bluuebunny/crossref_metadata_2025 huggingface dataset:
TRIM31: A Protein With an Oncogenic Role in Esophageal Adenocarcinoma
Authors: Mast Jesse , Hassan Md Sazzad , Ritter Annie , Singh Akashdeep , Von Holzen Urs
Published: January 2024

Background: Esophageal adenocarcinoma (EAC) is a major cancer in the United States with increasing incidence. It is an aggressive cancer involving columnar-type cells different from the normal esophageal (NE) squamous cells. This metaplasia often involves an intermediary morphology called Barrett’s esophagus (BE), which occurs from repeated acid exposure of the esophagus from gastroesophageal reflux disease (GERD). GERD leading to BE is a common pre-occurrence in EAC patients, but the mechanism remains obscure. To explore the mechanism and its components, we compared gene expression in BE and EAC cells with normal cells and discovered the overexpression of TRIM31 in the pathogenic cells. Although previous studies have shown oncogenic potential of TRIM31 in some cancers, its role in EAC is yet to be understood.
Methods: RNA sequencing and transcriptomic profiling were performed on human NE, BE, and EAC epithelial tissue samples. TRIM31 expression in NE cell line (Het-1A) and EAC cell lines (OE19, Flo-1, OE33, SK-GT-2, and OACM5.1C) were identified by Western blot. The Het-1A cell line, after exposure to acidic pH and bile acid, was assessed for variable TRIM31 expression. Cell viability analysis of NE and EAC cell lines after exposure to acidic pH and bile acids was observed by WST-1 assay.
Results: RNA sequencing, transcriptomic profiling, and western blot revealed overexpression of TRIM31 in BE and EAC epithelium. Exposure of Het-1A cells to bile acids in acidic pH changed the cell morphology with enhanced expression of TRIM31. WST-1 revealed that EAC cells were more resistant to acidic pH and bile acid exposure.
Conclusions and potential impact: Our data suggests that increased TRIM31 expression correlates with esophageal epithelium resistance when exposed to bile acids and acidic pH. Consequently, TRIM31 may be a key player in the metaplasia of GERD-induced EAC development and may be an innovative therapeutic target and marker for EAC.
Pharmacological Inhibition of PAK1 for the Treatment of NF2-Associated Vestibular Schwannoma
Authors: Mazurek Emma C. , Mitchell Dana , Hawley Eric , Angus Steve , Clapp D. Wade , Yates Charles
Published: January 2024

Neurofibromatosis Type 2 (NF2) is an autosomal-dominant genetic disorder characterized by loss of Merlin, a tumor suppressor in Schwann cells, resulting in pathognomonic bilateral vestibular schwannoma, among other complications. Depletion of Merlin results in pathologic elevation of p21-activated kinase 1 (PAK1), which promotes tumor cell proliferation, survival, and motility. Previous studies investigating the Nf2flox/flox; PAK1-/-; Postn-Cre+ genetically engineered mouse model (GEMM) revealed that PAK1 genetic knockout in Nf2-cKO mice mitigated tumor size and preserved hearing. This study builds upon this previous work to identify efficacious therapeutic agents that target PAK1. In vitro dose response curves evaluated the efficacy of five PAK inhibitors in merlin-deficient immortalized Schwann cells (MS03). Dose response curves revealed variable IC50s among the five PAK inhibitors tested. Synergy screensrevealed synergy between PAK inhibitors NVS-PAK1-1 or BGJ-398 and selumetinib, a MEK inhibitor FDA-approved for the treatment of NF1. Colony formation assays revealed robust inhibition with NVS-PAK1-1 in combination with VS6766, a RAF/MEK inhibitor currently being evaluated in clinical trial in other cancers. Western blot analysis revealed marked decrease in downstream effectors of PAK1, including phospho-ERK1/2 in cells treated with BGJ-398, NVSPAK1-1, and PAKi plus selumetinib. Together, these findings suggest that inhibition of PAK1 and MEK pathways may be an efficacious therapeutic strategy for the treatment of NF2- associated vestibular schwannoma. Establishing reproducibility of these results in cells derived from human vestibular schwannoma is necessary to continue investigating pharmacological PAK1 and MEK inhibition. Further studies are needed to verify tolerability and therapeuticefficacy of PAK1 and MEK pharmacological inhibition in vivo.
Characterization of the Function of Carbonic Anhydrase 8
Authors: Chen Jenny , Smith Laura , Gaston Benjamin
Published: January 2024

