University of North Texas
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EXOSOME PROFILING OF BRONCHIAL LAVAGE FLUID IN A MOUSE MODEL OF SURGERY RESECTION OF BREAST CANCER WITH LUNG METASTASIS
No full textThe lung serves as a primary site for breast cancer metastasis, carrying profound implications for patient prognoses. About 60% of people diagnosed with metastatic breast cancer have lesions in either the lungs or the bones, with triple-negative breast cancer (TNBC) more likely than other types of breast cancers to metastasize to the lungs. Although current targeted chemo-radiotherapy and surgery result in higher survivorship, studies have documented that such curative treatments may also increase risk of lung metastasis. To date, the causal factors that mediate metastasis in the context of cancer treatments remain elusive. Our long-term goal is that a deeper understanding of the mechanisms that mediate relocation of breast tumor cells from its primary origin to its distal site (e.g., lung) will reveal novel complementary diagnostic and preventative treatments to improve TNBC survivorship. Exosomes, serving as tiny extracellular vesicles within tumor cells and other cells (e.g., immune cells) release diverse biomolecules have been implicated in tumor pathogenesis. Specifically, miRNAs as cargo within exosomes are known to regulate cellular function. miRNAs are small RNA molecules that can bind to messenger RNA (mRNA) and inhibit protein synthesis or promote mRNA degradation. This regulatory function allows miRNAs to modulate the expression of multiple genes involved in various cellular processes and their dysregulation has been implicated in various diseases, including cancer. The objective of this study was to determine the expression of miRNA-200b-3p and miRNA-141-5p as known regulators of lung cancer are influenced by surgical removal of a primary breast cancer. We hypothesized that miRNA-200b-3p and miRNA-141-5p mRNA expression is increased in response to surgery. Using an established model of breast cancer metastasis, exosomes were isolated from the bronchiole alveolar lavage fluid (BALF) of tumor bearing mice and mice in which primary tumors were resected compared to tumor-free mice. Results demonstrated that miRNA-200b-3p was present in both tumor-bearing and non-tumor-bearing mice. In contrast, miRNA-141-5p was not expressed in tumor-bearing, non-tumor-bearing mice, and naïve mice determined by quantitative reverse transcriptase polymerase chain reaction (qrtPCR). In conclusion, as we navigate the intricacies of miRNA dynamics in the lung microenvironment, future studies will involve broadening the miRNA panel and refining exosome recovery techniques. This strategic evolution aims to enhance sensitivity, facilitating the detection of elusive, tumor-derived exosome miRNAs. All studies have been approved by UNTHSC IACUC, approval number #2018-0031. Acknowledgement: This research is partially supported by a grant from the Cancer Prevention and Research Institute of Texas (Award#: RP210046) to Dr. Jamboor K. Vishwanatha and National Institute of Cancer Research of the Health under Award 1 P20 CA233355-01 (Vishwanatha, Jones-Project 1).Cancer Prevention & Research Institute of Texa
Assessment of Neuroinflammation in Cognitive and Motor Brain Regions in Female Rats Exposed to Chronic Intermittent Hypoxia
No full textResearch Appreciation Day Award Winner - School of Biomedical Sciences, 2024 Department of Physiology & Anatomy (Integrative Physiology) Award - 2nd PlaceSleep apnea increases the risk of neurodegenerative disorders in postmenopausal women. In this study, we tested whether chronic intermittent hypoxia (CIH), a preclinical model of sleep apnea-associated cyclical hypoxia, can be used to identify early changes in the brain that might contribute to impair neurological function in intact (INT) and ovariectomized (OVX) female rats. To test this hypothesis, we conducted immunohistochemistry studies using markers for glial activation and neuroinflammation. We hypothesize that CIH will increase glial activation in ovariectomized (OVX) relative to intact (INT) female rats.
Adult female Sprague Dawley INT (n=4) or OVX (n=4) rats that were part of a larger study and underwent 7 days of CIH (10% O2 and 21% O2 cycle, every 6 mins, 8h/day during the light phase) or continuous normoxia (CON) were euthanized on day 8, and their brains were collected. Brains were processed for microglia (IBA1) and astrocytes (GFAP) activation markers in (CA1) hippocampus, medial prefrontal cortex (mPFC), and caudate putamen (CP) striatum.
Confocal images from each region are being used to optimize a fractal analysis protocol to test for changes in glial morphology. Raw images will be linearly processed in Huygens Essentials software to limit noise and optimize quality for further analysis in ImageJ. Skeletal and fractal analyses will be performed on randomly selected cells in the photomicrographs to determine cell ramification (branching, junctions, endpoint voxels, branch lengths) and complexity (fractal dimension, cell span ratio, density) to complement cell counts of immunohistochemical markers of activation.
