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Evaluation of the Anti-Cancer Mechanism of Tolfenamic Acid and its Copper (II) Complex
No full textBackground and Significance: Medulloblastoma (MB) is a common pediatric brain tumor, representing 20% of childhood brain neoplasms. While treatments provide a five-year survival rate of approximately 75%, long-term survival rates for children over three years old range between 70% and 85%. Standard therapies, including chemotherapy, radiation, and surgery, often result in significant long-term side effects and morbidity in young patients. There is a growing need for safer treatments to minimize these adverse effects. Tolfenamic Acid (TA), a non-steroidal anti-inflammatory drug, has shown potential as a safer treatment option for MB. This study aimed to investigate TA’s mechanism of action and compare its effectiveness to a novel copper(II) complex of TA (Cu(II)-TA), as a possible safer and more effective alternative. We hypothesized that Cu(II)-TA is more effective due to a distinct mechanism of action, particularly its ability to induce DNA damage, cell cycle arrest, and apoptosis. Methods: MB cells were cultured and treated with increasing doses of TA and Cu(II)TA. Cell viability was assessed after 48 hours using standard viability assays. DNA damage and apoptosis were evaluated through various techniques, including staining for markers of double-strand DNA breaks (γ-H2AX) and assessing expression levels of proteins associated with apoptosis and cell cycle arrest. Cell cycle profiles were analyzed using flow cytometry to determine the effects of the treatments. Results: Cu(II)-TA was significantly more effective than TA at reducing cell viability, with an IC50 value substantially lower than that of TA. Both drugs induced DNA damage, as shown by increased levels of γ-H2AX. However, DNA damage was more pronounced with TA compared to Cu(II)-TA. Both drugs induced apoptosis and influenced the expression of proteins related to cell cycle regulation, such as p27 and Survivin. Flow cytometry showed that TA led to significant cell cycle arrest at the G2/M phase, consistent with DNA damage. In contrast, Cu(II)-TA caused less prominent dose dependent changes in the cell cycle. Conclusion: Cu(II)-TA demonstrated increased effectiveness in reducing cell viability compared to TA.. While both drugs caused DNA damage, TA’s effects were more pronounced, suggesting that Cu(II)-TA likely operates through alternative mechanisms. These findings support the potential of Cu(II)-TA as a promising candidate for use in conjunction with standard treatments for pediatric medulloblastoma. Further studies are needed to explore the specific mechanisms by which Cu(II)-TA exerts its anticancer effects and to validate its efficacy in preclinical and clinical settings
Preliminary analysis of the impact of lab results on large language model generated differential diagnoses
Full text linkDifferential diagnosis (DDx) is crucial for medicine as it helps healthcare providers systematically distinguish between conditions that share similar symptoms. This study evaluates the influence of lab test results on DDx accuracy generated by large language models (LLMs). Clinical vignettes from 50 randomly selected case reports from PMC-Patients were created, incorporating demographics, symptoms, and lab data. Five LLMs-GPT-4, GPT-3.5, Llama-2-70b, Claude-2, and Mixtral-8x7B-were tested to generate Top 10, Top 5, and Top 1 DDx with and without lab data. Results show that incorporating lab data enhances accuracy by up to 30% across models. GPT-4 achieved the highest performance, with Top 1 accuracy of 55% (0.41-0.69) and lenient accuracy reaching 79% (0.68-0.90). Statistically significant improvements (Holm-adjusted p values < 0.05) were observed, with GPT-4 and Mixtral excelling. Lab tests, including liver function, metabolic/toxicology panels, and serology, were generally interpreted correctly by LLMs for DDx.This work was supported by the Agency for Healthcare Research and Quality grant R21HS029969 (PI: Z.H.). This project was also partially supported by the University of Florida-Florida State University Clinical and Translational Science Award, which is supported in part by the National Institutes of Health (NIH) National Center for Advancing Translational Sciences under award UL1TR001427. Q.J. and Z.L. were supported by the NIH Intramural Research Program, National Library of Medicine. We would like to thank the four undergraduate students Angelique Deville, Hailey Thompson, Maggie Awad, and Yash Alvafor their work in extracting key information from the case report
The Effects of Bisphosphonate and Exercise Treatment on Craniofacial Morphology in a Mouse Model of Osteogenesis Imperfecta
