Open Access Journals at IU Indianapolis
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Effects of Diet, Gender, and Age on Liver Metabolism Upon Feeding a High Fat Diet
Get PDFBackground/Objective: Currently, 30% of the USA population has non-alcoholic fatty liver disease (NAFLD), a condition that is increasing in parallel with the global obesity epidemic and life expectancy and is a risk factor for type 2 diabetes and cardiovascular disease. Aberrant transcriptional control of genes is a hallmark of metabolic disease. Thus, it is of interest to characterize how diet, age, and sex impacts various metabolic and signaling pathways upon progression to NAFLD.
Methods: A cohort of 7-week or 52-week-old male and female mice (n=8) were assigned a high-fat diet (HFD) or a low-fat diet (LFD) feeding regimen for 10 weeks, after which serum chemistries were obtained. Subsequently, gene expression in hepatic tissue samples was analyzed using RNA-seq and Western Blot.
Results: In both males and females, HDL, LDL, and total cholesterol were significantly increased with HFD in both age groups. In females, there was no significant difference in fasting blood glucose and insulin levels between any groups, while in males, both markers were significantly increased with HFD. RNA-seq data showed significant changes in gene expression correlating with diet, gender, and age. KEGG pathway analysis showed clustering of genes in fatty acid oxidation and synthesis pathways in mice fed a HFD, without affecting cholesterol synthesis enzymes. In aged mice, genes involved in extracellular matrix-receptor interaction were among the most affected. In males and females, young and aged, Western Blot analysis showed decreased expression of lipogenic enzymes ATP-citrate lyase and fatty acid synthase with HFD, but no changes of enzymes of cholesterol synthesis, confirming the RNA-seq data. No significant alterations were observed in insulin signaling.
Conclusion and Potential Impact: A HFD leads to a more severe phenotype in males than females, including increased fasting and non-fating glucose as well as insulin, and age exacerbates these abnormalities. Cholesterol is increased in both genders and is also exacerbated by age
Detection of Bowel and Mesenteric Injuries Using Deep Learning Computer Vision Models
Get PDFBackground/Objective:While only seen in 1-5% of patients who undergo a CT (computed tomography) scan, blunt bowel and mesenteric injuries (BMI) are associated with significantly increased morbidity and mortality. A significant cause of the increased morbidity of BMI is due to the difficulty of diagnosis from clinical and imaging information which leads to delay in diagnosis. Accurate and timely diagnosis is vital to reduce the morbidity of BMI.
Methods:For this project, our primary objective is to create a binary prediction model that determines if a patient has BMI based on their abdominal CT scans. Due to the importance of the early and definitive diagnosis of BMI in trauma patients, an extension of this project will seek to introduce explainability into the model to highlight which features on the CT scan caused the model to make its prediction. The patients with BMI were sourced from a trauma registry that recorded trauma cases from IU Health with relevant diagnosis codes. The images from our search will be reduced to the relevant slices for diagnosis of BMI and then used to train an ML model to makea yes/no prediction from the image. Once the model is trained, testing data will be evaluated on the model and the gradient vectors from the model during inference will be used to create a heatmap with GRAD-CAM that illustrates what portions of the image were relevant for the decision made by the algorithm.
Future Directions:Using the collected abdominal CTs, we can train our machine learning pipeline to detect BMI. Based on the performance of the model, we will determine if we need to collect more data. Then, we can evaluate the explainability of the model using GRAD-CAM and compareperformance of the ML model to the performance of expert and trainee radiologists
Clinical Markers for Small Vessel Pathology in Alzheimer’s Disease
Get PDFBackground:White matter hyperintensities (WMH) and cerebral microhemorrhages (MH) are common small vessel pathologies that often co-occur with hallmarks of Alzheimer’s Disease (AD) including amyloid-β and tau deposition, neurodegeneration, and decreased cognition. We investigated the relationship among these pathologies to better understand their roles in AD pathogenesis.
Methods:A sample from the AD Neuroimaging Initiative (ADNI) with baseline WMH volume WMHV), MH counts, and serum lipids measurements using the Nightingale Health metabolomics platform included cognitively normal, mild cognitive impairment, and AD participants. Spearman rank correlations coefficient and rank regression models were generated to assess the relationship between vascular pathology and mean arterial pressure (MAP), history of hypertension, and serum biomarkers. Models were covaried for age, sex, APOE status, BMI, and years of education. Further analysis was conducted by dividing participants based on APOE status. False discovery rate was controlled by the Benjamini-Hochberg method.
Results:WMHV and MH were weakly positively associated (ρ=0.197, p<1*10-10). MH and MAP were positively correlated (p<.05), but MH was not related to history of hypertension, or serum lipids. WMHV was negatively associated with serum VLDL cholesterol (p<1*10-12), LDL cholesterol (p<.0001), and remnant cholesterol (p<1*10-11). In APOE4 carriers only, WMHV was negatively associated with triglycerides (p<.001) and total fatty acids (p<.001), and positively associated with HDL cholesterol (p<.002). WMHV was not related to MAP or history of hypertension.