Our preliminary analysis has allowed us to determine the appropriate parameters needed for image capture and subsequent analysis. We have observed some possible qualitative changes indicative of increased activation in the CA1, CP, and mPFC regions following CIH in OVX rats relative to intact rats. The results of this study aim to contribute to our understanding of the potential impact of CIH in female rats of differing ovarian function, providing insights into sleep apnea-associated CNS dysfunction in women.RO1 HL15597
Evaluation of Fat Distribution as a Potential Risk Factor for Infection and Wound Healing Complications in Total Hip Arthroplasty
No full textPurpose: Surgical site infection (SSI) following joint replacement is a feared complication, as it is associated with worsened outcomes for both the patient and the healthcare system. There is conflicting evidence regarding BMI as a risk, as it does not consider body composition or the distribution of fat relative to the surgical site. This study evaluated the relationship between site-specific fat distribution and SSI following total hip arthroplasty (THA). Methods: Prospective data collection of surgical-site fat depth measured intraoperatively from the skin surface to the center of the greater trochanter. The ratio between fat depth and the size of the lateral trochanter was determined. Chart review of surgeries (n=98) to collect information on patient history, demographics, and various risk factors. Conclusion: Data collected in this study illustrates a statistically significant risk of THA SSI and wound healing complications with higher BMI and a statistical trend with increased localized fat distribution; however, evaluation of a larger patient population will be important to fully characterize the risk factors of THA postoperative complications and the impact of localized fat distribution
Platelet Releasate and ESWT for Treatment of a Partial Supraspinatus Tear in an Adolescent Baseball Player
No full textBackground: Rotator cuff injuries are a prevalent orthopedic concern, often arising from repetitive overhead activities, traumatic events, or age-related degeneration with the supraspinatus muscle being the most frequently injured. As the muscle responsible for initiating abduction of the arm, the supraspinatus is particularly susceptible to strain and tears, contributing to the majority of rotator cuff injuries. The incidence of rotator cuff tears in the general population is 5-30%, the prevalence of the condition is about 25% in people over age 65 and above 50% in individuals over age 80. Case Presentation: An 18-year-old right-hand dominant male baseball player who plays the catcher position presents to the clinic with right shoulder pain. The patient reports that they had a rotator cuff injury in his anterior shoulder area about 9 months prior which led to him sitting out of his previous season. On ultrasound imaging, the supraspinatus muscle showed a twenty-five percent partial tear on the bursal surface of the anterior aspect, with no retraction seen on dynamic exam. There was no other tendinosis or tear noted, with normal muscle appearance without any atrophy or fatty infiltration, or evidence of impingement with dynamic imaging. The ESWT was conducted before the Platelet Releasate injection procedure. With the patient in a supine crass position, 3000 total pulses at 15 MHZ were applied to the affected area using 2.6-3.6 bars of energy with a D-Actor C15 tip. The patient portrayed good tolerance to treatment, with a reported decrease in pain and improved range of motion. Following ESWT, a platelet releasate procedure was conducted on the right shoulder. On imaging, the patient’s supraspinatus muscle showed significant improvement in the tear, with only ten percent of the tear in the anterior supraspinatus still apparent (15 percent reduction total in the supraspinatus tear). There was evidence of acute supraspinatus tendinitis, with no impingement on dynamic testing. There was also some newly acquired bursitis in the subacromial bursa. There was no other noted tendinosis or tear, with a normal-looking muscle appearance. Conclusion: Generally, it can be difficult to highlight specifics and attribute them to the therapeutic effects of a treatment that facilitates various regenerative and healing properties. The main point of this case is to surface a less popular therapy compared to PRP: platelet releasate/ESWT and their therapeutic effects for MSK-related injuries. Platelet releasate paired with ESWT is a minimally invasive outpatient procedure and should be presented as a potential therapeutic treatment option to patients before considering invasive alternatives
Amelioration of Fibrosis via S1P Inhibition Is Regulated by Inactivation of TGF-beta and SPL Pathways in the Human Cornea
