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Malignant Childhood Ovarian Cancer: A Ten-Year Retrospective Review
Get PDFThe 62nd Annual Medical Student Research Forum at UT Southwestern Medical Center (Tuesday, January 30, 2024, 3-6 p.m., D1.700 Lecture Hall)BACKGROUND: Although pediatric ovarian cancer is rare (2.1-2.6/ 100,000 females per year), 10-30% of masses are malignant. Our primary aim was to confirm the incidence and type of ovarian malignant and borderline neoplasms over a ten-year period, and to describe their presentation and clinical characteristics. Furthermore, through analysis of pre-operative workups, we sought to elucidate better predictive indicators of malignancy to help guide future treatment.
METHODS: Retrospective analysis of patients (<19 years old) who underwent surgery for borderline or malignant ovarian tumors from 01/01/2009 to 12/31/2018 was performed. Patient records were analyzed for age, presentation, serum marker levels, imaging findings, treatment (surgical plan and therapy), and patient outcomes.
RESULTS: A total of 42 malignant and 7 borderline ovarian tumors were included in this study. Germ cell tumors were the most common malignancy (64%) followed by stromal tumors (31%), while one epithelial mucinous tumor and one small cell tumor were found (2% each). Of the borderline tumors, serous (71 %) were more common than mucinous tumors (29%). Average patient age was 13 ± 3.9 years, and the primary presenting symptoms were pain (45%) or abdominal distension (43%). Significant elevations in alpha fetoprotein, beta human chorionic gonadotropin, lactate dehydrogenase and cancer antigen-125 serum tumor markers were noted in malignancies. Eighty-eight percent of surgeries were performed as laparotomies, and the most common operation was salpingo-oopherectomy (67%). The average tumor size was 14.6 cm. ±6.6 cm. and the majority were characterized as heterogeneous (80%). All tumors were resected, and 21 (50%) malignant tumors received postoperative chemotherapy, while no borderline cases received therapy. Average postoperative follow-up time was 38.6 months, and forty-five (92%) patients were alive at the time of data collection.
CONCLUSIONS: Germ cell tumors were confirmed as the most common pediatric ovarian malignancy, followed by stromal tumors. Very few epithelial tumors were noted, as compared to prior studies. Borderline neoplasms were uncommon and had favorable outcomes. In treating pediatric ovarian malignancy, we aim to maximize patient survival while preserving fertility. We recommend a standardized preoperative workup consisting of multi-modal imaging studies and a complete tumor marker panel for all patients presenting with suspicion for an ovarian tumor.Southwestern Medical Foundatio
ADAP1 Promotes Latent HIV-1 Reactivation by Tuning the KRAS-ERK-AP-1 Signaling-Transcriptional Axis
Get PDFImmune stimulation fuels cell signaling-transcriptional programs that induce biological responses to eliminate virus-infected cells. Yet, retroviruses that integrate into host cell chromatin, such as HIV-1, co-opt these programs to switch between latent and reactivated states. However, many regulatory mechanisms are still unfolding. As such, here I take advantage of the unique intrinsic reliance HIV-1 has on host cell signaling-transcriptional programs to discover undescribed cell signaling regulators. Specifically, I implemented a functional screening platform, given HIV-1 gene expression relies on CD4+ T cell activation state, to identify host factors modulating CD4+ T cell signaling-transcriptional axes and consequently HIV-1 fate. Among the hits, I focus on ADAP1 (ArfGAP with Dual PH Domains 1), a previously thought neuro-restricted factor, and discover it is an amplifier of select human CD4+ T cell signaling programs. Using physiological models, I characterize ADAP1 expression is low in naïve and memory CD4+ T cells, but largely induced upon immune stimulation where it interacts with the immune signalosome. Using complementary biochemical and cellular assays, I demonstrate ADAP1 directly stimulates the GTPase activity of KRAS to amplify CD4+ T cell signaling through targeted activation of ERK-AP-1 axis. In primary CD4+ T cells which I have genetically ablated ADAP1, I show loss of ADAP1 function blunts gene expression programs in response to stimulation thereby reducing CD4+ T cell expansion and dampening latent HIV-1 reactivation. Supporting the impact of these findings, I propose the reduced CD4+ T cell programs and proliferation upon ADAP1 loss validates Genome-wide Association Studies linking ADAP1 single nucleotide polymorphisms in non-coding enhancers to an altered T lymphocyte count trait, potentially attributed to ADAP1 haploinsufficiency. Through these combined experimental approaches, I was able to define ADAP1 as an unexpected tuner of CD4+ T cell activation programs and co-opted by HIV-1 to escape latency
Development of Deep Learning Artificial Intelligence to Detect Osteoporosis and Osteopenia
No full textThe 62nd Annual Medical Student Research Forum at UT Southwestern Medical Center (Tuesday, January 30, 2024, 3-6 p.m., D1.700 Lecture Hall)Each year the Medical Student Research Program awards students for the best oral presentation and the best poster presentation as judged by faculty across campus. This author received an award as one of the best poster presentations at this forum.Osteoporosis poses a substantial social and economic burden, with estimated treatment costs reaching a combined six trillion USD in the USA, Canada, and Europe. Although dual-energy X-ray absorptiometry (DEXA) is the diagnostic gold standard, computed tomography (CT) scans have proven to be reliable proxies for bone density measurement. Opportunistic screening for low bone density using CT obtained for other purposes can potentially reduce complications from osteoporotic fractures and health care costs. In this study, we developed an artificial intelligence (AI) algorithm using neural networks and the MONAI library to estimate DEXA bone density from non-contrast cardiac CT obtained for coronary calcium scoring purposes.
