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Top Alzheimer's disease risk allele frequencies differ in HABS-HD Mexican- versus Non-Hispanic White Americans
Get PDFINTRODUCTION: Here we evaluate frequencies of the top 10 Alzheimer's disease (AD) risk alleles for late-onset AD in Mexican American (MA) and non-Hispanic White (NHW) American participants enrolled in the Health and Aging Brain Study-Health Disparities Study cohort. METHODS: Using DNA extracted from this community-based diverse population, we calculated the genotype frequencies in each population to determine whether a significant difference is detected between the different ethnicities. DNA genotyping was performed per manufacturers' protocols. RESULTS: Allele and genotype frequencies for 9 of the 11 single nucleotide polymorphisms (two apolipoprotein E variants, CR1, BIN1, DRB1, NYAP1, PTK2B, FERMT2, and ABCA7) differed significantly between MAs and NHWs. DISCUSSION: The significant differences in frequencies of top AD risk alleles observed here across MAs and NHWs suggest that ethnicity-specific genetic risks for AD exist. Given our results, we are advancing additional projects to further elucidate ethnicity-specific differences in AD.Research reported in this publication was supported by the National Institute on Aging of the National Institutes of Health under Award Numbers R01AG054073, R01AG058533, R01AG070862, T32AG020494, and U19AG078109. This work is partially supported by grant #RP17301 from the Cancer Prevention and Research Institute of Texas (CPRIT). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or CPRIT
GW525701 Treatment Alters Cellular Morphology and Decreases Triple-Negative Breast Cancer Viability
No full textPurpose: Breast cancer is the second leading cause of death in women in the United States. Triple-negative breast cancer (TNBC) is named for its lack of estrogen (ER) and progesterone (PR) receptors, as well as HER2. The lack of receptors makes these tumors increasingly more difficult to treat, resulting in worser clinical outcomes compared to other receptor-positive subtypes. Kinase inhibitor compounds have been of great interest for treating TNBC patients. Specific kinase inhibitors have been successful against other cancer subtypes, namely chronic myeloid leukemia (CML), which has substantially bettered the outcomes associated with this disease. However, in total, only 72 kinase inhibitors have been approved for clinical use, many of which are not used as cancer therapeutics at all, let alone for breast cancer. Much more research remains to determine the role of other, understudied kinases in cancer proliferation and survival. One kinase inhibitor compound, GW525701, targets STK10, TNIK, SLK, MAP4K4, MINK, and DDR1, none of which are targeted by FDA-approved therapeutics. If treating cancer cells with this kinase inhibitor compound reduces cancer survival and proliferation, then it may be a potential future therapeutic, and will give better insight into the mechanisms controlling TNBC survival. Methods: Breast cancer cells (4IC, BT-549, MCF-7) were treated with GW525701 for 72 hours at a range of concentrations (1nM, 10nM, 100nM, 1µM, 10µM), then stained with phalloidin to visualize cytoskeletal changes. Cellular proliferation and viability were tested using a Cell Titer Glo assay. Migration changes were visualized and quantified using a Boyden migration chamber and ImageJ analysis. All treatment groups were compared to vehicle-treated controls. Results:GW525701 treatment at all concentrations caused morphologic changes consistent with senescence and apoptotic cell death. Cellular proliferation and viability were inversely correlated with GW525701 treatment concentration. Conclusions: Treatment with GW525701 may give insight into the roles of STK10, TNIK, SLK, MAP4K4, MINK, and DDR1 in TNBC survival. This information will be crucial to determining an effective means of targeting TNBC in a therapeutic manner in the future. The specific kinase(s) responsible for the phenotypic outcomes in this experiment will be elucidated in the future as well.Cancer Prevention and Research Institute of Texas (CPRIT
UNTHSC’s MedSci Program Prepares Students for Medical School Success
No full textPurpose: It is well known that a medical school acceptance is difficult to obtain. The Association of American Medical Colleges’ most recent report of medical school acceptances shows that in 2021, a total of 62,443 students applied to U.S. medical schools, and 23,711 were accepted1. With a greater demand for seats than are available, admissions committees must determine who is or is not eligible for attending their program. The Texas College of Osteopathic Medicine (TCOM) has a class size generally seating 230–240 students from a pool of about 4,500–5,000 applicants2. For students whom the office of admissions feels could benefit from additional curriculum preparation, the University of North Texas Health Science Center (UNTHSC) offers a postbaccalaureate Master of Science in Medical Science.