Background/Objective: Severe asthma is a complex pulmonary disease characterized by airway inflammation, bronchoconstriction, and acid-base dysregulation. In the Severe Asthma Research Program bronchoscopies, transcriptomics showed CA8 as a gene that is strongly associated with asthma severity. CA8, however, lacks classical CA enzyme function: it does not catalyze hydration and dehydration of CO2. The function of CA8 in the airway epithelium remains unknown. We hypothesize that CA8 serves a protective role in the airway due to its down regulation in patients with severe asthma. We aim to characterize the function of CA8 bystudying its potential as an enzymatic protein.
Methods: We used colorimetric assays to detect and quantify nitrogen oxides. We tested for Snitrosothiolsynthase, denitrosylase, nitrate and nitrite synthase, and nitrite reductase activitiesusing the Griess reagent in conjunction with Saville denitrosylation reagents and with reduction using vanadium chloride. Samples were incubated for 60 minutes. We then went on to design ametabolomic experiment in which products will be identified by NMR: for these, we transfected Chinese hamster ovary (CHO) cells using lentivirus containing GFP-labeled CA8 or emptyvector (negative control).
Results: CA8 protein does not have these following enzymatic functions: SNO synthase,denitrosylase, nitrite and nitrate synthase, and nitrite reductase. We successfully transfected with GFP-labeled CA8 and are awaiting results of the metabolomic studies.
Conclusion and Potential Impact: Isolated CA8 does not appear to have any nitrogen oxideredox activities relevant to asthma. The next steps include confirmatory western and SNOwestern blots to determine protein s-nitrosylation using transfected CHO whole cell lysate. Extracellular medium pH will also be measured. We will then move on to NMR-basedmetabolomics. This will help us better understand the biochemical mechanisms of CA8.Ultimately, this can provide researchers with a novel approach to asthma treatments.
Assessment of Patient Referrals with Large Numbers of Non-pedunculated Colorectal Lesions
Authors: Cheng William , Rex Douglas
Published: January 2024

Background: Large (≥20mm) non-pedunculated colorectal lesions are frequently referred to specialty centers for endoscopic resection. These lesions are technically challenging to resectand associated with substantially greater risk than smaller lesions. Patients with such polypsoften have synchronous lesions. We sought to identify evidence for whether synchronouslesions were sometimes the true basis for referral of large non-pedunculated colorectal polypsfrom community endoscopists to a tertiary center.
Methods: We utilized a prospectively collected database of 1356 consecutive referred patients to an expert colonoscopist at our tertiary center between August 2019 and May 2023. We identified patients with ≥30 precancerous lesions resected from the colorectum during their first two colonoscopies at our center. Patients in the database with the same gender, within 3 yearsof age, and with the same location (proximal vs. distal colon) of the index large lesion referred for resection were identified as controls. Groups were compared for the size of index lesion,  number of polyps resected by both centers, and size of polyps resected.
Results: Among 1356 patients, 49 (3.6%) had ≥30 precancerous lesions resected at our center. Compared to controls, the index lesion was smaller in patients with ≥30 lesions (mean 28.9mmvs 23.3mm). Among patients with ≥30 synchronous polyps, the referring physician resected 10.6% of all synchronous lesions, compared to 47.8% in the control group (p<0.0001). Inpatients with ≥30 lesions, 84% of all synchronous lesions were <10mm, 15% were 10-19mm, and only 1% were >20mm.
Conclusion: Our results suggest a subset of patients with large non-pedunculated colorectal precancerous lesions referred to tertiary centers are referred because of the number of lesions present, rather than technical challenges associated with resection of individual lesions. The rationale for these referrals is uncertain. It may lie in the reimbursement system, which only compensates physicians for the first polypectomy.
Analysis of Lung Cancer Disparities in Northwest Indiana
Authors: Colston Kyra , Ndama Mia , Han Amy
Published: January 2024

Background 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.
The Effects of Age and Sex of Megakaryocyte Secreted Factors on Endothelial Cell Growth and Function
Authors: Nazzal Murad K. , Battina Hanisha L. , Tewari Nikhil P. , Mostardo Sarah L. , Nagaraj Rohit U. , Awosanya Olatundun D. , Majety Saveda K. , McGuire Anthony C. , Samson Sue , Blosser Rachel J. , Dadwal Ushashi C. , Mohamad Safa F. , Srour Edward F. , Bruzzaniti Angela , Kacena Melissa A.
Published: January 2024

With an aging population, the risk of fractures and compromised healing increases. Angiogenesis and vasculogenesis are impaired with aging. Vascularization at the callus plays a significant role in bone healing, and we have previously shown the important role ofmegakaryocytes (MKs) in regulating bone healing. Notably, MK-derived conditioned media (CM) contains factors known to promote angiogenesis. Whether differences exist with aging and/or based on sex was the primary focus of this study. Here, we examined the effects of CM secreted from MKs derived from young (3-4-month-old) and aged (22-24-month-old) male and female C57BL/6J mice on bone marrow endothelial cell (BMEC) growth and function. Specifically, BMEC proliferation, vessel-like formation, wound/transwell migration, and RNA expression were examined. Both young and aged female MK CM saw a >65% increase in BMEC proliferation(p<0.001 and p<0.05, respectively). In addition, female MK CM, regardless of age, improved all four parameters of vessel-like formation by >115% (p<0.05). Likewise, young male MK CM increased vessel-like formation in all parameters by more than 160% (p<0.001). Although aged male MK CM resulted in higher vessel-like formation parameters, including significant >150% increases in the formation of nodes and meshes, 62% fewer vessel-like structures formed compared to that observed with young male MK CM treatment (p<0.05). Additionally, aged MK CM, irrespective of sex, improved transwell migration by over 2500% (p<0.01). On the other hand, aged female and male MK CM inhibited wound closure by 46% and 17%, respectively (p<0.05). RNA analysis found MK CM yielded significantly different levels of expression in CXCR4, CXCR2, CD36, CD74, PDGFRB, and TGFBRB not only relative to controls, but also between sexes and ages. Further testing to identify the mechanisms responsible for these age-associated differences may allow for novel treatment strategies to improve MK-mediated angiogenesis, vasculogenesis, and bone healing, particularly within the aging population.
Intraoperative Cognitive Load Differences between Trainees and Attending Surgeons
Authors: Nelson Alex , Anton Nicholas , Kalantar Mohammed , Stefanidis Dimitrios
Published: January 2024