No full textPoster Highlight: College of Biomedical and Translational Science, RAD 2025 Award Winning Posters & Oral PresentationsOsteogenesis imperfecta (OI or “brittle bone disease”) is a rare, heritable disorder of type I collagen. OI results in increased fractures and abnormal skeletal development. Patients with severe OI often exhibit craniofacial dysmorphologies, including hypoplastic facial skeletons and macrocephaly. Bisphosphonates, considered the “gold standard” treatment for OI, are successful in preventing fractures, but are unable to recover the normal skeletal growth trajectory. Biomechanical loading-based interventions have been shown to improve skeletal growth outside of OI, and are one potential treatment to recover skeletal size and shape. Here, we evaluate how a combination treatment of bisphosphonates and increased biomechanical loading impacts the craniofacial growth of a mouse model for OI. We hypothesize that mice with OI, when treated with a combination therapy, will have craniofacial phenotypes more similar to unaffected mice OIM (B6C3Fe a/a-Col1a2oim/oim) and unaffected wild-type (WT) mice were randomly assigned into either control (C) or combination (COMBO) treatment groups (n=9-11/genotype/group). COMBO mice received four monthly subcutaneous injections of zoledronate (80 µg/kg) between 4-16 weeks, as well as ad-libitum access to wooden gnawing items to increase biomechanical loading of the craniofacial skeleton. The craniofacial skeleton of all mice was imaged with a micro-CT scanner (20 µm3 voxels) monthly between 4-16 weeks. The ALPACA function in SlicerMorph (3D Slicer Software) was used to collect 82 fixed landmarks and 1026 sliding landmarks from each cranium. A general Procrustes analysis was applied to all landmark data, and a principal component analysis used to assess shape variation among the treatment groups. The craniofacial morphologies of OIM and WT mice separated along PC1 (19.5% total variance). A Procrustes ANOVA revealed a significant effect of genotype (p=0.001) and trend for a difference between C and COMBO treatments (p=0.062). While the PCA revealed overlap between the treatment groups within genotypes, morphological variation was significantly reduced in OIM-COMBO compared to OIM-C mice (p=0.048). This preliminary data provides partial support for the hypothesis that a combination intervention recovers the craniofacial phenotype in OIM mice. Specifically, this treatment regime may potentially reduce morphological variation and minimize the more extreme phenotypes. This suggests that supplementing bisphosphonate treatments with biomechanical loading interventions may reduce the severity of the craniofacial phenotype and improve quality of life related to breathing, feeding, and other cranial functions in patients with OI
The Impact of Inhibiting Histone Deacetylase 4/5 In A Mouse Model Of Glaucoma
No full textPoster Highlight: HSC College of Pharmacy, RAD 2025 Award Winning Posters & Oral PresentationsPurpose: Glaucoma is the second leading cause of blindness globally. Despite advancements in research, there is no cure. Epigenetic modifications have been key in regulating gene expression and metabolism within ocular structures, influencing the development and progression of glaucoma. Over the years, elevated histone deacetylase (HDAC) activity has been reported in various ocular injury models, including optic nerve crush, ischemia/reperfusion, and glaucoma. However, the role of its inhibition remains largely unexplored. This study investigates the impact of HDAC 4/5 inhibition using the small molecule LMK-235 in mitigating glaucoma progression. We hypothesize that inhibition of HDAC 4/5 using LMK-235 will mitigate glaucoma-related retinal ganglion cell death. Methods: C57BL/6 mice (4-5 month old, n=25) were randomly assigned to five groups: naïve control, ocular hypertension (OHT), OHT + Vehicle, OHT + LMK-235 (1 mg/kg), and OHT + LMK-235 (3 mg/kg). OHT was induced by injecting magnetic microbeads into the anterior chamber of the eye and directing them to occlude the trabecular meshwork using a neodymium magnet. Intraocular pressure (IOP) was measured before and after OHT induction. Five days post-OHT, mice received vehicle or LMK-235 every other day for two weeks. The control group received no injections. Four weeks following OHT onset, mice were euthanized, their eyes were enucleated, and their retinas were analyzed for HIF-1α expression via capillary electrophoresis. Retinal ganglion cell (RGC) density was assessed using stereology after immunohistochemistry with RGC marker, RBPMS. One-way Anova was used for statistical analysis. Results: HIF-1α levels were significantly elevated in the OHT + Vehicle group compared to controls but were reduced in the OHT + LMK-235 (1 mg/kg) group (p=0.0425). LMK-235 at 1 mg/kg effectively lowered HIF-1α expression after four weeks of OHT compared to the vehicle group. RGC density was significantly reduced in the OHT group; however, LMK-235 administration preserved RGC density at both 1 mg/kg and 3 mg/kg doses (p=0.0219 and p=0.0083, respectively). Conclusion: HDAC 4/5 inhibition with LMK-235 reduces HIF-1α expression and preserves RGC density in a mouse model of glaucoma. These findings suggest that targeting HDAC 4/5 may offer a neuroprotective strategy in glaucoma by mitigating hypoxic stress and preserving neuronal integrity
