Recent Research Publications- January 2024
The biology of hope: Inflammatory and neuroendocrine profiles in ovarian cancer patients.
Lutgendorf SK, Telles RM, Whitney B, Thaker PH, Slavich GM, Goodheart MJ, Penedo FJ, Noble AE, Cole SW, Sood AK, Corn BW.
Brain Behav Immun. 2023 Dec 9:S0889-1591(23)00396-3. doi: 10.1016/j.bbi.2023.12.014. Epub ahead of print. PMID: 38081436.
Introduction: Although the concept of hope is highly relevant for cancer patients, little is known about its association with cancer-relevant biomarkers. Here we examined how hope was related to diurnal cortisol and interleukin-6 (IL-6), a pro-inflammatory cytokine previously associated with tumor biology and survival in ovarian cancer. Secondly, we examined whether hope and hopelessness are distinctly associated with these biomarkers.
- Participants were 292 high-grade ovarian cancer patients who completed surveys and provided saliva samples 4x/daily for 3 days pre-surgery to assess diurnal cortisol. Blood (pre-surgery) and ascites were assessed for IL-6. Hope and hopelessness were assessed using standardized survey items from established scales (Center for Epidemiological Studies Depression Scale; Profile of Mood States, Functional Assessment of Cancer Therapy). Two hopeless items were z-scored and combined into a composite for analysis. Regression models related these variables to nocturnal cortisol, cortisol slope, plasma and ascites IL-6, adjusting for cancer stage, BMI, age, and depression.
- Greater hope was significantly related to a steeper cortisol slope, β = -0.193, p = 0.046, and lower night cortisol, β = -0.227, p = 0.018, plasma IL-6, β = -0.142, p = 0.033, and ascites IL-6, β = -0.290, p = 0.002. Secondary analyses including both hope and hopelessness showed similar patterns, with distinct relationships of hope with significantly lower nocturnal cortisol β = -0.233,p = 0.017 and ascites IL-6, β = -0.282,p = 0.003, and between hopelessness and a flatter cortisol slope, β = 0.211, p = 0.031.
Conclusions: These data suggest a biological signature of hope associated with less inflammation and more normalized diurnal cortisol in ovarian cancer. These findings have potential clinical utility but need replication with more diverse samples and validated assessments of hope.
Low indoleamine 2, 3 dioxygenase (IDO) activity is associated with psycho-obstetric risk.
Gumusoglu S, Meincke CR, Kiel M, Betz A, Nuckols V, DuBose L, Steidele J, Sweezer E, Santillan D, Stroud AK, Pierce GL, Santillan MK.
Pregnancy Hypertens. 2023 Dec 7;35:12-18. doi: 10.1016/j.preghy.2023.11.008. Epub ahead of print. PMID: 38064980.
Objectives: Preeclampsia and depression in pregnancy are among the most prevalent obstetric disorders with no known cures. While depression and preeclampsia each increase risk for the other, shared mechansisms are unclear. One possibility is low levels of Indoleamine 2,3 dioxygenase (IDO), which links immune dysregulation and oxidative arterial damage resulting in poor vascular function in both preeclampsia and depression. We hypothesized low circulating IDO activity levels in pregnancy would correspond to poor vascular function and depression symptoms.
Study design: In this nested case-control study, clinical, demographic, and biologic data from a cohort of pregnant women recruited to longitudinal studies measuring noninvasive vascular function and circulating factors were analyzed.
Main outcome measure: IDO activity across all three trimesters of pregnancy was measured using a colorimetric assay. Carotid-femoral pulse wave velocity (cfPWV), a measure of arterial stiffness, was also assessed throughout gestation by non-invasive applanation tonometry. Depression symptoms were assessed in pregnancy via the validated patient health questionnaire 9 (PHQ9).
Results: Participants with low second and third trimester IDO activity had significantly decreased cfPWV. This association remained statistically significant when controlled for confounders such as BMI and chronic hypertension in the third but not second trimester. While PHQ9 scores were not associated with cfPWV differences, IDO activity was lower in moderate and severely depressed relative to non-depressed pregnant individuals.
Conclusion: These results implicate IDO in arterial stiffness and depression symptoms, suggesting that decreased IDO may be a central target for improved psycho-obstetric health.