Background/Objective: Cognitive load (CL) is the amount of mental effort and resources required to complete a task and process information in the working memory. In a surgical setting, high CL decreases attention to critical details, and slows down decision-making, increasing errors which can compromise patient safety. Our aim was to determine if CL differences exist between trainees and experienced attending surgeons. Such differences could inform readiness for trainee autonomy and training paradigms.
Methods: Eye trackers were used by attending general surgeons and trainees during robotic gastrointestinal procedures to determine their CL. Average fixation rate (AFR), fixation to saccade (F:S) ratio, and change in pupil size, were recorded and compared between attending surgeons and trainees to determine differences in intraoperative cognitive load.
Results: Three attendings and three trainees participated. While operating, trainees had a lower AFR (M=0.775, SD= 0.093) and a lower F:S (M=0.497, SD=0.102) compared to attendings (M=0.842, SD=0.152 and M=0.592, SD=0.243, respectively). Both trainees and attendings had a larger pupil size (M=4.29, SD=0.773 and M=3.63, SD=0.077, respectively) while operating compared to their pupil size while not operating (M=4.057, SD=0.821 and M=3.496, SD=0.059, respectively.
Conclusion and Potential Impact:In this pilot study, we determined eye tracking metrics can be used to detect differences in intraoperative CL between trainees and attending surgeons and while they were operating or observing. Further research should determine methods that decrease CL of trainees.
A Case Study on the Relationship Between a Multimodal Approach to Opioid Treatment and Opioid Cessation in Low-Income BIPOC Communities
Authors: Okolocha Adaobi , Khairallah Jasser
Published: January 2024

Background and Hypothesis:In the United States, the opioid crisis has been centered around white individuals in suburban and rural areas. However, communities of color who have a low socioeconomic status (SES) are facing an increasing amount of opioid overdose related deaths. Even with pharmacological opioid agonist therapy, this specific population still does not have the support to remain abstinent from opioids. We have conducted a case study with Mr.G, a 32 year old black male patient with opioid use disorder (OUD) who is from a low SES. Mr. G suffered from four overdoses over a six-month period (two of them occurring within 24 hours). He was treated for each overdose at three different large academic medical centers. The first three academic medical center offered him solely Buprenorphine-Naloxone, whereas the current medical center took a multimodal approach. We hypothesize that populations of color with opioid use disorder who are from a low socioeconomic class will benefit more from a multimodal approach to OUD treatment.
Methods:In this work, we conducted a literature review to construct a multitude of questions to assess Mr.G’s experience at his previous academic medical centers versus his current academic center and why his current treatment has resulted in successful opioid cessation.
Results:Thus far, we have not received a response from Mr. G. However, since a multimodal approach was taken towards his treatment, he has enrolled in college courses, has gained employment, and has maintained sobriety.
Conclusion and Potential Impact:Patients like Mr. G who come from communities of color and lower socioeconomic status may benefit from a multimodal approach when treating their OUD. This study will potentially lead to more research focusing on how to address the holistic needs for communities of color with opioid use disorder who come from a lower socioeconomic status.
Non-Fatal Strangulation Injuries: Improving Physician Knowledge and Attitudes
Authors: Pankratz Sarah , Motzkus Christine
Published: January 2024

