in Church teaching, and provide examples of how patients and clinicians might apply them in a clinical setting. Participants will learn concepts and language to talk to patients about end-of-life care and help identify when seeking ethics expertise might be helpful.UT Southwestern--Program in Ethic
Nuclear Export Signal Recognition by CRM1 Carrying the Oncogenic E571K Mutation and Structure-Based NES Prediction
Get PDFNuclear-cytoplasmic trafficking is an essential cellular process in eukaryotes that maintains and regulates the spatial distribution of key cellular processes in the nucleus and the cytoplasm. CRM1 is the major nuclear export mediator, which facilitates nuclear export of hundreds of protein and RNA molecules. CRM1 is essential to the survival of eukaryotic cells and is overexpressed or mutated in a variety of cancers. This involvement of CRM1 in cancer cell survival has led to the development of novel small molecule inhibitors such as XpovioTM or Selinexor, which has been approved for treatment of advanced and relapsed multiple myeloma and is also in many clinical trials for a variety of cancers. In addition, the point mutant CRM1(E571K) is found in a variety of tumors and is highly prevalent in some B-cell lymphomas.
A deep understanding of how CRM1 recognizes the diverse NESs in hundreds to thousands of cargos is needed to understand the role of CRM1 in cancer pathogenesis and the mechanism of action of its inhibitors. My work has focused on expanding our foundational knowledge of CRM1-NES interactions in the presence and absence of the oncogenic E571K mutation.
Previous studies measured the affinities of CRM1 interactions with 22 different nuclear export signals (NESs) from protein cargos using a low-throughput differential photobleaching assay. However, hundreds of very diverse CRM1 cargos and their NESs have yet to be characterized, limiting our understanding of the biological roles of CRM1 in disease. I developed a high-throughput, quantitative fluorescence polarization assay to measure the affinity of >100 NES peptides for WT CRM1 and for the oncogenic CRM1(E571K) to understand how the mutation affects NES binding. The large body of CRM1-NES affinity data was also used to develop a new structure-based NES prediction method.
The CRM1 oncogenic mutation E571K is highly prevalent in some subtypes of B-cell lymphomas and can drive tumors in mouse B-cell models, but the mechanism of tumorigenesis is unclear. Using structural and biophysical approaches, I studied the recognition of 27 diverse NESs by CRM1(E571K) and showed that while most cargos are unaffected by the mutation, a small subset of highly charged NESs have greater than 10-fold affinity changes for the cancer mutant. To study whether these affinity changes cause nuclear export defects in cells, I used CRISPR/Cas to generate generated HEK 293 cells with either monoallelic CRM1WT/E571K or biallelic CRM1E571K/E571K. HEK 293 cells with CRM1WT/E571K or CRM1E571K/E571K had decreased proliferation and cells with homozygous CRM1E571K/E571K had obvious cell cycle defects. The eIF4E-Transporter which binds 10-fold weaker to CRM1(E571K) is mislocalized in HEK 293 cells with CRM1(E571K) and in chronic lymphocytic leukemia patient cells burdened with the CRM1 mutation. Additionally, I solved crystal structures of CRM1 bound to covalent KPT inhibitors, which showed that the mutation site, position 571 of CRM1, is located far from the bound drugs and thus unlikely to substantially affect their ability to inhibit CRM1.
In order to understand the effects of the E571K on CRM1 activity and further illuminate possible cancer mechanisms, it is crucial to identify many more NESs across the entire human proteome. Therefore, NES prediction is of great interest, but existing sequence-based approaches give high false positive rates. My work also shows that may NES-like peptides are not accessible in the full-length cargos to to CRM1, in ways that many existing NES predictors cannot identify. To improve NES prediction, our collaborators in the Grishin Lab utilized CRM1-NES crystal structures as templates to develop a structure-based NES predictor and incorporated full-length protein context considerations to accurately identify novel NESs that are likely to be functional. I contributed to this work by expanding the CRM1-NES structural dataset and I helped to interpret modeling outliers to iteratively improve the CRM1-bound NES models. I also assisted the Grishin lab in using this structure-based predictor to map somatic mutations found in cancer patients that may disrupt nuclear export of the NES-containing proteins.