A total of 2797 Dallas Heart Study phase 2 participants (39% male, 61% female) were included. The AI algorithm was first developed to automatically segment trabecular bone from cortical bone. This was trained and validated with manual segmentation of the trabecular bone by two medical students, a radiologist, using MONAI 3D autoseg. The ML algorithm achieved a Dice score of 0.97 when compared to human segmentation. A second AI model was developed utilizing segmentations of the first model. This AI was trained utilizing corresponding DEXA bone mineral density (BMD) for thoracic vertebrae. The best performing model was trained for 102 epochs, resulting in a training root mean square error (RMSE) of 0.0628 mg/cm2 and validation RMSE of 0.0842 mg/cm2. The final AI algorithm predictions yielded an R2 value of 0.71 compared to DEXA (Figure 1).
Our findings underscore the clinical feasibility for an automated neural network to predict DEXA scores from non-contrast cardiac CT.
This approach may help in the early detection of unsuspected low bone mineral density in patients undergoing CT scans for other reasons, allowing for potential improvements in patient outcomes and resourceful utilization of diagnostic imaging.Southwestern Medical Foundatio
Narcissist
Get PDFThe author submitted this entry in the 10-Word Story category (Amateur division) for the 2024 On My Own Time (OMOT) Art Show.Many stories in our life touch us. Some inspire us to pen notes, journals, and poems. This one was inspired from a story
Systematic Review of the Global Literature on Uncomplicated Recurrent Urinary Tract Infections in Women: Underscoring Major Heterogeneity
No full textThe 62nd Annual Medical Student Research Forum at UT Southwestern Medical Center (Tuesday, January 30, 2024, 3-6 p.m., D1.700 Lecture Hall)Each year the Medical Student Research Program awards students for the best oral presentation and the best poster presentation as judged by faculty across campus. This author received an award as one of the best poster presentations at this forum.INTRODUCTION: Urinary tract infections (UTI) are common infections affecting over 60% of women and often become recurrent (rUTI). Despite their prevalence, research on rUTIs is limited and results are heterogenous due to varying definitions and populations. This systematic review examines global literature on uncomplicated rUTI and assesses differences in data based on geographic region.
METHODS: Databases PubMed, Embase, WHO Global Index Medicus, and SciELO were searched for the keywords and/or MESH terms for recurrent and UTI, 2000- 2023. Studies were restricted to females ≥18 with uncomplicated rUTIs. Studies were excluded if they did not provide a definition for rUTI or did not cite/report an estimate for rUTI prevalence. The review was registered in PROSPERO and conformed to PRISMA.
RESULTS: The search yielded 2,947 studies of which 124 were included (Table 1). Most studies were conducted in Europe (41%) or North America (39%), were prospective (52%), at tertiary centers (49%) and included all age groups (60%). Public institutions were the most common in North America (67%) while multi-center and public institutions were equally frequent in Europe (39% each). The most common definition for rUTI was 2 UTI/6m or 3 UTI/1y (62%). Regardless of study location, most studies cited prevalence estimates for rUTI from U.S.-based populations. Convenience samples were used for 91% of studies and sample sizes were: 30% n<50, 29% n=50-99, 22% n=100-199, 36% n≥200.