Background and Objective:In the emergency department, providers are expected to evaluate patients who have experienced strangulation resulting from sexual assault or interpersonal violence. Non-fatal strangulation can lead to significant injuries, including carotid artery dissection. Given the prevalence of strangulation injuries, providers must feel confident in their decision-making for this population. Previous educational interventions effectively improved provider knowledge of sexual assault and domestic violence patients, however, no studies have been conducted with the goal of improving provider knowledge about strangulation injuries in this population. We aimed to assess and improve emergency department provider knowledge surrounding nonfatal strangulation injuries.
Project Methods:Preintervention and postintervention surveys were administered to emergency department physicians and advanced practice providers assessing both provider comfort and knowledge regarding treatment of survivors of sexual assault, domestic violence, and strangulation. Key content areas included: physician comfort in treating sexual assault survivors, understanding of trauma-informed care, satisfaction with prior training regarding nonfatal strangulation, and physician attitudes. 6 vignette-style questions designed to evaluate knowledge in clinical scenarios were also administered. A 15-minute, interactive, educational presentation was administered during the pre-existing departmental meeting. Survey responses were collected via email and data was stored in REDCAP. Preintervention and postintervention results were compared via t-tests.
Results:There were 22 pre-intervention and 10 post-intervention responses. Median years of practice were 8. Survey participants tended to rate awareness of imaging recommendations and resources, decisionmaking, history taking, and use of trauma-informed care higher than preintervention participants. Postintervention participants tended to answer more clinical vignettes correctly than preintervention participants.
Conclusion and Potential Impact:A 15-minute educational intervention was effective in improving provider knowledge, confidence, and comfort in treating patients who have experienced non-fatal strangulation. In the future, similar interventions may be implemented in other emergency departments to increase awareness about the evaluation and treatment of nonfatal strangulation injuries.
Breast Cancer Disparities Among Women in Underserved Communities in Northwest Indiana
Authors: Patel Pooja , Altarshan Basem , Han Amy
Published: January 2024

Background: Breast cancer is the second most common cancer found in women, after skin cancers. Research has discovered that factors such as race, socioeconomic status, and education affect both screening levels and cancer staging at diagnosis. Black women as well as lower-income individuals usually have higher grade staging as well as higher mortality. Since Lake County medical systems serve both high and low-income communities we wanted to analyze breast cancer staging in Lake County to see how it compares to national trends.
Methods: “Hospital A” provided data from 393 positive breast cancer diagnoses along with the clinical staging at diagnosis from January 2019 to December 2022 for both high and low-income neighborhoods. Using a Mantel-Haenszel chi-square test we compared staging levels among the different income neighborhoods as well as among different races.
Results: When looking at total staging data from 2019-2022, there was a significant difference between the race category of "Black or African American" and "White" population staging data. White patients tend to have lower stages, during initial clinical diagnosis, compared to Black patients. The "Other" category, which included all other races that did not fit into the "Black or African American" or "White Category" such as Asians, also had lower staging upon diagnosis when compared to the “Black or African American” group but no statistically significant difference with the “White” population.
Conclusion: Our data showed that in Lake County, Indiana there are disparities in cancer staging among both income levels as well as race. The lower-income areas in our study were correlated with a greater proportion of Black residents as compared to the higher income areas. This data shows that Lake County needs to be more proactive in screening its minority communities.
Evaluation of a Pediatric High-Flow Nasal Cannula Training Program for Providers at Moi Teaching and Referral Hospital in Eldoret, Kenya
Authors: Roberts Kaitlyn A. , Bhutta Emaan G. , Bhutta Adnan , McHenry Megan S. , Mandi Polycarp , Ngetich Eric , Sila Faith , Jemeli Hellen , Kimetto Sarah , Ruhl Laura J. , Nyandat Joram , Kaplan Julika
Published: January 2024

Background: High-flow nasal cannula (HFNC) is a relatively safe, effective, and well-tolerated form of non-invasive ventilation for children with respiratory distress and is regularly used in resource-rich settings. Pediatric HFNC has been successfully implemented in resource-limited settings; however, little is known about the training process required to integrate HFNC into care. The present study evaluates a pediatric HFNC training program conducted at Moi Teaching and Referral Hospital (MTRH) in Eldoret, Kenya prior to HFNC implementation at Shoe4Africa Children’s Hospital.
Methods: This study took place within the Academic Model Providing Access to Healthcare (AMPATH) program, a partnership among MTRH, Moi University, and a consortium of North American universities led by Indiana University. The training program curriculum included information about HFNC; clinical signs of respiratory distress; a demonstration and hands-on practice with HFNC machines; a locally adapted protocol for pediatric HFNC implementation; and a sample patient case. Fifty-nine acute care providers (nurses, clinical officers, medical officers, and registrars) participated in training. Participants completed pre-tests and post-tests (immediate and 3-month follow-up) containing open-ended questions to assess HFNC knowledge and five-point Likert scale questions to assess HFNC comfort and attitudes. Data were analyzed using descriptive statistics and two-proportion Z-tests (α=0.05).
Results: Average knowledge assessment scores significantly increased from pre-test (2.19/6) to post-test (5.59/6; p<0.001). While scores decreased slightly at the 3-month follow-up, they remained increased from pre-test levels (4.53/6; p<0.001). The percentage of respondents who answered each knowledge assessment question correctly on the post-test and 3-month followup were significantly increased from the pre-test. Participant comfort using HFNC was increased on both the post-test (p<0.001) and 3-month follow-up (p=0.038).
Conclusions: This program successfully trained providers in pediatric HFNC use at MTRH and could inform future HFNC training in resource-limited settings. Future studies should evaluate pediatric outcomes at Shoe4Africa after HFNC implementation.
Socio-Demographic and Behavioral Predictors of Admission for Kidney Disease in an Urban Hospital in Northwest Indiana
Authors: DeMichael Kelly , Muvuka Baraka , Guerrero Jonathan , Gosporadek Kyle
Published: January 2024

