Open Access Journals at IU Indianapolis
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Analysis of Lung Cancer Disparities in Northwest Indiana
Get PDFBackground and Hypothesis: Lung cancer is the first leading cause of cancer death worldwide (~1.8 million deaths pa.). Low-Dose Computed Tomography (LDCT) screening is a preventative measure to diagnose lung cancer at an early stage, which increases the chance of survival. Northwest Indiana is a diverse region (830,000 pop.) that faces unique challenges to equitable health outcomes and access to preventative treatments, particularly within minoritized communities from a low socioeconomic status. We investigated whether the vulnerable populations of Northwest Indiana have a higher incidence of lung cancer, low LDCT screening rates, and a late stage of diagnosis, in order to identify potential gaps in healthcare access and delivery.
Methods: We used LDCT screening (n = 2,481), lung cancer incidence (n = 268) and staging (n = 257) data from ZIP Codes of six cities/towns in Northwest Indiana, provided by an urban hospital system in Northwest Indiana between 2018 and 2023. The cities/towns were grouped into ‘lower’ and ‘upper’ income according to median household income level reported by 2020 U.S. census data. Chi-Squared tests were used to determine significance.
Results: There is no significant difference in the incidence of lung cancer between upper and lower income cities/towns (p= 0.163). However, there is a significant difference in stage I, II, and IV diagnoses between the two income groups (p = 0.021, 0.007, and 0.013 respectively), which demonstrates an inverse relationship between income level and stage of diagnosis. The lower income group is diagnosed at a younger age (p = 0.02) with advanced stage lung cancer, despite similar rates of lung cancer incidence.
Conclusion and Potential Impact: Barriers to screening for vulnerable populations in urban areas include patient-provider mistrust, health illiteracy, and lack of healthcare services. Late stage diagnosis necessitates the development of local interventions to increase early screening
Exploring a Transcriptome-forward Approach for Genetic Evaluation in Thoracic Aortopathy
Get PDFBackground/Objective: Thoracic aortic aneurysm (TAA) is an aortopathy that predisposes to aortic dissection and rupture. Transcriptomic analysis has diagnostic utility in other diseases, but this has not been developed for TAA. We therefore sought to implement the Genome Analysis Toolkit (GATK) as a tool for high-throughput detection of novel variants in RNA sequencing (RNA-seq) data from patients with TAA.
Methods: Human proximal aortic tissue samples from 63 TAA patients and 15 controls were used to establish primary smooth muscle cell (SMC) lines in culture. Total RNA was extracted at early passage; RNA-seq was performed using 150 base pair paired-end reads. Variants were called from RNA-seq reads using the GATK’s HaplotypeCaller tool. The MarkDuplicates tool tagged duplicate reads, but these were retained for variant analysis. Singletons were defined as heterozygous variants unique to one sample in the overall group.
Results: The RNA-seq pipeline was validated by confirming known mutations in 2 patients, inspecting reads directly in the Integrative Genomics Viewer (IGV), and genotyping for a common single nucleotide polymorphism. Across all 78 samples, the GATK pipeline identified 4,823,462 variant sites, 236,495 of which were in coding regions. Variant sites were filtered for those located within the coding regions of 31 genes curated for known evidence of aortic disease causality. Among the 511 coding variant sites in these genes, 330 single nucleotide variants and 33 insertions/deletions were identified as singletons. Singleton variant calls were evaluated for quality and annotated in order to predict their likelihood of pathogenicity, thus far identifying strong candidate causal variants in FBN1, TGFBR1, TGFB3, GATA4, and HEY2.
Conclusion: Application of the GATK RNA-seq pipeline expands our prior IGV analysis, further demonstrating the potential diagnostic utility of transcriptomic analysis of aortic SMCs in TAA.
Scientific Impact: Identifying novel aortopathy-associated variants could improve future disease detection and prediction of severity
Social Determinants of Health Associated with Inpatient Admissions for Congestive Heart Failure, Diabetes, Chronic Obstructive Pulmonary Disease, and Asthma
Get PDFIntroduction: The CDC and American Lung Association estimate that congestive heart failure (CHF), diabetes, chronic obstructive pulmonary disorder (COPD), and asthma (COPD/asthma) cost Americans 327 billion, and $50 billion respectively each year. They account for most inpatient readmissions at St. Mary Medical Center (SMMC), an urban hospital in Northwest Indiana. There is need for further research on the social, behavioral, and demographic determinants associated with these conditions. This study examined the social, behavioral, and demographic determinants associated with inpatient admission for CHF, diabetes, COPD/asthma in SMMC’s service area.
Methods: This retrospective study was part of a multi-phased Community-Based Participatory Research partnership between SMMC and Indiana University School of Medicine Northwest. SMMC implemented a pilot screening and referral program to assess social determinants of health in their service area as part of their Hospital Readmission Reduction Program. This study included data from 10,953 inpatient admissions between January 2021 to March 2023, majority of whom were transferred from the emergency department. Data analysis consisted ofunivariate, bivariate (Chi-square), and multivariate (binary logistic regression) analysis in SPSS 29.0.
