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Cholestatic Drug Induced Liver Injury From Rad-140 Successfully Treated With Corticosteroids
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Current Status of Colorectal Cancer Screening Among Adults With and Without Cognitive Disabilities in the United States, 2022
No full textObjective: Evaluate the prevalence of non-compliance with colorectal cancer screening guidelines among US adults aged 45-75, comparing individuals with cognitive disabilities to those without.
Methods: This study utilized data from the 2022 Behavioral Risk Factor Surveillance System survey, which uses weighted and complex survey sampling methodologies. Participants under 45 were excluded, resulting in a study sample of 220,879. Univariate, bivariate, and multivariable logistic regression analyses were conducted to assess the prevalence odds ratio of colorectal cancer screening among individuals with and without cognitive disabilities.
Results: Those with cognitive disabilities had 1.07 (95% CI: 0.99-1.15) times the odds of not adhering to colorectal cancer screening guidelines compared to those without, indicating that there was no difference between those with and without CD after adjusting for sociodemographic and health factors.
Conclusion: There is insufficient evidence to support an association between cognitive disability and non-adherence to colorectal cancer screening guidelines. Further research is needed to uncover factors contributing to poorer health outcomes in individuals with cognitive disabilities across the cancer care continuum
Asporin/Crabp2 Axis Drives Cell-State Transition to Enable Neuroendocrine-Like Phenotype In Prostate Cancer
No full textProstate cancer (PCa) stands as the top frequently diagnosed malignancy and the second-most leading cause of death in males in the United States in 2024. Androgen-targeted therapies are effective for early-stage PCa. However, it recurs with castration resistant PCa, leading to survival for less than 2 years. Further advancement of PCa causes it to metastasize and develop “de novo” and treatment related neuroendocrine PCa cancer (NEPC), a lethal form of PCa with a poor survival of 7 months. Hence, to understand the biology beyond PCa metastasis, we developed a composite mouse model with loss of Pten and p53 function and gain of MYC amplification. Our composite mouse triple transgenic model exhibited poor survival due to high metastasis to visceral organs. To understand the mechanism behind this aggressive phenotype of the mouse we performed global transcriptomic analysis of less aggressive and highly aggressive mice (which differs by gains of p53 function). We found ASPORIN (ASPN) to be the top differentially regulated ECM gene in the aggressive mouse model of PCa. ECM and associated proteins are known to be significant contributors to PCa development, growth, proliferation, and EMT, but their role in metastasis is not explored completely in PCa. ASPN displayed significantly high protein expression in human and mouse PCa tissues and cells compared to their normal counterparts. To understand the functional significance of ASPN, we generated stable knockdown of ASPN in 22Rv1 cells and simultaneously overexpressed (OE) ASPN in normal immortalized RWPE1 cells and PC-3 PCa cells. We performed in vitro functional studies such as sphere formation, growth kinetics, proliferation, colony formation, wound-healing, transwell-migration assays, and biochemical assays on ASPN knockdown and ASPN overexpressing cells. Our results revealed a reduction in tumor-forming-, colony-forming-, wound healing-, migratory abilities, growth kinetics, and associated signaling (P-ERK, -AKT), and cell cycle (Cyclin D1 and D3) proteins upon ASPN knockdown while the opposite effects were observed in ASPN OE cells. RNA sequencing analysis of ASPN KD revealed the downregulation of top significant genes related to EMT- and neuroendocrine-like phenotype. Interestingly, ASPN KD and OE are associated with EMT switching by downregulating E-cadherin and ZO-1 with subsequent increased protein expression of N-cadherin and Zeb1. Upon RNA sequencing validation, CRABP2 emerged to be a neuroendocrine-associated protein significantly regulated by ASPN. Further, ASPN KD and OE regulate neuroendocrine markers such as Chromogranin A, NeuroD1, and INSM1 along with loss of RB function.