Background: The CDC estimates more than 1 in 7 American adults have Chronic Kidney Disease (CKD) and nearly 800,000 live with End-Stage Renal Disease (ESRD); the majority of whom require dialysis. Current literature demands further exploration on how social determinants of health (SDOH) influence inpatient and emergency services utilization for CKD/ESRD-related exacerbations. This study examined socio-demographic and behavioral factors associated with hospital admission for CKD/ESRD. It is part of a three-phased Community-Based Participatory Research (CBPR) partnership between IUSM-NW and St. Mary Medical Center (SMMC) to examine and address relationships between SDOH, patient demographics, health behaviors, and health outcomes from January 2022-January 2025.
Methods: This retrospective study analyzed a limited dataset generated by SMMC from EPIC™ with SDOH, demographic, health behavior, and health outcomes data obtained from adult inpatients between January 2021 and March 2023. CKD/ESRD was determined by admission diagnosis ICD-10 Code N18. Data analysis utilized SPSS 29.0 to produce frequencies, Chi-Square tests (p<0.05), and a binary logistic regression (p<0.05). This study was exempted by Indiana University Human Research Protection Program (IRB # 14040).
Results: This study included 10,953 inpatient admissions involving predominantly white (78.4%) and older adult (68 ± 21) patients. CKD/ESRD represented 96 admissions. The bivariate analysis found a significant association between CKD/ESRD admissions and age (p<0.001), race (p<0.001), sex (p=0.008), insurance type (p=0.030), and smoking tobacco use (p=0.004). After adjusting for all factors, being Asian (OR=12.172, p<0.001), Black (OR=3.702; p<0.001), female (OR=0.518; p=0.003), publicly insured (OR=2.76; p=0.014), and former smoking (OR=1.606; p=0.045) were significantly associated with CKD/ESRD admission.
Conclusions: This study revealed several demographics, SDOH, and health behaviors associated with CKD/ESRD admission in an urban hospital. Uncovering predictors of CKD/ESRD admission enables focused interventions to decrease admissions. The next CBPR phases will apply advanced statistical analyses to further explore these relationships and codevelop interventions.
HB007 Administration Inhibits LN-229 and Patient-Derived Neurospheroid Glioblastoma Cell Growth With the Degradation of SUMO1 and Cell Cycle Regulator CDK4
Authors: Dougherty Carson , Wohlford Reagan , Jung Sunghan , Hao Chunhai
Published: January 2024

Background and Hypothesis: Glioblastoma is the most common and malignant brain cancer and there is no effective therapy currently available to patients with this malignancy. Small ubiquitin-related modifier 1 (SUMO1) is a key regulator of cancer cell proliferation through its role in its modification of cellular proteins in various human cancers, especially glioblastoma. Degradation of SUMO1 through small molecule degrader, HB007, has been shown to inhibit growth in cancer cell lines and xenografts. Here, we hypothesize that HB007 can inhibit the glioblastoma cell growth through degradation of SUMO1 protein in glioblastoma cells and the cancer stem cell enriched neurospheres.
Experimental Design: LN-229 glioblastoma cell viability was measured in response to increasing concentrations of HB007. LN-229 and patient-derived neurospheroid glioblastoma cells were cultured and seeded in 4 different plates at 1000 cells/ml concentrations before being treated with HB007 at increasing concentrations encircling the previously described IC50. Cells were then subjected to a SUMO lysis buffer and analyzed via western blot with antibodies specific to SUMO1, CDK4, and actin.
Results: HB007 treated LN-229 cells exhibited an IC50 of 1.470μM. Western blot analysis confirmed the dose dependent reduction in SUMO-1-ylated proteins in HB007 treated cells. A reduction in CDK4 confirmed that cell progression is halted in a dose dependent manner in LN-229 and patient-derived neurospheroid glioblastoma cells when treated with HB007. Specificity of HB007 is towards SUMO1 with no nonspecific degradation of SUMO2/3.
Conclusion: The cell growth of LN-229 and patient-derived neurospheroid glioblastoma cells was confirmed, through western blot, to be inhibited in a dose dependent manner by HB007. These results further establish the therapeutic potential of SUMO1 degraders as a novel anticancer drug for glioblastoma therapy. In the future, it is hoped that the bioavailability, potency, and blood brain barrier permeability can be improved to make this drug a potential treatment for patients.
Brain activation during scene encoding fMRI in the Alzheimer’s disease continuum: Association with amyloid and tau burden in PE
Authors: Trueblood Mia S. , Saykin Andrew J. , Risacher Shannon L.
Published: January 2024