Conclusion:Vascular imaging markers have distinct risk factors with lipid profiles most associated with WMH burden, whereas MAP was predictive of MH. Counterintuitively, lipids associated with higher risk of systemic vascular pathology appeared protective against WMH in the ADNI sample. This phenomenon was particularly notable in APOE4 carriers. Further investigation should be conducted to better understand the relationship between serum lipids and small vessel pathology, and how these contribute to AD pathogenesis
Suppression of Inflammation-induced Abdominal Aortic Aneurysm Formation by Induction of Elastin Tolerance
Get PDFAbdominal aortic aneurysm (AAA) is a vascular disease process whereby the aorta expands to apoint where rupture may occur. This serious condition is diagnosed in approximately 200,000 people in the United States per year and accounts for over 15,000 deaths annually. The only medical intervention proven to reduce the risk of AAA rupture is surgical repair; however, such repair is associated with high risk of death, reduced quality of life, and high expense. AAA is caused by the weakening of the artery wall due to inflammation-induced destruction of its structural components. Our clinical data shows increased levels of circulating elastin degradation products in patients with AAA, especially smokers, compared to risk factor matched controls. This observation led us to hypothesize that an immune reaction to elastin fragments initiates the inflammatory cascade in the aorta that leads to AAA formation. To test this hypothesis, C57BL/6 mice were injected with poly(lactide-co-glycolide) nanoparticle-encapsulated IL-10 to induce immune tolerance or nanoparticle-encapsulated control ovalbumin. Injection of elastin fragments was performed 7 days later to induce an immune response. AAA of the infrarenal aorta was induced by topical application of elastase during laparotomy procedure 14 days after nanoparticle injection. Aorta diameter was measured 16 days post-operatively with Microfil. Immunologic changes were evaluated by cytokine analysis, Tr1/Th17 cell ratio inperipheral blood, and splenic Th17 and Tr1 response to elastin. Based on prior work, we expect that induction of elastin tolerance using poly(lactide-co-glycolide) nanoparticle-encapsulated IL-10 will suppress abdominal aortic aneurysm expansion and promote an anti-inflammatoryenvironment characterized by increased Tr1/Th17 cell ratio, increased levels of anti-inflammatory cytokines, and decreased pro-inflammatory cytokine expression
Therapeutic Effects of a Placental Tissue-Derived Allograft on Fracture Healing
Get PDFBackground:As 5-10% of fractures will not heal without medical intervention, there is an ongoing need for effective treatments to promote fracture healing. CTM Biomedical produces human placental tissue-derived allografts that are used clinically and may assist in healing; however, no pre-clinical studies assessing these products have been performed. Our study investigating the impact of CTM products on the healing of a standard femoral fracture and a critical sized femoral defect (CSD) aims to fill this gap. We hypothesize that CTM product application will improve fracture healing and reduce pain-related behaviors.
Methods:Femoral fractures were induced in 45 mice. CTM membrane, CTM paste, a combination of CTM membrane and paste, or saline was applied to each fracture. X-rays were taken twice weekly over 22 days, and blinded modified Radiological Union Scale for Tibia (mRUST) fracture scoring was performed. Complete blood analysis was conducted weekly. Following euthanasia 23 days post-surgery, μCT and histomorphometric analyses were conducted. CSDs have also been surgically induced in the femurs of 95 mice, with plans for similar fracture analyses.
Results:CTM product application did not significantly alter the levels of inflammatory cells, suggesting that the mice did not undergo immunological reactions. mRUST scoring indicated that CTM products may not alter fracture healing rates. However, combined application of CTM membrane and paste significantly increased the fracture callus’s mineralized volume (by ~90%) and the percent of the callus that was bone. CTM membrane and paste application also led to an increased threshold for hind paw withdrawal, suggesting that CTM products may decrease pain-related behaviors.
Future Directions:We hypothesize that in our CSD model, mice treated with the combination of CTM membrane and paste will display improved fracture healing and decreased pain-related behaviors. If shown to be effective, CTM product use may decrease fracture nonunion risk and increase comfort
Assessment of Patient Referrals with Large Numbers of Non-pedunculated Colorectal Lesions
Get PDFBackground: 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
Clinical Applications of Next-Generation Sequencing for Cancer Diagnostics and Targeted Cancer Therapy
Get PDFNext-generation sequencing (NGS) is a revolutionary technology that has effectively sequence massive quantities of genomic DNA or RNA at a shorter time and a lower cost. The NGS is routinely used in oncology to tailor care for individual patient. In this review, we discuss the role of NGS how it can provide a more personalized approach to targeted cancer therapy. A literature review was conducted via PubMed and articles were screened for publication dates within the past 10 years. Primary literature consisting of clinical trials and review articles were utilized. Search terms included “(next-generation sequencing) AND (cancer)”, “(next-generation sequencing) AND (cancer diagnostics)”, and “(next-generation sequencing) AND “(cancer therapy)”.