Role of monocarboxylate transporters (MCTs) in Fibrotic and Hypoxic Responses of the Cornea in Diabetes
No full textPoster Highlight: College of Biomedical and Translational Science, RAD 2025 Award Winning Posters & Oral PresentationsPurpose: Diabetes Mellitus (DM) is a progressive, chronic condition that is rapidly increasing and emerging as one of the most significant challenges in modern healthcare. DM affects various ocular structures, including the cornea, leading to both structural and functional changes. Monocarboxylate transporters (MCTs) are a family of proton-coupled plasma membrane transporters that helps in the transport of monocarboxylates, such as lactate and pyruvate, across the plasma membrane. Our recent studies have shown the presence and modulation of MCTs in the diabetic cornea in vitro. The aim of this study was to delineate the role of MCTs in corneal stromal fibrosis and hypoxia in the context of DM. Methods: Primary human corneal stromal cells were isolated from Healthy subjects (HCFs), as well as from subjects with Type 1 Diabetes Mellitus (T1DM) and Type 2 Diabetes Mellitus (T2DM). Cells were seeded on polycarbonate membranes with a density of 1*10⁶ cells/well and stimulated with stable Vitamin C (0.5mM) for four weeks. We investigated the expression of MCTs under normoxic (21% O₂) and hypoxic condition (2% O₂) while we also looked at the role of MCTs following cell culture stimulation with TGF-β1 (0.1ng/ml) and TGF-β3 (0.1ng/ml) in normoxic conditions. Results: Significant downregulation of MCT4 was observed for hypoxic HCFs compared to normoxic HCFs. MCT4 was significantly upregulated in hypoxic T1DMs compared to normoxic T1DMs. Both TGFβ-1 and TGFβ-3 treatments led to significant upregulation of MCT2 and downregulation of MCT4. Additionally, we found significant upregulation of MCT5 and MCT10 with TGFβ-3. Conclusions: Our study, revealed the downregulation of MCT4 when treated with TGFβ suggesting lactate accumulation changes. However, the observed upregulation of MCT2 within the same group suggests a potential pyruvate mediated glycolysis of the corneal stromal cells under in normoxic conditions. Under hypoxic conditions, HCFs showed disrupted metabolic adaptation, whereas T2DM cells showed upregulation of MCTs, which indicates an increased dependence on lactate export to meet their metabolic needs. These findings highlight the critical role of MCTs in diabetic corneal stroma under hypoxia and fibrosis, warranting further investigation
Utilizing ATN Plasma Biomarkers and Machine Learning Models to Predict Early Alzheimer's Disease Among HABS-HD Cohort
No full textAlzheimer’s disease (AD) is a progressive condition of neurodegeneration in the brain resulting in a decline of cognitive function over time. Early detection of AD is essential for improving outcomes for Alzheimer’s patients because of the irreversible nature of the neurodegeneration. Previous studies have demonstrated the predictive capabilities of amyloid, tau, and neurofilament (ATN) biomarkers for denoting amyloidosis and neurodegeneration in the brain. Furthermore, studies suggest that the biomarker of greatest predictive power for AD is different depending on the race and ethnicity of the patient population. While most studies of ATN biomarkers predicting brain amyloidosis have been conducted in predominantly non-Hispanic White cohorts, further investigation of these biomarkers in different racial and ethnic groups is a current focus of AD researchers. In this project, we investigated the role of ATN biomarkers Amyloid Beta (Aβ) 40, Aβ 42, T-Tau, Ptau-181, and Neurofilament Light Chain (Nf-L) in support vector modeling (SVM) to predict amyloidosis in the HABS-HD cohort (N = 1,442, Amyloid PET Positive N = 108, Amyloid PET Negative N = 1,334). The HABS-HD cohort is a racially and ethnically diverse patient population consisting of non-Hispanic Whites, non-Hispanic Blacks, and Hispanics. By studying these ATN biomarkers in this cohort, we were able to determine that SVMs with a combination of all ATN biomarkers (Aβ 40, Aβ 42, T-Tau, Ptau-181, and Nf-L) were the most successful at predicting brain amyloidosis in our non-Hispanic Whites (AUC = 0.88), non-Hispanic Blacks (AUC = 0.79), Hispanics (AUC = 0.88), and overall (AUC = 82). Furthermore, we discovered that while the Aβ 42/40 ratio had the greatest predictive power in our non-Hispanic White cohort and overall, PTau-181was the greatest driver in predicting brain amyloidosis in the non-Hispanic Black SVM model, and Nf-L was the greatest driver in predicting brain amyloidosis in the Hispanic SVM model. Moving forward, we will continue to investigate the relationship of these ATN biomarkers and more and work to incorporate more combinations of biomarkers, racial groups, and ethnic groups until the most precise and accurate SVM models for predicting brain amyloidosis in each patient population can be achieved