Background and Hypothesis:This project assessed brain activation during a scene encoding task in 4 groups: older adults who were cognitively normal (CN), subjective cognitive decline (SCD), mild cognitive impairment (MCI), and dementia due to Alzheimer’s disease (AD). Associations between scene encoding related brain activation and tau, amyloid, and other biomarkers were analyzed. Our hypothesis was that higher levels of cerebral tau and amyloid would be associated with reduced scene encoding activation. In addition, we hypothesized that scene encoding activation would be significantly different between cognitively normal and cognitively impaired groups.
Methods:234 individuals from the Indiana Memory and Aging Study (79 CN, 67 SCD, 70 MCI, and 18 AD) completed structural and functional MRI, clinical/cognitive assessment and biomarkers; 155 underwent amyloid ([18F]florbetapir/[18F]florbetaben) PET, while 111 also underwent [18F]flortaucipir PET. For the fMRI scene encoding task, participants were asked to view and remember a set of images. A one-way ANOVA test was used to analyze scene encoding related activation differences among the 4 groups. Regression was used to identify associations between scene encoding activation and tau and amyloid deposition.
Results:Significant differences in activation were observed between the MCI and CN groups, including less activation in widespread regions during the task and reduced deactivation in the default mode network (DMN) in MCI participants relative to CN. Significant associations between higher amyloid and tau deposition and altered scene encoding activation were also observed.
Conclusion and Potential Impact:Cognitive decline is associated with activation changes during scene encoding, as well as reduced deactivation in the DMN, especially in the posterior cingulate region. Higher cerebral amyloid and tau deposition predicted decreased scene encoding related activation. These findings are consistent with models linking cognitive status, functional brain activation during episodic encoding, and pathophysiological processes in the AD continuum.
Familial Alzheimer’s Disease Mutation PSEN2 Exacerbates Toxoplasma gondii-mediated Human Blood-Brain Barrier Damage
Authors: Wilson William Luke , Bitters Abigail , Chamberlain Angela , Hughes Jason , Canfield Scott , López-Yglesias Américo H.
Published: January 2024

Background and Hypothesis
Toxoplasma gondii is an obligate intracellular parasite that infects one-third of the global population. T. gondii  transmission to humans primarily occurs from the consumption of contaminated meats, water, or produce. Unfortunately, T. gondii will evade the host clearance, allowing it to cross the blood-brain barrier (BBB), infecting neurons where it transitions into slow-growing cysts, leading to a life-long chronic infection. Recently, studies have suggested that T. gondii infection may exacerbate the decline of cognitive function. The BBB is critical for restricting neurotoxic blood-derived products, leukocytes, and pathogens from entering the brain. Studies have shown that BBB dysfunction and damage to the barrier integrity may also contribute to cognitive impairment. Alzheimer’s disease (AD), the most common form of dementia, is a progressive neurodegenerative disease and its neuropathology is associated with b-amyloid plaques. Familial Alzheimer’s Disease is associated with the proteins, presenilin-1 and presenilin-2, encoded by PSEN1 and PSEN2. Mutations in these two genes contribute to early onset AD. Furthermore, dementia has been linked with an increased breakdown of the BBB. Therefore, we hypothesized that T. gondii infection will exacerbate barrier damage and dysfunction in brain microvascular endothelial cells (BMECs) containing familial AD mutations compared to healthy controls.
Experimental Design
To test our hypothesis, we infected human induced pluripotent stem cell (iPSC)-derived BMECs, which display near in vivo like BBB properties, containing the familial AD PSEN2 mutation or healthy controls with T. gondii.
Results
Using immunofluorescence and transendothelial electrical resistance, our results show that BMECs containing the PSEN2 mutation have a quicker onset of barrier damage, but we observed no difference in the loss of tight junctions ZO-1, Occludin, and Claudin-5 compared to healthy controls after infection.
Potential Impact
These data suggest that a T. gondii infection can exacerbate the breakdown of the BBB in patients with the PSEN2 mutation, worsening the prognosis of familial AD patients.
Development of a Community Informed Approach for Implementing Support Network Trainings for Children with Autism Spectrum Disorder in Western Kenya
Authors: Baumberger Geneva , Chelagat Saina , McNally Keehn Rebecca , Rutto Anita , McHenry Megan S. , Rispoli Mandy
Published: January 2024