CONCLUSIONS: This study represents the first formal investigation of the global literature base on uncomplicated rUTI. Studies on rUTIs are globally of small scale and definitions used for rUTI are heterogeneous. More studies are needed to ascertain the true prevalence of rUTI outside of North America and Europe.Southwestern Medical Foundatio
β-Globin Enhancers Regulate Bistable Gene Expression States
No full textMultiple enhancers can coordinately regulate a target gene to ensure robust expression. Under the failure rate model, each redundant enhancer contributes a probability of target gene expression in the cell, and genetic deletion will cause single-cell expression phenotypes. However, this model has been challenging to test in human cells. To examine the role of the human β-globin enhancers in controlling single-cell expression phenotypes, we engineered a haploid locus in K562 cells that fluorescently reports the expression of HBG1. We isolated combinatorial enhancer deletion clones having single-cell expression phenotypes. Genetic and epigenetic analysis shows that deletion of HS3 or HS4 yields clonal cells having bimodal expression of HBG1. Time course analysis indicates that clonal cells can transition between bimodal expression states, and that GFP+ cells have more open chromatin at the HBG1 promoter than GFP- cells. Finally, we derive failure rate contributions for several enhancers. Thus, β-globin enhancers regulate bistable gene expression states, supporting the failure rate model of enhancer redundancy in human cells
Protecting the legitimacy of medical expertise: combating misinformation in medicine
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 Crosstalk Between DNA Mismatch Repair and Replication
No full textDNA replication fidelity relies on DNA mismatch repair (MMR) and the proofreading nuclease activity of DNA polymerases. Normally, biosynthetic errors can be removed by the polymerase's proofreading nuclease activity upon their incorporation, and those errors that have escaped the proofreading nuclease are corrected by MMR. However, this model is challenged by the fact that cells expressing a proofreading-deficient P286R polymerase ɛ (Polɛ-P286R) display a hypermutable phenotype usually seen in MMR-deficient cells, implying the blockage of MMR function by Polɛ-P286R. We show here that consistent with frequent misincorporation by Polɛ-P286R, elevated levels of MMR proteins were found in replicating DNA/chromatin in Polɛ-P286R cells, but this does not result in a reduced mutation frequency, suggesting that cluster binding of MMR proteins at the replication fork inhibits MMR. Instead, the high-level binding of MMR proteins blocks the recruitment of fork protection factors FANCD2 and BRCA1 to replication forks, and promotes MRE11-catalyzed nascent strand degradation. This MMR-dependent degradation causes DNA breaks and chromosome abnormalities, thereby promoting an ultramutator phenotype. Therefore, our findings identify a novel MMR function in triggering replication stress response to promote genome instability when replication forks are filled with biosynthetic errors.
The importance of MMR in maintaining genome stability prompts us to further study the mechanism of MMR in vitro, particularly how the MMR initiation complex is formed in response to misincorporation. Using purified recombinant proteins, we assembled MMR initiation complex in vitro and visualized protein-protein and protein-DNA interactions under transmission electron microscopy. These analyses allowed us to gain molecular insights into the mechanism of MMR initiation
Factors Governing Gastrointestinal Colonization of Candida albicans
Get PDFCandida albicans can colonize the human gastrointestinal tract (GI) and cause disseminated infections in immunocompromised hosts. Depletion of specific gut commensal microbiota is associated with or results in increased C. albicans burden in the gut and increased likelihood of dissemination in human patients and mice, respectively. The exact mechanisms by which gut microbiota mediate C. albicans colonization resistance in the gut, however, are unknown. Here, we show that gut microbiota-derived short chain fatty acids (SCFA) directly inhibit C. albicans growth in vitro. SCFA inhibit C. albicans hexose uptake and induce intracellular acidification. In contrast, SCFA promote C. albicans GI colonization resistance in vivo but only when an intact gut microbiome is present. SCFA induce gut microbiota composition changes that promote C. albicans colonization resistance. Commensal gut microbiota unable to produce SCFA have a diminished capacity to reduce C. albicans GI colonization. Prebiotic therapy results in increased GI SCFA levels which enhance C. albicans GI clearance. This work also describes two C. albicans isolates 529L and CHN1 that can stably colonize the murine GI tract without the use of antibiotics. These clinical isolates have a higher resistance to antimicrobial peptide CRAMP compared to the most commonly studied C. albicans laboratory strain SC5314. Thus, the work sheds light on mechanisms that might be critical in governing C. albicans gastrointestinal colonization levels. It provides mechanistic insights into the importance of gut microbiota-derived metabolites in maintaining C. albicans colonization resistance and may have therapeutic implications for modulating C. albicans gastrointestinal colonization levels in order to prevent invasive candidiasis in immunocompromised patients. Further, C. albicans strain-specific difference in colonization ability appears to depend on the sensitivity to these host immune effectors. The described isolates can further serve as valuable tools to probe the mechanisms of C. albicans gastrointestinal colonization without the intervention of any antibiotics
Revealing hidden systems in clinical care
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