Results: Bivariate analysis revealed a statistically significant association between CHF and smoking, age, insurance type, and income. Diabetes was significantly associated with smoking, smokeless tobacco use, age group, race, income, and sex. COPD/asthma was significantly associated with smoking, age group, transportation needs, stress, insurance, ethnicity, and sex. Multivariate analysis found the following significant associations: age group with both CHF (p<0.001) and diabetes (p<0.001), former smoking with both CHF (p = 0.007) and COPD/asthma (p = 0.049), current smoking with COPD/asthma (p = 0.016), and sex with diabetes (p <0.001).
Conclusions: These findings indicate significant associations between multiple sociobehavioral factors and admission for CHF, diabetes, COPD/asthma. Multi-risk-factor interventions may address these interactions and contribute to reducing readmission
Exploring Differentiation and TEAD Inhibition in NF2-Knockdown NES Cells
Get PDFBackground: The NF2 gene is a tumor suppressor encoding gene on chromosome 22 that is a known regulator of the Hippo pathway. When the mammalian version of the pathway is inactive, such as with a loss of NF2, downstream proteins YAP/TAZ remain unphosphorylated, enter the nucleus to form a complex with TEAD 1/2/3/4, and begin transcription. Hyperactivation of theYAP/TAZ-TEAD complex has been observed in many cancers, allowing for targeting with TEAD inhibitors. Here, we assess how the loss of NF2 in human neuroepithelial stem (NES) cells affect their differentiational development. We also seek to understand the effects of TEAD inhibition on wildtype (WT) and NF2-knockdown NES cells.
Materials and Methods: Differentiation. WT and NF2-knockdown cells were grown in media without growth factors to differentiate them. TEAD Inhibition. Non-differentiating and differentiating WT and NF2-knockdown cells were treated with TEAD Inhibitor 690 (TEADi). During both conditions, cells were harvested at 5 points throughout the growth period.
Results: Decreased NF2 in cells promoted retention of an earlier cell morphology compared to WT, which appeared to develop neuronal features, such as axons. WT cells exhibited elevated expression of genes characteristic of NES differentiation when compared to NF2-knockdown cells. Following the addition of TEADi, cell culture imaging revealed seemingly increased cell death in WT cell populations compared to NF2-knockdown cells. Interestingly, differentiating NF2-knockdown cells adhere to one another to form clusters, but with TEADi, these clusters are formed to a much lesser extent.
Conclusion: Although more experimentation is needed, these are early steps in demonstrating how NF2 loss appears to halt the differentiation of NES cells. Additionally, TEAD inhibition seems to reduce the clustering seen in differentiating NF2-knockdown cells; however, experimental concentrations need to be explored in the future. Further work is needed to understand the effects of TEAD inhibition on NF2-knockdown cells
Inhibition of HSF1 as a Mechanism for Overcoming Hsp90 Treatment Resistance
Get PDFHsp90 inhibitors have been attempted as a targeted therapy with poor results. Despite numerous clinical trials, there are currently no FDA approved Hsp90 inhibitors available. It is known that Hsp90 sequesters HSF1 in the cytoplasm to suppress HSF1 activity, an oncogenic transcription factor. We hypothesize that HSF1 activation in response to Hsp90 inhibition is a significant reason that previous Hsp90 inhibitors have failed. Once released, HSF1 enters the nucleus and drives expression of many processes that promote the initiation and progression of tumors. This hypothesis was tested by evaluating the response of cancer cells to Hsp90 inhibition with or without combined inhibition of HSF1, thereby removing HSF1 activity as a consequence of Hsp90 inhibition. We observed synergy between Hsp90 inhibition (17-DMAG) and HSF1 inhibition (KRIBB11) from calculation of combination index in ovarian cancer cells (OVCAR8) and breast cancer cells (BT474). This synergy observed in cell viability assays were further reinforced in spheroid formation and clonogenic growth assays where the combination of these inhibitors had a greater effect than either treatment alone. These results further support the hypothesis that Hsp90 inhibition efficacy is mitigated by increased HSF1 activity and that HSF1 inhibitors synergize with Hsp90 inhibitors to improve their efficacy
Student Perceptions of Two Preclinical Medical School Exam Feedback Approaches
Get PDFBackground: In medical school, where learning an abundance of information in a short period of time is required, it is necessary that learners receive valuable feedback after summative assessments (i.e., unit exams). First-year medical students at Indiana University School of Medicine (IUSM) begin their education with a course titled Human Structure (HS), followed by Molecules to Cells and Tissues (MCT). Both courses provided different formats for exam feedback, resulting in anecdotal comments about preference and utility of feedback. This study uses qualitative research methods to examine IUSM-Bloomington students’ perceptions of exam feedback formats with respect to their utility and applicability.