Davis HA, Santillan DA, Ortman CE, Hoberg AA, Hetrick JP, McBrearty CW, Zeng E, Vaughan Sarrazin MS, Dunn Lopez K, Chapman CG, Carnahan RM, Michaelson JJ, Knosp BM.
J Am Med Inform Assoc. 2023 Dec 15:ocad236. doi: 10.1093/jamia/ocad236. Epub ahead of print. PMID: 38102790.
Importance: This manuscript will be of interest to most Clinical and Translational Science Awards (CTSA) as they retool for the increasing emphasis on translational science from translational research. This effort is an extension of the EDW4R work that most CTSAs have done to deploy infrastructure and tools for researchers to access clinical data.
- : The Iowa Health Data Resource (IHDR) is a strategic investment made by the University of Iowa to improve access to real-world health data. The goals of IHDR are to improve the speed of translational health research, to boost interdisciplinary collaboration, and to improve literacy about health data. The first objective toward this larger goal was to address gaps in data access, data literacy, lack of computational environments for processing Personal Health Information (PHI) and the lack of processes and expertise for creating transformative datasets.
- : A three-pronged approach was taken to address the objective. The approach involves integration of an intercollegiate team of non-informatics faculty and staff, a data enclave for secure patient data analyses, and novel comprehensive datasets.
- To date, all five of the health science colleges (dentistry, medicine, nursing, pharmacy, and public health) have had at least one staff and one faculty member complete the two-month experiential learning curriculum. Over the first two years of this project, nine cohorts totaling 36 data liaisons have been trained, including 18 faculty and 18 staff. IHDR data enclave eliminated the need to duplicate computational infrastructure inside the hospital firewall which reduced infrastructure, hardware and human resource costs while leveraging the existing expertise embedded in the university research computing team. The creation of a process to develop and implement transformative datasets has resulted in the creation of seven domain specific datasets to date.
- The combination of people, process, and technology facilitates collaboration and interdisciplinary research in a secure environment using curated data sets. While other organizations have implemented individual components to address EDW4R operational demands, the IHDR combines multiple resources into a novel, comprehensive ecosystem IHDR enables scientists to use analysis tools with electronic patient data to accelerate time to science.
Welch BM, Keil AP, Buckley JP, Engel SM, James-Todd T, Zota AR, Alshawabkeh AN, Barrett ES, Bloom MS, Bush NR, Cordero JF, Dabelea D, Eskenazi B, Lanphear BP, Padmanabhan V, Sathyanarayana S, Swan SH, Aalborg J, Baird DD, Binder AM, Bradman A, Braun JM, Calafat AM, Cantonwine DE, Christenbury KE, Factor-Litvak P, Harley KG, Hauser R, Herbstman JB, Hertz-Picciotto I, Holland N, Jukic AMZ, McElrath TF, Meeker JD, Messerlian C, Michels KB, Newman RB, Nguyen RHN, O'Brien KM, Rauh VA, Redmon B, Rich DQ, Rosen EM, Schmidt RJ, Sparks AE, Starling AP, Wang C, Watkins DJ, Weinberg CR, Weinberger B, Wenzel AG, Wilcox AJ, Yolton K, Zhang Y, Ferguson KK.
Environ Health Perspect. 2023 Dec;131(12):127015. doi: 10.1289/EHP12831. Epub 2023 Dec 20. PMID: 38117586.
Background: Phthalate exposures are ubiquitous during pregnancy and may contribute to racial and ethnic disparities in preterm birth.
Objectives: We investigated race and ethnicity in the relationship between biomarkers of phthalate exposure and preterm birth by examining: a) how hypothetical reductions in racial and ethnic disparities in phthalate metabolites might reduce the probability of preterm birth; and b) exposure-response models stratified by race and ethnicity.
- : We pooled individual-level data on 6,045 pregnancies from 16 U.S. cohorts. We investigated covariate-adjusted differences in nine urinary phthalate metabolite concentrations by race and ethnicity [non-Hispanic White (White, 43%), non-Hispanic Black (Black, 13%), Hispanic/Latina (38%), and Asian/Pacific Islander (3%)]. Using g-computation, we estimated changes in the probability of preterm birth under hypothetical interventions to eliminate disparities in levels of urinary phthalate metabolites by proportionally lowering average concentrations in Black and Hispanic/Latina participants to be approximately equal to the averages in White participants. We also used race and ethnicity-stratified logistic regression to characterize associations between phthalate metabolites and preterm birth.