In conclusion, our studies revealed the significance of the ASPN/CRABP2 axis in the PCa initiation, progression, and cell-type phenotypic switch to neuroendocrine PCa (NEPC). In the future, this study will help to develop drugs targeting the ASPN/CRABP2 axis to control the specific mechanisms driving PCa towards NEPC, which would be crucial in overcoming t-NEPC
Disrution of 3D Genome Organization Can Explain Alcohol Fetal Spectrum Disorder
Get PDFFetal Alcohol Spectrum Disorders (FASD) refers to a range of disorders caused by prenatal alcohol exposure and are characterized by neurodevelopmental impairment with or withoutspecific facial features, congenital anomalies, and poor growth. The spectrum is composed of four diagnostic categories: fetal alcohol spectrum (FAS), partial fetal alcohol spectrum (PFAS), alcohol-related neurodevelopmental disorder (ARND), and alcohol-related birth defects (ARBD). There is no specific diagnostic test or molecular biomarker for FASD, and without one, patients require evaluation through a multidisciplinary team approach. Epigenetics is the study of changes in gene activity that do not involve alterations to the DNA sequence. Alcohol exposure during pregnancy can lead to chromatin modifications like DNA methylation and histone modifications, indicative of an epigenetic mechanism for the FASD phenotype. Chromatin is an epigenetic componentwithin the 3D nuclear space, efficiently packaging the genome while allowing proper expression and replication of the genetic material. 3D Organization of the genome is a property of chromatin and its components, with CTCF acting as a major architectural protein, working jointly with cohesin to generate thousands of high-intensity chromatin loops. We hypothesize that disruption of these loops by prenatal alcohol exposure drives neurodevelopmental defects by altering the expression of genes critical for brain development and function. In this study, we used chromatin immunoprecipitation sequencing (ChIP-seq) and found that alcohol exposure increases the intensity of CTCF loops, and we hypothesize this is through the formation of adducts.https://digitalcommons.unmc.edu/surp2024/1000/thumbnail.jp
Synthesis and Characterization of Block Copolymer Based Nanoparticles for Sustained Release of Therapeutics to Address Secondary Injury Events Upon Traumatic Brain Injury
No full textTraumatic brain injury (TBI) poses a significant global health challenge, contributing to approximately 2.5 million emergency room visits annually worldwide, 56,000 fatalities, and over $60 billion in direct medical costs for palliative care and cognitive rehabilitation in the United States alone(Acosta et al., 2016). The complex pathophysiology of TBI involves a multifaceted combination of neuroinflammation, oxidative stress, blood-brain barrier disruption (BBB), and Deoxyribonucleic Acid (DNA) damage. This research examines the development of a novel therapeutic system comprising dexamethasone-conjugated block co-polymeric nanoparticles loaded with olaparib, aiming to address multiple aspects of TBI pathology, particularly secondary injury (McConeghy et al., 2012). The dual-drug approach, featuring olaparib (Ola) and dexamethasone (DXM), targets key mediators of TBI progression. Olaparib, a potent poly (ADP ribose) polymerase-1 inhibitor, interferes with the overactivated DNA repair processes in injured cells post-TBI, otherwise exacerbating neuronal damage(d\u27Avila et al., 2012). Dexamethasone, a glucocorticoid, offers anti-inflammatory and anti-edema effects, reducing neuroinflammation and oxidative stress. In this thesis, nanoparticles were synthesized using methoxy poly(ethylene glycol) (mPEG) and N-carboxyl-α-amino-ץ-benzyl-L-glutamic anhydride (Glu(Bzl)-NCA) to form a methoxy poly(ethylene glycol) block polyglutamate benzyl (mPEG-b-pGlu(Bzl)m) copolymer, with dexamethasone conjugated via an ester bond to create a hydrophobic domain of amphiphilic block co-polymeric micelles that self-assemble in aqueous solutions, facilitating the efficient physical loading of olaparib into the hydrophobic core (Baldwin et al., 2018). In vitro studies demonstrated no cytotoxic effects within the tested concentration range of 0-200 µM for both drugs in the macrophage RAW 264.7 cell line. This novel dual-drug combinatory approach aims to address the limitations of earlier failed monotherapies in phase III clinical trials for TBI, highlighting the potential of block copolymeric nanoparticle-based drug delivery systems in enhancing the therapeutic outcomes of TBI, particularly in improving secondary outcomes(Stein et al., 2015)
Tyrphostin (AG-879) Decreases AKT Activation Through NGFR Inhibition in Human Glioblastoma Cell Lines
Get PDFGlioblastoma is an aggressive malignant brain cancer with a dismal 5-year survival rate of 6.9%. Despite current treatments – surgical resection, radiation, and chemotherapy – GBM remains incurable, highlighting the urgent need for more effective targeted therapies. Nerve Growth Factor Receptor (NGFR) plays a key role in the maintenance and growth of gliomas and is upregulated during GBM progression. Tyrphostin (AG-879), an inhibitor of TrkA in the NGFR pathway, was investigated in this study. We hypothesized that NGFR contributes to GBM progression by promoting proliferation and its pharmacological targeting will inhibit GBM growth. The objective was to determine the impact of AG-879 on cell proliferation and elucidate the underlying mechanisms of its anti-GBM effects. To evaluate this, U118 GBM cells were split into control and treatment (10µM AG-879) groups and allowed to incubate for 72-hours at 37.5oC. Afterwards, cell lysate was collected, and Lowry protein estimation was performed. Western Blot analysis was conducted, and membranes were probed with antibodies that targeted β-actin (loading control), phospho-AKT (proliferation marker), and total AKT. Our results demonstrated that AG-879 effectively decreases U118 cell proliferation by inhibiting AKT activation (phospho-AKT) at 10µM. Future studies should evaluate the effect of AG-879 on markers of apoptosis and cell cycle arrest.https://digitalcommons.unmc.edu/surp2024/1003/thumbnail.jp
Effect of Advanced Patient Scheduling on Patient-and Resident Continuity
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The Body Shamer Within: Incorporating the Teaching of Weight Bias Internalization into Weight Bias Education
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