Policy Implementation Mapping for Dissemination of Best Practice in School Health
No full textPurpose: Significant health challenges exist among children, including issues related to nutrition, physical education, mental health, asthma control, and other chronic condition management. These unmet health needs can pose risks at the intersection of health and education and underscore the need for effective school health policies. While health policies addressing these challenges are in place, there remain critical gaps in the implementation and adherence to best practices. This study evaluates the dissemination of school health policies through implementation mapping, a systematic process aimed at improving real-world application. A rapid literature review was conducted to determine how policy-focused implementation mapping has been utilized by schools and state school health programs in the United States thus far to address gaps in the dissemination of health practices with the objective of aligning health policies with best practices and enhancing health outcomes for school-aged children. Methods: A rapid review methodology was used to evaluate current literature on implementing health policies in schools. Comprehensive searches included three databases, Scopus, Cinahl, and PubMed. Key words and queries were standardized across searches. Titles and abstracts were screened using inclusion and exclusion criteria, and Covidence software. Abstract and full-text reviews were conducted to include studies that provide insights into the barriers and facilitators of policy implementation. Google Sheets was used to systematically extract and organize data from selected studies. Key information from each study was documented in a structured spreadsheet for categorization and analysis. Data extracted included type of health policy, stakeholder influence, implementation strategies, and barriers. This approach facilitated an efficient synthesis of existing research, informing recommendations for aligning school policies with best practices. Results: We initially identified 305 articles through our search, and 22 articles met all inclusion and exclusion criteria for data extraction. Wellness policies were most frequently addressed, followed by asthma policies. Stakeholder engagement and continuous monitoring are highlighted as critical factors for effective policy implementation and sustainment. Sixteen of 19 articles mentioned stakeholder engagement as positive, while six referenced specific implementation frameworks, primarily the Consolidated Framework for Implementation Research (CFIR). Common barriers included limited stakeholder involvement, resource constraints, and geographical inequalities, with inadequate resources being the most frequent. Conclusion: Our rapid review highlights significant gaps in the implementation of health policies within school settings. Although these policies are in place, application remains inconsistent due to several barriers, such as insufficient resources, inadequate training for school personnel, and variability in adherence across districts. These challenges underscore the need for targeted solutions to bridge the gap between policy design and real-world practice. The review identifies several key areas for future research, including strategies to scale interventions for diverse school environments, reduce implementation costs, and strengthen team support. Additionally, the findings emphasize the importance of enhanced stakeholder engagement, improved training programs, and robust systems for continuous monitoring. These measures are essential for ensuring that health policies are effectively implemented and sustained over time. Addressing these challenges is critical to improving student health outcomes and fostering equitable access to care in schools
The Hidden Impact of Diabetes: Oxidative Damage and Redox Imbalance in ZSF1 Rat Kidneys