Background:Autism spectrum disorder (ASD) impacts a large global community, with a prevalence of nearly 1 in 100 children. However, little is known about the educational experience of children with ASD and other neurodevelopmental disorders (NDD) in low- and middle-income countries (LMICs). Guidance from local communities is essential when developing a cultural inquiry into this educational landscape. Our project objective was to evaluate community perspectives on ASD and areas of development for future support network trainings.
Methods:This qualitative study was performed within the Academic Model Providing Access to Healthcare (AMPATH) program in Eldoret, Kenya. Using group discussions, this approach engaged stakeholders from three areas: medical personnel, educators, and caregivers/families. Kenyan professionals in child psychiatry, occupational therapy, and special education guided discussion and led the recruitment of key informants for interviews. Within this qualitative analysis, brief thematic analysis of dialogue elucidated key themes.
Results:Four focus groups were held, with 87 total participants (group size = 12-29). Four main themes were identified in the data: beliefs about causes, treatment options, barriers to education, and a need for community advocacy. Advocacy was a major focus of discussions, due to a sentiment of fragmentation and poor acceptance from the community. Stigmatization carried over into localbeliefs about causes of ASD, which included poor nutrition, witchcraft, and genetics. Finding resources to access education and therapy was a challenge, especially for families in rural settings. These viewpoints informed study protocol adaptation by expanding recruitment to include community-based service providers and staff from additional schools, and integrating themes into interview questions.
Conclusion:This project prioritized dialogue with stakeholders to gain insights to inform the development of a cultural inquiry into the special education landscape in western Kenya. Themes elucidated from this project provided critical feedback to inform future study protocol and an expanded recruitment plan.
Neighborhood Disadvantage and Healthcare Utilization in Pediatric Sickle Cell Patients
Authors: Catanzarite Ashley , Bouck Jillian , Jacob Seethal
Published: January 2024

Background: Sickle cell disease (SCD) is a complex heritable blood disorder associated with higher acute healthcare utilization further complicated by psychosocial and socioeconomic factors. Other studies have indicated a relationship between neighborhood disadvantage and increased healthcare utilization. We hypothesize that those with greater neighborhood disadvantage will have greater acute healthcare utilization.
Methods: Data was collected retrospectively from the electronic medical record between 9/30/2021 and 7/11/2023 for patients followed at Riley Hospital for Children’s Pediatric SCD Clinic who completed a psychosocial needs assessment (PAT). Number of emergency department (ED) visits, hospitalizations, and missed clinic visits were collected from the time the PAT was completed up to 1 year after (or the end of the data collection period). Data regarding area deprivation index (ADI) and childhood opportunity index (COI) were collected utilizing patient home address. Descriptive statistics were performed on all data above, as well as t-tests and chi square tests for univariate analyses.
Results: 142 patients completed a PAT during the study period. 88% had a primary care provider documented, and 73% had public insurance. The median state and national ADI (6, 76.5) and COI (2, 2) demonstrated greater neighborhood disadvantage and less childhood opportunity. There was no statistically significant difference between ADI or COI and number of ED encounters or hospitalizations. However, patients who missed 1 or more SCD visits had a higher median state ADI than those who did not miss a visit (7.5 vs 5, p=0.002). Median state COI was also lower in this group than those who did not miss a visit (1 vs 2, p=0.001).
Conclusion: Those with higher ADI and lower COI could benefit from more directed support to improve access to preventative care visits. Further analysis accounting for comorbidities (seizures, asthma, depression) could disambiguate a relationship between ADI or COI and acute care utilization.
Neuromuscular dysfunction precedes muscle atrophy in C26 tumor-bearing mice
Authors: Giffin Davis , Clouse Morgan , Huot Joshua R.
Published: January 2024

Background: Cancer patients frequently develop skeletal muscle wasting and weakness, which are hallmarks of cachexia, a wasting disease which worsens quality of life and is directly responsible for up to 30% of all cancer-related deaths. While advancements in detection and treatment have increased the population of cancer survivors, skeletal muscle dysfunction can persist for years following cancer remission. We previously demonstrated that late-stage cachexia is associated with impaired skeletal muscle innervation, linking loss of motor unit (MU) connectivity to cancer-induced wasting and weakness. In the present study, we investigated the onset of neuromuscular dysfunction in a preclinical model of cancer cachexia.
Methods: CD2F1 male mice (8-week-old) were subcutaneously injected with C26 colorectal cancer cells (1.0x106) or saline and randomized into one the following timepoint groups: day 6, day 8, or day 10 (n=8-10). Animals were assessed for indices of MU connectivity and muscle function at each timepoint. Following functional assessment, skeletal muscles were harvested, weighed, and processed for molecular analyses.
Results: 6 days post tumor injection, C26 hosts displayed reductions in neuromuscular junction (NMJ) transmission and motor unit connectivity, while muscle torque and mass were preserved. Specific torque was reduced in C26 hosts at day 8, while reductions in muscle mass or cross-sectional area did not occur until day 10. Molecular analysis revealed alterations of NMJ components as early as day 6 in C26 hosts, further suggesting that neuromuscular dysfunction precedes muscle atrophy.
Conclusions: Altogether our data demonstrate that cancer-induced neuromuscular dysfunction precedes cancer-induced muscle atrophy, identifying impaired innervation as an early prognosticator of cachexia progression. Our work supports strategies to counteract impaired neuromuscular function in the treatment of cancer cachexia, in hopes of sustaining quality of life in cancer patients and the growing population of cancer survivors.
Percutaneous Liver Biopsy Adverse Events in Stable Fontan Patients
Authors: Glass Brendon , Pfaff Sean , Sinsabaugh Christopher
Published: January 2024