- : In comparison with concentrations among White participants, adjusted mean phthalate metabolite concentrations were consistently higher among Black and Hispanic/Latina participants by 23%-148% and 4%-94%, respectively. Asian/Pacific Islander participants had metabolite levels that were similar to those of White participants. Hypothetical interventions to reduce disparities in metabolite mixtures were associated with lower probabilities of preterm birth for Black [13% relative reduction; 95% confidence interval (CI): −34%, 8.6%] and Hispanic/Latina (9% relative reduction; 95% CI: −19%, 0.8%) participants. Odds ratios for preterm birth in association with phthalate metabolites demonstrated heterogeneity by race and ethnicity for two individual metabolites (mono-n-butyl and monoisobutyl phthalate), with positive associations that were larger in magnitude observed among Black or Hispanic/Latina participants.
- Phthalate metabolite concentrations differed substantially by race and ethnicity. Our results show hypothetical interventions to reduce population-level racial and ethnic disparities in biomarkers of phthalate exposure could potentially reduce the probability of preterm birth. https://doi.org/10.1289/EHP12831.
Multiplexed live-cell imaging for drug responses in patient-derived organoid models of cancer.
Colling KE, Symons EL, Buroni L, Sumanisiri HK, Andrew-Udoh J, Witt E, Losh HA, Morrison AM, Leslie KK, Dunnill CJ, De Bono JS, Thiel KW.
bioRxiv [Preprint]. 2023 Nov 17:2023.11.15.567243. doi: 10.1101/2023.11.15.567243. PMID: 38014133; PMCID: PMC10680710.
Patient-derived organoid (PDO) models of cancer are a multifunctional research system that better recapitulates human disease as compared to cancer cell lines. PDO models can be generated by culturing patient tumor cells in extracellular basement membrane extracts (BME) and plating as three-dimensional domes. However, commercially available reagents that have been optimized for phenotypic assays in monolayer cultures often are not compatible with BME. Herein we describe a method to plate PDO models and assess drug effects using an automated live-cell imaging system. In addition, we apply fluorescent dyes that are compatible with kinetic measurements to simultaneously quantitate cell health and apoptosis. Image capture can be customized to occur at regular time intervals over several days. Users can analyze drug effects in individual Z-plane images or a Z Projection of serial images from multiple focal planes. Using masking, specific parameters of interest are calculated, such as PDO number, area, and fluorescence intensity. We provide proof-of-concept data demonstrating the effect of cytotoxic agents on cell health, apoptosis and viability. This automated kinetic imaging platform can be expanded to other phenotypic readouts to understand diverse therapeutic effects in PDO models of cancer.
Ruiz-Ciancio D, Veeramani S, Embree E, Ortman C, Thiel KW, Thiel WH.
bioRxiv [Preprint]. 2023 Nov 15:2023.11.13.566453. doi: 10.1101/2023.11.13.566453. PMID: 38014343; PMCID: PMC10680646.
Aptamers are short single-stranded DNA or RNA molecules with high affinity and specificity for targets and are generated using the iterative Systematic Evolution of Ligands by EXponential enrichment (SELEX) process. Next-generation sequencing (NGS) revolutionized aptamer selections by allowing a more comprehensive analysis of SELEX-enriched aptamers as compared to Sanger sequencing. The current challenge with aptamer NGS datasets is identifying a diverse cohort of candidate aptamers with the highest likelihood of successful experimental validation. Herein we present AptamerRunner, an aptamer clustering algorithm that generates visual networks of aptamers that are related by sequence and/or structure. These networks can then be overlayed with ranking data, such as fold enrichment or data from scoring algorithms. The ability to visually integrate data using AptamerRunner represents a significant advancement over existing clustering tools by providing a natural context to depict groups of aptamers from which ranked or scored candidates can be chosen for experimental validation. The inherent flexibility, user-friendly design, and prospects for future enhancements with AptamerRunner has broad-reaching implications for aptamer researchers across a wide range of disciplines.