No full textPoster Highlight: Texas College of Osteopathic Medicine - Research, RAD 2025 Award Winning Posters & Oral PresentationsPurpose: Diabetic kidney disease (DKD) is a significant complication of diabetes, contributing to high morbidity and mortality rates worldwide. Despite its clinical relevance, the underlying mechanisms driving DKD remain incompletely understood. This study seeks to study the role of oxidative stress and redox imbalance in DKD using ZSF1 rats as a model of type 2 diabetes. By investigating the effects of normal and high-fat diets (HFD) on oxidative damage and mitochondrial dysfunction, we aimed to identify potential therapeutic targets. Specifically, we evaluated the involvement of mitochondrial NAD+-dependent enzymes, NAD kinase (NADK2) and complex I, in diabetic kidney pathology and assessed the impact of the complex I superoxide suppressor S1QEL on diabetic ZSF1 rats. Methods: Male ZSF1 lean (control) and obese (diabetic) rats were obtained from Charles River Laboratories. A total of 24 rats were randomly divided into four groups: lean-control diet, lean-Purina 5008 diet (HFD), obese-control diet, and obese-Purina 5008 diet. Animals were fed their respective diets for 20 weeks. In the last two weeks (14 days), three obese rats from each diet group were treated with S1QEL (2 mg/kg daily). At the end of the study, all animals were euthanized, and kidney tissues were collected. Body weight was recorded weekly, and weekly blood glucose levels were measured using a commercial glucose meter. Kidney indices were calculated as kidney weight normalized to body weight. Protein oxidation was assessed using protein carbonyl content, lipid peroxidation was quantified by thiobarbituric acid-reactive substances (TBARS), and Western blotting determined protein expression of NADK2 and complex I subunit NDUFV1. Results: There were no significant differences in body weight, kidney index, or blood glucose levels between rats on the control diet and those on the HFD after 20 weeks of feeding. However, protein oxidation and lipid peroxidation were significantly increased in the kidneys of diabetic rats compared to controls, indicating elevated oxidative stress. Western blot analysis revealed significantly increased protein expression of NADK2 and complex I subunit NDUFV1 in the kidneys of diabetic rats. Interestingly, S1QEL treatment did not affect blood glucose levels but unexpectedly increased body weight and kidney index in diabetic rats, with no such effect observed in lean control rats Conclusion: The high-fat Purina 5008 diet did not exacerbate body weight, kidney index, or blood glucose levels in diabetic ZSF1 rats, suggesting diet composition may have a limited impact on this study’s model parameters. Oxidative damage to proteins and lipids was significantly increased in diabetic kidneys, likely driven by elevated redox enzymes, such as NADK2 and complex I, expression. These findings emphasize the central role of mitochondrial dysfunction and redox imbalance in DKD pathogenesis, highlighting NADK2 and complex I as potential therapeutic targets. While S1QEL demonstrated potential in modulating oxidative stress, its unexpected effects on body weight and kidney index underscore the complexity of targeting mitochondrial pathways. Further studies are needed to clarify the mechanisms underlying these effects, evaluate higher dosages of S1QEL, and optimize interventions to ameliorate oxidative stress and protect against DKD progression
Investigating Differences in Methodological Approaches to Scoring Fracture Angle, Outline, and Surface
No full textFracture characteristics are expected to change as bone transitions from wet to dry over the postmortem interval. Various studies have investigated similar fracture characteristics (especially fracture angle, outline, and surface) to draw conclusions about this transition. Because each study presents its own protocols for scoring fracture characteristics, results may not be comparable due to methodological differences. It is currently unknown how these differences may impact the results of bone taphonomy studies and, potentially, interpretations of fracture timing based on these characteristics. This study aimed to 1) evaluate method agreement on fracture angle, outline, and surface scores, and 2) investigate whether different methods produce different score distributions. Materials included 40 deer femora exposed to outdoor conditions for different intervals of time. Experimental blunt force impacts were delivered to five bones every two weeks from 0 to 14 weeks post-exposure. Four methods were applied to score fracture angle, outline, and surface expressions for each femur. The most distal and proximal fragments of each bone were scored using all methods. One method (Green and Schultz, 2017) generated an overall bone score based on combining proximal and distal fragment scores, while other methods considered these scores separately. Fracture angle, outline, and surface expressions were initially scored according to the original publications. To facilitate comparison between methods, these scores were converted to scores of "wet," "intermediate," or "dry" as presented in the original publications. Fleiss' kappa tests were used to assess method agreement for converted scores. Pairwise chi-square tests were used to investigate