Methods: Five, second-year IUSM-Bloomington medical students participated in a focus group to discuss their utilization and perceived usefulness of HS and MCT exam feedback. A thematic analysis was used to interpret data from the focus group. This study was deemed exempt by the IU-IRB (19409).
Results: The thematic analysis revealed that students’ discussions fell into three categories: logistics, utilization, and mentality. These categories were further broken into themes and subthemes, revealing 13 unique codes. Students spent a substantial amount of time discussing logistics of exam feedback. Barriers to utilization of exam feedback included a lack of information provided at the feedback sessions and a lack of time in the schedule available for feedback sessions. Students preferred MCT approach to exam feedback, however they recognized HS course logistics may prevent similar adoption. Students had small suggestions on how to improve feedback in both courses.
Conclusions/Implications: The data suggest students would benefit from small changes in how first-year medical school courses at IUSM provide exam feedback. Improvements could include extending the time of exam review sessions, incorporating a discussion on commonly missed exam concepts, providing answer explanations for incorrect and correct answers, and transitioning statewide reviews to be campus led
Comparing Complication Rates of Transcatheter Aortic Valve Replacement to Surgical Aortic Valve Replacement
Get PDFBackground/Objective: Transcatheter aortic valve replacement (TAVR) and surgical aortic valve replacement (SAVR) are the two procedures used to treat severe symptomatic aortic stenosis. One of the most feared outcomes of both procedures is stroke. Conduction abnormalities and arrhythmias after TAVR are relatively common, but few studies have been done comparing the rate of these events between TAVR and SAVR. The objective of our study is to find if there are any differences between the rates of stroke, conduction abnormalities, and arrhythmias between patients that have undergone TAVR and patients that have undergone SAVR.
Methods: The CRC/Sidus Real World Evidence Cardiology Dataset was used to obtain samples for this project. Patients who underwent TAVR and SAVR were identified using CPT codes. These two cohorts of patients were tracked for complications between 0 to 30 days after the procedure and between 0 days to 1 year after the procedure using ICD-10 codes.
Results: Patients who underwent TAVR (n=3621) were much more likely to have conduction disorders and arrhythmias both in the 0-30 day range and 0 days-1 year range after the procedure compared to patients who underwent SAVR (n=2137). Cerebral infarction and transient cerebral ischemic attack rates were also higher in the TAVR group. Mortality rates for TAVR were lower than mortality rates for SAVR, both 30 days and 1 year after the procedure.
Conclusion/Impact: TAVR has revolutionized aortic valve replacement and allowed many patients with aortic stenosis (many of whom are at high surgical risk) a minimally invasive option to improve their quality of life. Finding ways to reduce the rates of stroke, arrhythmias, and conduction abnormalities; for example, through improved devices and techniques, and improvedanti-thrombotic therapy, is extremely important as TAVR becomes more and more widely utilized
Blood Product Utilization Among Adolescent and Young Adult Patients with Acute Lymphoblastic Leukemia: A Single Center Ex
Get PDFBackground: Adolescent and young adult (AYA, 15-39 years old) patients with acute lymphoblastic leukemia (ALL) often experience pancytopenia and severe immunosuppression. Particularly during intensive phases of chemotherapy, allogeneic blood transfusion support is essential in their care. The utilization of both red blood cell (RBC) and platelet transfusions, as well as the thresholds used to determine when transfusions are needed, are poorly described in this population. The objective of this study is to describe blood product utilization in AYA patients with ALL treated at our institution.
Methods: A cohort of 20 AYA patients with ALL treated at Riley Hospital for Children from October 2020 to July 2023 were identified for data collection. Pre- and post-transfusion laboratory values, transfusion totals, comorbid events or complications, transfusion reactions, and minimal residual disease (MRD) values were collected and analyzed. All values reported are mean ± standard deviation for continuous variables and n (%) for categorical variables. Values were calculated individually for each patient for each phase of therapy and averaged across all patients.
Results: Patients studied had varying needs for transfusions throughout their therapy (50.75 ± 48.06), with an average of 22.95 ± 15.65 RBC transfusions and 25.60 ± 29.65 platelet transfusions. Patients being treated with standard chemotherapy protocols required moretransfusions during induction (14.13 ± 21.56) and delayed intensification (14.07 ± 24.29) phases compared to other phases. Patients with MRD positive status required more transfusions (69.14 ± 58.14) than patients with MRD negative status (40.92 ± 40.84).
Conclusions and Potential Impacts: This study helped to elucidate the need for transfusions among the AYA ALL patient population, throughout the different phases of treatment. These findings hold implications for establishing guidelines that could clarify when transfusions should be given in this population, helping physicians provide the best care to future patients