No full textHuman corneal fibrosis can lead to opacity and ultimately partial or complete vision loss. Currently, corneal transplantation is the only treatment for severe corneal fibrosis and comes with the risk of rejection and donor shortages. Sphingolipids (SPLs) are known to modulate fibrosis in various tissues and organs, including the cornea. We previously reported that SPLs are tightly related to both, transforming growth factor beta (TGF-beta) signaling and corneal fibrogenesis. The aim of this study was to investigate the effects of sphingosine-1-phosphate (S1P) and S1P inhibition on specific TGF-beta and SPL family members in corneal fibrosis. Healthy human corneal fibroblasts (HCFs) were isolated and cultured in EMEM + FBS + VitC (construct medium) on 3D transwells for 4 weeks. The following treatments were prepared in a construct medium: 0.1 ng/mL TGF-beta1 (beta1), 1 muM sphingosine-1-phosphate (S1P), and 5 muM Sphingosine kinase inhibitor 2 (I(2)). Five groups were tested: (1) control (no treatment); rescue groups; (2) beta1/S1P; (3) beta1/I(2); prevention groups; (4) S1P/beta1; and (5) I(2)/beta1. Each treatment was administered for 2 weeks with one treatment and switched to another for 2 weeks. Using Western blot analysis, the 3D constructs were examined for the expression of fibrotic markers, SPL, and TGF-beta signaling pathway members. Scratch assays from 2D cultures were also utilized to evaluate cell migration We observed reduced fibrotic expression and inactivation of latent TGF-beta binding proteins (LTBPs), TGF-beta receptors, Suppressor of Mothers Against Decapentaplegic homologs (SMADs), and SPL signaling following treatment with I(2) prevention and rescue compared to S1P prevention and rescue, respectively. Furthermore, we observed increased cell migration following stimulation with I(2) prevention and rescue groups, with decreased cell migration following stimulation with S1P prevention and rescue groups after 12 h and 18 h post-scratch. We have demonstrated that I(2) treatment reduced fibrosis and modulated the inactivation of LTBPs, TGF-beta receptors, SPLs, and the canonical downstream SMAD pathway. Further investigations are warranted in order to fully uncover the potential of utilizing SphK I(2) as a novel therapy for corneal fibrosis.The authors would like to acknowledge the National Eye Institute for their funding support (EY031316)
The ethical implications of gender bias in clinical research: a Narrative Review
No full textIntroduction: Sex bias in clinical research emerged in the 1960s after the 'thalidomide babies' incident, causing ethical concerns and a culture of abundance of caution. This led to the systematic exclusion of females, contributing to the exclusion of women as a gender identity. While sex bias has been extensively explored, gender bias merits separate consideration as gender bias affects the healthcare of an expanded group of individuals.
Purpose: The purpose of this study was to conduct a narrative review on the ethical implications of gender bias in research with the following questions in mind: What are the implications of sex and gender bias in clinical research? What is the current landscape of gender bias in clinical research? Where can we improve consideration of sex and gender in clinical research to increase healthcare outcomes for women and those assigned female at birth? What are the participation differences in research by gender? What are barriers (social, economic, practical) to research by gender? Are there ethical implications to the inclusion/exclusion criteria for research participants by gender identity?
Methods: A narrative review utilizing 8 databases (PUBMED, Scopus, CINAHL Complete, EBSCO host, APA Psych Info, Families Studies Abstract, MEDLINE Complete) from 2013 to August 2023 was performed. Search terms: “women OR woman OR female,” “research OR clinical research,” “sex bias or gender bias” and “underrepresent OR ethic OR equity.” 90 articles were reviewed by 3 researchers and evaluated for inclusion. A total of 45 articles were utilized for the final review.
Results: In the analysis of five key questions, gender-related discussions were limited. The ethical implications of sex and gender bias in clinical research were acknowledged, emphasizing the need for ethical considerations related to sex bias, including varied safe doses, potential risks to pregnant individuals, and the impact on patient outcomes.
The current landscape of gender bias in clinical research remained largely unaddressed, but insights into sex bias were provided, highlighting recent guidelines, disparities in representation, and the pervasive issue of sex bias across different specialties.
Participation differences and barriers in research by gender were explored, with a focus on social, economic, and practical aspects. Barriers included education, economic stability, practical challenges, and researcher-imposed biases, affecting recruitment and retention.
In addressing the ethical implications of inclusion/exclusion criteria based on gender identity, the study touched on the utility of studying transgender individuals due to hormone profiles, with one author recognizing the importance of the question.