From the literature review, we found that NGS is indicated for daily practice as a diagnostic tool for advanced NSCLC, colon cancer, prostate cancer, cholangiocarcinoma, and some advanced rare cancers. We also found evidence suggesting that NGS is helpful in identifying actionable mutations that will, in turn, allow the patient to be matched to a more individualized cancer treatment.
As oncology care continues to move in the direction of more personalized care, the potential applications of NGS in the field of oncology will continue to evolve. Our review will help further the understanding of NGS and provide context for its value in patient care and its ability to provide an avenue for targeted therapy
The Potential Tripartite Connection: Alzheimer\u27s Disease, Fracture Healing, and the Gut Microbiome
Get PDFAlzheimer\u27s disease (AD), fracture healing, and the gut microbiome are interconnected aspects of health that have gained significant research interest. Recent studies suggest gut dysbiosis may play a role in AD pathogenesis, potentially through the gut-brain axis, a bidirectional communication system. Moreover, the gut microbiome\u27s role in bone health could link dysbiosis and fracture risk. Furthermore, research reports have revealed that the brain communicates with bone, termed the bone-brain axis. Despite these insights, the effect of the gut microbiome on fracture healing in AD remains largely unexplored.
To uncover these connections, our study uses the AD mouse models, 3xTg and 5xFAD. We conducted osteotomies on these mice and analyzed fecal samples that were collected at different timepoints. Fecal samples are being examined via qPCR and 16s RNA analysis toidentify and quantify bacterial phyla. These findings will be linked to both AD progression, gauged through behavior and histological analyses, and fracture healing, quantified using X-ray mRUST scoring, microCT, and histology.
We hypothesize that the progression of AD could alter the gut microbiome, potentially affecting fracture healing. This might occur through inflammation pathways triggered by specific gut bacteria. We may identify specific gut bacteria that play critical roles in both fracture healing and AD. We anticipate finding a shift towards pro-inflammatory bacterial phyla in the context of AD progression and during the fracture healing process. If this hypothesis is validated, it could unlock new therapeutic strategies aimed at targeting the gut microbiome to improve bone health, fracture healing, and AD progression in patients
Perioperative Risk Factors Predicting Hardware Exposure after Mandibulectomy and Reconstruction
Get PDFBackground and Hypothesis:Mandibulectomy is often required in the management of tumors, infection, or trauma of the head and neck. Reconstruction of the defect is accomplished via osteocutaneous free flaps and the use of titanium plates for fixation of the bone segments. Postoperative exposure of the mandibular hardware is an unfortunate outcome which results in significant quality of life detriment and often requires substantial revision surgery and reconstruction. We hypothesize that individuals with vasculopathic conditions and other circumstances that contribute to poor wound healing are more likely to experience hardware plate exposure following mandibular reconstruction.
Methods:A single-institution, retrospective cohort study was performed on all adults undergoing mandibulectomy and osteocutaneous free flap reconstruction from 2010-2020. Demographics, patient history, surgical parameters, and follow-up data were collected. Comparisons and logistic regression were used to determine factors associated with postoperative hardware exposure.
Results:The cohort consisted of 134 predominantly white (92.5%) male (65.7%) patients with mean age 58.4±13.0 years, 32 (23.9%) of whom had postoperative plate exposure. Between patients with and without exposure, there were no differences observed in demographics, substance use, surgical indications, or reconstructive techniques, neoadjuvant or adjuvant chemoradiation, nor 30-day major surgical site infection. The comorbidities of peripheral vascular disease, hypothyroidism, and immunosuppression were significantly more common in the plate exposure group. In multivariate logistic regression, peripheral vascular disease (OR [95%CI] = 18.8 [1.8-196.3]), hypothyroidism (OR [95%CI] – 3.5 [1.1-10.6]), and immunosuppression (OR [95%CI] =11.3 [2.4-54.1]) remained significant predictors of post-mandibulectomy hardware exposure.
Conclusion and Potential Impact:Patients with pre-existing peripheral vascular disease, hypothyroidism, and/or immunosuppression have an increased risk of post-mandibulectomy hardware exposure. Understanding these risk factors can improve shared patient-surgeon decision making and counseling, as well as guide practitioners to focus on mitigating these comorbidities prior to surgery
Brain activation during scene encoding fMRI in the Alzheimer’s disease continuum: Association with amyloid and tau burden in PE
Get PDFBackground 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