Overall, I have added >100 new CRM1-NES binding affinity measurements and 16 CRM1 (WT or E571K) crystal structures to the field. These results have shown how the oncogenic E571K mutation binds very differently to small subset of highly charged cargos, and provided a robust dataset to develop a new structure-based NES prediction tool. Future work will build on this foundation to clearly illustrate how nuclear export defects lead to oncogenesis, and potentially give key insights into improving use of CRM1-targeted therapeutics
Cesarean Section and Risk of Adenomyosis: A Retrospective Study
Get PDFThe 60th Annual Medical Student Research Forum at UT Southwestern Medical Center (Tuesday, February 1, 2022, 3-6 p.m., Microsoft Teams)BACKGROUND: History of uterine surgery, most notably a history of dilation and curettage (D&C), has been shown to be a risk factor for the development of adenomyosis. The association between prior cesarean sections (CS) and adenomyosis remains unclear.
OBJECTIVE: The primary aim of this study is to determine if there is an association between adenomyosis and history of uterine surgery, including CS, D&C, and myomectomy. We also examine if repeat uterine surgery increases the risk of adenomyosis development.
STUDY DESIGN: In this retrospective case control study we collected data from the electronic medical records of all women who underwent hysterectomy for benign indications at Parkland Hospital between January 2014 and December 2018. We then compared patients with and without adenomyosis on surgical pathology regarding history of uterine surgery, including CS, myomectomy and D&C.
RESULTS: 2,911 patients were included in final analysis. History of any uterine surgery was associated with an increased risk of adenomyosis. Patients with a history of D&C were significantly more likely to have adenomyosis on surgical pathology (OR 1.57, 95% CI 1.30-1.90). There was also risk associated with repeat D&C (OR 1.31, 95% CI 1.01-1.72). The association between history of prior CS was not statistically significant (OR 1.12, 95% CI 1.00-1.37). A history of prior myomectomy was also not significantly associated with adenomyosis (OR 0.95, 95% CI 0.59-1.54).
CONCLUSION: Of the risk factors explored, history of any uterine surgery, D&C and repeat D&C were associated with an increased risk of adenomyosis, which is consistent with prior studies. There was not an association between history of CS or increasing numbers of repeat cesareans with adenomyosis development. This contradicts the theory that disruption of uterine endometrium and the trauma of cesarean section predisposes individuals to developing adenomyosis. This is the largest retrospective case control study to date investigating this association, and with the results found, it can be concluded that CS individually do not increase the risk of adenomyosis.Southwestern Medical Foundatio
Riding in an Elevator with a Nobel Prize Winner
Get PDFThis work received a First Place Award in the "Open Verse Poetry" category from all literary works submitted in the 2022 On My Own Time show.This poem came from two prompts from Rattle Magazine's open mic. One was to write a demi-sonnet, and the other was "someone says something strange to you in an elevator". I decided to make myself the person who said something strange because it does feel awkward to be in an elevator with a Nobel Prize winner. The inspiration for the comment was actually my partner who didn't know what else to write in the guest book after the celebration honoring Dr. Beutler's Nobel Prize win
Tear Biomarkers and Corneal Sensitivity as an Indicator of Neuropathy in Type 2 Diabetes
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: Diabetic peripheral neuropathy (DPN) is a debilitating, progressive complication of type 2 diabetes. The high cost of management leads to amputations in approximately 6% of individuals with DPN in poor-resource settings due to medical noncompliance or lack of finances. Having an effective means of early detection of DPN is crucial for early intervention, which would have a major impact in alleviating its social, economic, and medical burden.
OBJECTIVES: To explore the potential of 31 tear biomarkers involved in both corneal growth and development and inflammatory pathways in screening for diabetic peripheral neuropathy (DPN). Additionally, the utility of aesthesiometry for measuring corneal damage in DPN was assessed.
METHODS: This screening test pilot study recruited 90 participants from a tertiary hospital in Lima, Peru. Participants were categorized into three groups based on diabetes and neuropathy status. Tears were collected on Schirmer strips, and proteins were measured by both ELISA and multiplex-bead assay. Corneal sensitivity was measured by aesthesiometry, and DPN was measured through vibration perception threshold testing.
RESULTS: A total of 89 participants were included in the analysis. The mean age was 55.7+1.46, and 58.4% were female. After adjusting for potential confounders, MMP-9 and TGF-alpha levels showed a strong upward trend in participants with DPN when compared to those with diabetes alone, though not significant. Decreased corneal sensitivity, as measured by aesthesiometry, was negatively correlated with MMP-9 levels (p<0.01) in individuals with DPN. Aesthesiometry was significantly decreased in individuals with DPN when compared to participants with diabetes alone (p<0.01) and normal controls (p<0.01).