associations between methods and scores. Method agreement was statistically significant (p < 0.05) for fracture angle, outline, and surface. Kappa values for fracture angle (κ = 0.591 proximal; κ = 0.876 distal) indicated moderate to near-perfect agreement. Kappa values for fracture outline (κ = 0.454 proximal; κ = 0.692 distal) reflected moderate to substantial agreement. However, kappa values for fracture surface (κ = 0.0594 proximal; κ = 0.0458 distal) revealed considerable variability in scoring across methods. Results indicate certain methods produced significantly different scores. Wheatley (2008) fracture surface scores differed from all other methods (p < 2.2e-16), likely due to the absence of an “intermediate” category, which resulted in more “wet” and “dry” scores. Green and Schultz (2017) fracture angle and outline scores differed from proximal fragment scores generated by other methods (p < 0.0003). This method scored more fracture angles and outlines as “intermediate” than “wet,” suggesting observation location influences scores. The results confirm that fracture angle, outline, and surface scores vary when evaluated using different methods, emphasizing that studies reporting on similar fracture characteristics may not be comparable due to differing scoring protocols. While the reviewed methods primarily aimed to explore fracture transition timelines rather than diagnose fracture timing, practitioners should note that different methods may produce different scores for certain fracture characteristics. If scores are taken at face value, methodological differences in scoring protocols could influence interpretations of fracture timing. The results highlight a need for clear, detailed, and widely accepted protocols for documenting skeletal trauma and taphonomy in research and casework
From Cellulitis to Hemolysis: The Diagnostic Challenge of Systemic Loxoscelism
No full textBACKGROUND: Systemic loxoscelism refers to the development of autoimmune hemolytic anemia following a brown recluse spider (Loxosceles reclusa) bite. It is primarily a clinical diagnosis, with an unpredictable clinical course. The venom of the brown recluse spider contains several compounds, including sphingomyelinase, which cause cellular death and inflammatory responses, that can lead to hemorrhagic necrosis and dermonecrosis at the site of envenomation. There are a few cases reporting hemolytic anemia after brown recluse spider bite. Red blood cell hemolysis is thought to be mediated by these venom components, in addition to immunoglobulin G (IgG) antibodies and complement activation. Typically, the site of envenomation becomes erythematous and warm within the first 24h, eventually ulcerating and becoming necrotic. This case highlights the diagnostic challenges associated in recognizing systemic loxoscelism, particularly when the presentation diverges from typical patterns. CASE INFORMATION: A 19-year-old male with no significant medical history presented to the emergency department with signs of sepsis, including fever and a cellulitic lesion on his right anterior chest wall with a necrotic center, suspected to be caused by an insect bite. The patient was unsure whether the bite was from a spider or another insect. Initially, he was treated empirically with IV vancomycin and ceftriaxone. Blood cultures, urine cultures, and a chest X-ray were negative. On hospital day 2, the patient developed a severe erythematous rash involving all four extremities, as well as his abdomen, chest wall, and face. He remained febrile, prompting further investigation. The differential diagnosis expanded to include vasculitis, tick-borne illnesses, and other rare conditions. Tests came back negative. Vancomycin was discontinued due to the erythema, which was not believed to be red man syndrome, and doxycycline was initiated. After two days without significant fever, the patient developed another fever spike on day 5, accompanied by jaundice and worsening anemia. This prompted a reassessment of his condition and a change in antibiotics from doxycycline to ceftaroline. By hospital day 6, the patient developed hemolytic anemia with positive coombs test and required five units of packed red blood cells. High-dose corticosteroids were administered, leading to an improvement in both jaundice and hemolysis. The patient's jaundice resolved completely by discharge. CONCLUSIONS: This case highlights the diagnostic complexity of systemic loxoscelism and emphasizes the need for increased awareness of this rare but serious condition. Additionally, systemic loxcelism can present with a spectrum of severity, from mild symptoms to severe systemic involvement, including hemolysis and multiorgan failure. The exact pathophysiology remains unclear on the development of hemolytic anemia. Early recognition of this condition is critical to ensure appropriate management