Background:In patients who have undergone a Fontan operation, altered cardiac circulation can lead to several organ pathologies, including Fontan-associated liver disease. Transjugular liver biopsies are the standard for assessing liver disease in these patients, however data for a percutaneous approach in these patients is limited. Percutaneous liver biopsies are the preferred method in the general population. The objective of this study was to compare the rate of adverse events for percutaneous liver biopsies in Fontan patients to the general pediatric population.
Methods:A retrospective chart review was conducted on percutaneous liver biopsy patients over a five-year period. For each patient, a 90-day period post-biopsy was investigated to look for any indications of adverse events (pain, hemorrhage) and related work-up (imaging, hospital admission), scoring the severity of these events based on SIR adverse event classification. Patients were stratified based on if they underwent a cardiac catheterization procedure immediately prior to biopsy or not.
Results:A total of 412 biopsies were reviewed, 367 without cardiac catheterization and 45 with catheterization. Across the entire population, 38 adverse events were found, giving an overall adverse event rate of 9.2%. Comparing populations, non-catheterized patients were found to have an adverse event rate of 9.0%, with a minor rate of 7.2% and a major rate of 1.8%. The catheterized group had an adverse event rate of 11.1%, with a minor rate of 8.8% and a major rate of 2.3%. There were no lethal events. These rates align with reported literature.
Conclusion and Potential Impact:There was no significant difference in adverse event rates between Fontan patients and the general population after a percutaneous liver biopsy. This information can guide clinical decisions, as these biopsies are cheaper, less invasive, and do not expose patients to ionizing radiation.
Comparing Complication Rates of Transcatheter Aortic Valve Replacement to Surgical Aortic Valve Replacement
Authors: Hedberg Jacob , Butler James
Published: January 2024

Background/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.
Peanut-Specific Immune Response in Bcl6 Heterozygote Knockout Mice
Authors: Hogan Riley , Abdi Abdullahi , Dent Alexander
Published: January 2024

Food allergies are common in the United States, yet the mechanisms for the development and regulation of IgE, one of the most important antibodies for these allergic responses, are not fully understood. Two cells, T follicular helper (TFH) and T follicular regulatory cells (TFR) have been shown to be critical in the production IgE in particular, as when these cells are absent, IgEproduction is significantly decreased while IgG1 production remains around normal levels. However, it has not been determined whether haploinsufficiency for Bcl6 or the number of TFH and TFR cells that develop in our mouse food allergy model affect allergic IgE responses. In this project, we show that haploinsufficiency of Bcl6 unexpectedly leads to a trend toward an increase in the number of TFH and TFR cells within mesenteric lymph nodes with trend toward an increase in IgE and IgG1 in CD4-Cre-Bcl6-fl/+ mice compared to wildtype mice. However, haploinsufficiency for Bcl6 led to a loss of TFH and TFR cells in the spleen. This points to the possibility that TFH and TFR production, along with antibody production, is regulated differently in the gut compared to the rest of the body. Much remains to be understood about how TFH and TFR cells regulate allergic IgE responses.
Comparison of Sinus Flora Using Various Next-Generation Sequencing Techniques Versus Standard Culturing
Authors: Kistler Benjamin , Patel Manav , Davis Thomas , Lei Guang-Sheng , Schreiber Danielle , Ramakrishnan Vijay
Published: January 2024

Background:Next generation sequencing methods are being developed to help diagnose infectious diseases at the point of care and to help resolve discrepant results. These new methods hope to replace longer, more tedious sequencing methods such as Sanger/shotgun sequencing and less sensitive culture results to provide a clinical diagnosis and start appropriate treatment sooner. In lieu of dated techniques, with next generation sequencing the physician could analyze samples in their clinic with relative ease and receive a sensitive diagnosis in a fraction of the time.
Objective:To compare percent agreement between standard culturing results of swabbed sinus samples on blood and chocolate agar to BIOFIRE® FILMARRAY® results, and use Oxford Nanopore and 16s illumina sequencing results to resolve discrepancies.
Study design:Swabs were taken of the nasal sinuses of 21 patients and flash frozen. Some of these swabs (15/21) were sequenced with 16s illumina sequencing. All these swabs were put into a saline solution and plated on blood and chocolate agar plates as a 1:100 loop dipped into the solution and as the original swab. These solutions were sequenced through the BIOFIRE® FILMARRAY® Torch System on a pneumonia and blood culture (BCID2) panel and through the Oxford Nanopore® MinION Mk1C® system.
Results:The pneumonia panel had 36% agreement with blood agar and 52% agreement with chocolate agar plates. Using the top 3 genus results, either Nanopore or 16s illumina sequencing resolved 92% of discrepancies between the pneumonia panel and blood agar and 90% of discrepancies between the pneumonia panel and chocolate agar plates. The blood culture panel had 43% agreement with blood agar and 57% agreement with chocolate agar plates. Nanopore or 16s illumina sequencing resolved 92% of discrepancies between the blood panel and blood agar and 89% of discrepancies between the blood panel and chocolate agar.