CONCLUSIONS: Although tears are a simple and inexpensive resource with promise to help detect DPN, it is an insufficient standalone tool for detecting DPN based on the present study. Aesthesiometry is a simple, inexpensive, and accurate method to assess corneal damage associated with DPN, and its integration into screening practices has potential to improve detection of DPN in poor-resource settings
Albumin Is Predictive of 1-Year Mortality After Transcatheter Aortic Valve Replacement
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: A validated model for predicting 1-year outcomes after transcatheter aortic valve replacement (TAVR) does not exist. Frailty markers have been proposed as potential variables to assess individual patient risk. TAVR-specific risk models may benefit from frailty markers, and sarcopenia may represent an objective frailty marker.
OBJECTIVE: This study assessed the predictive ability of sarcopenia and frailty markers on 1-year mortality after TAVR.
METHODS: We evaluated 470 patients undergoing TAVR at a single center. Frailty was assessed using 4 markers (gait speed, handgrip strength, serum albumin, and Katz activities of daily living). Sarcopenia was measured as the cross-sectional psoas muscle area on pre-TAVR computed tomography. Performance of four models incorporating Society of Thoracic Surgeons Predicted Risk of Mortality (STS-PROM), frailty, and/or sarcopenia metrics for predicting 1-year mortality was assessed with area under the curve, Hosmer-Lemeshow statistics, and calibration plots.
RESULTS: A total of 63 (13.4%) deaths occurred by 1-year. STS-PROM alone was poorly predictive of 1-year mortality (AUC 0.52, 95%CI: 0.42, 0.68). Only the model including both sarcopenia and all frailty markers (AUC 0.61, 95%CI: 0.53, 0.68) significantly improved predictive ability compared to STS-PROM alone (p = 0.05). Albumin was the only frailty marker significantly associated with increased risk for 1-year mortality (p=0.03). Psoas muscle area, as a surrogate for sarcopenia, was not significantly associated with increased risk for 1-year mortality.
CONCLUSIONS: Most commonly used pre-TAVR risk assessments are poorly predictive of 1-year mortality. Albumin was the only frailty marker that was associated with higher mortality. Future studies should investigate whether optimization of nutritional status can improve outcomes following TAVR
Translational Repression of G3BP in Cancer and Germ Cells Suppresses Stress Granules and Enhances Stress Tolerance
Get PDFMelanoma antigen (MAGE) genes are conserved in all eukaryotes and encode for proteins sharing a common MAGE homology domain. Although only a single MAGE gene exists in lower eukaryotes, the MAGE family rapidly expanded in eutherians and consists of more than 50 highly conserved genes in humans. A subset of MAGEs initially garnered interest as cancer biomarkers and immunotherapeutic targets due to their antigenic properties and unique expression pattern that is primary restricted to germ cells and aberrantly re-activated in various cancers. However, further investigation revealed that MAGEs not only drive tumorigenesis, but also regulate pathways essential for diverse cellular and developmental processes. Therefore, MAGEs are implicated in a broad range of diseases including neurodevelopmental, renal, and lung disorders, as well as cancer. Recent biochemical and biophysical studies indicate that MAGEs assemble with E3 RING ubiquitin ligases to form MAGE-RING ligases (MRLs) and act as regulators of ubiquitination by modulating ligase activity, substrate specification, and subcellular localization. Here, we present a comprehensive guide to MAGEs highlighting the molecular mechanisms of MRLs, their physiological roles in germ cell and neural development, oncogenic functions in cancer, and potential as therapeutic targets in disease.
Stress granules (SG) are membrane-less ribonucleoprotein condensates that form in response to various stress stimuli via phase separation. SG act as a protective mechanism to cope with acute stress, but persistent SG have cytotoxic effects that are associated with several age-related diseases. Here, we demonstrate that the testis-specific protein, MAGE-B2, increases cellular stress tolerance by suppressing SG formation through translational inhibition of the key SG nucleator G3BP. MAGE-B2 reduces G3BP protein levels below the critical concentration for phase separation and suppresses SG initiation. Importantly, knockout of the MAGE-B2 mouse ortholog or overexpression of G3BP1 confers hypersensitivity of the male germline to heat stress in vivo. Thus, MAGE-B2 provides cytoprotection to maintain mammalian spermatogenesis, a highly thermo-sensitive process that must be preserved throughout reproductive life. These results demonstrate a mechanism that allows for tissue-specific resistance against stress and could aid in the development of male fertility therapies
The M&M conference: let's stop sugar-coating the facts
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