Conclusion: There is a need for education of the scientific community on the difference between gender and sex. The dataset gathered yielded limited information due to the inconsistent use of gendered and sex terms. More women need to be included in research both as participants and as authors to address gaps in professional development in academia and address the underpinnings of bias in the workforce. Further strategies to work towards equity include enforcing pre-existing guidelines, utilizing the participation-to-prevalence ratio, combating misinformation, and modifying inclusion criteria for greater inclusivity
Navigating The Moral Prospect: Ethical Consideration in The Digital Age
Get PDFTechnology is advancing rapidly with an increase in interpersonal interactions. The digital environment gives new opportunities to the learner. The COVID-19 pandemic prompted an unprecedented shift from face-to-face to online learning. Presenting both unique opportunities and challenges. Educators, in response, embraced digital engagement to cater to 21st-century learners, fostering critical thinking and innovation. However, the digital environment also brought forth ethical considerations, which have led to prominent discussions in education. This paper delves into the crucial aspect of developing a comprehensive code of ethics for online education while advocating for the establishment of clear internal procedure, policies, and guidelines to support ethical practices. The creation of such a robust code of ethics serves as a cornerstone not to push technological development, but to guide ethical integration by outlining principles that promote responsible behavior, safeguard privacy, and ensure equitable access to educational resources. Furthermore, the paper explores how educators can play a critical role in promoting ethical behavior among 21st-century learners. By incorporating, critical thinking skills, and encouraging discussions and assignments rooted in personal, professional, and life experiences, educators can introduce a sense of responsibility and ethical awareness in their students. The paper underscores the importance of initiative-taking measures, such as a well-defined code of ethics, to navigate the evolving landscape of online education responsibly. It contributes to the ongoing discourse on ethical considerations, offering insights and recommendations for fostering a digital learning environment characterized by integrity and ethical conduct
Molecular Modeling and In Vitro Functional Analysis of the RGS12 PDZ Domain Variant Associated with High-Penetrance Familial Bipolar Disorder
No full textBipolar disorder's etiology involves genetics, environmental factors, and gene-environment interactions, underlying its heterogeneous nature and treatment complexity. In 2020, Forstner and colleagues catalogued 378 sequence variants co-segregating with familial bipolar disorder. A notable candidate was an R59Q missense mutation in the PDZ (PSD-95/Dlg1/ZO-1) domain of RGS12. We previously demonstrated that RGS12 loss removes negative regulation on the kappa opioid receptor, disrupting basal ganglia dopamine homeostasis and dampening responses to dopamine-eliciting psychostimulants. Here, we investigated the R59Q variation in the context of potential PDZ domain functional alterations. We first validated a new target for the wildtype RGS12 PDZ domain-the SAPAP3 C-terminus-by molecular docking, surface plasmon resonance (SPR), and co-immunoprecipitation. While initial molecular dynamics (MD) studies predicted negligible effects of the R59Q variation on ligand binding, SPR showed a significant reduction in binding affinity for the three peptide targets tested. AlphaFold2-generated models predicted a modest reduction in protein-peptide interactions, which is consistent with the reduced binding affinity observed by SPR, suggesting that the substituted glutamine side chain may weaken the affinity of RGS12 for its in vivo binding targets, likely through allosteric changes. This difference may adversely affect the CNS signaling related to dynorphin and dopamine in individuals with this R59Q variation, potentially impacting bipolar disorder pathophysiology.The studies were supported by National Institutes of Health grants R01 DA048153 (to D.P.S.) and K08 AI159619 (to D.E.B.). P.S.A.-M. was supported by an internal seed grant from the UNTHSC Division of Research and Innovation (DRI
Investigating the Correlation Between Hyperthyroidism and 10-Year Onset of Essential Tremor
Get PDFEssential Tremor (ET) is a prevalent common neurological condition, spanning individuals from adolescence to late adulthood. When ET occurs alongside thyroid disorders such as Hyperthyroidism or Hypothyroidism, the resulting combination can lead to significant alterations throughout life. This investigation aims to explore whether these thyroid conditions exacerbate Essential Tremor symptoms and establish any potential links between these common health issues. This retrospective study analyzes data from previous participants in two clinical trials. It will extract information from existing records, including Thyroid Stimulating Hormone (TSH) panels, Essential Tremor Rating Assessment Scale (TETRAS) score reports, and performance on the Archimedean spiral test. The data will help evaluate the severity of Essential Tremor and its correlates using Microsoft Excel. When reassessed at North Texas Clinical Trials, LLC, it became evident that ET predominately affects males more than females, while Hypothyroidism shows a higher prevalence among females compared to males. Notably, subjects diagnosed with both Primary Hypothyroidism and ET exhibited a significant increase of >50% in their TSH levels compared to those diagnosed solely with ET. Interestingly, the activities of daily living (ADL) and performance charts reflected a <2% difference between the two groups. Primary Hypothyroidism is associated with significantly elevated TSH levels, contributing to various symptoms. However, when examining the etiology of ET, these thyroid disorders do not have a direct impact or correlation. Given the etiology being unknown in ET with the absence of hyperthyroidism, further research is warranted to provide further analysis