UNTHSC had its first Post-Baccalaureate Premedical Certification Program class in the fall of 2000 with a total of 7 students. The Medical Science master’s program was offered in 2005. The intent was to provide qualified, yet ultimately not accepted, applicants an opportunity to prepare for the rigors of medical school while improving their medical school application. In 2017, about 82% of the students who completed the program were successful in receiving either admission to a medical or dental school in the United States3. Currently, the program has grown to over 300 students and includes face-to-face and online cohorts.
Methods: Our study examines the development and changes to the program over a 20-year period including curriculum and cohort size. We also examine the academic readiness of the TCOM-attending “MedSci” students to their non-MedSci classmates by comparing individual TCOM course GPAs and both COMLEX and STEP medical board examination passing scores.
Results: Over the span of the program, the required courses have become more similar to the year 1 curriculum that TCOM offers. In 2021, the average TCOM GPA of former MedSci students was 86.61. The average GPA of their non-MedSci counterparts was 85.45. The general trend from 2015–2021 shows comparable scores for the MedSci students. For the 2021 COMLEX exam, 94.12% of MedSci students passed on their first attempt compared to the 97.62% of non-MedSci students. The average COMLEX 1 score for MedSci students was 559.83 compared to the non-MedSci average score of 546.92. Although not required, some students chose to take STEP 1, the first USMLE board examination. Of the MedSci students, 46 of 51 chose to take the exam with a first-time passing rate of 97.83% and an average score of 230.81. Of the non-MedSci students, 133 of 168 chose to take the exam with a first-time passing rate of 96.99% and an average score of 226.15.
Conclusion: The MedSci program offered by UNTHSC allows students who were originally not accepted to medical school to match or exceed the academic expectations for medical students.
1Association of American Medical Colleges. (2021, December). 2021 Fall Applicant, Matriculant, and Enrollment Data Tables.
2TCOM admissions statistics. Texas College of Osteopathic Medicine. (2023, May 18). https://www.unthsc.edu/texas-college-of-osteopathic-medicine/admissions-and-outreach/tcom-admissions-statistics/
3Medical science. School of Biomedical Sciences. (2024, February 2). https://www.unthsc.edu/school-of-biomedical-sciences/medical-science
ADAM19 and ADAMTS4 expression in Human Optic Nerve Head Astrocytes
No full textSummary: Glaucoma is characterized by the degeneration and death of retinal ganglion cells (RGCs) and their axons, causing irreversible blindness. Various risk factors contribute to glaucoma onset, including intraocular pressure (IOP), age, and family history (1). In glaucoma, the primary site of damage is the optic nerve head (ONH), specifically the lamina cribrosa (LC) region. The ONH undergoes significant stress and structural changes in response to elevated IOP, leading to the death of RGCs (2). ONH astrocytes, a major cell type in the LC, are believed to play a significant role in the pathological remodeling of the extracellular matrix (ECM) during glaucoma. These cells respond notably to biomechanical stresses and increased levels of the fibrotic cytokine transforming growth factor beta 2 (TGFβ2), which is commonly found in the aqueous humor, trabecular meshwork, and optic nerve head (ONH) of glaucoma patients (2). Our lab has previously shown that ONH tissues treated with TGFβ2 show an increase in proteins that could be involved in glaucoma pathology. In this study, we primarily investigated the expression and regulation by TGFβ2 of A Disintegrin and Metalloproteinase (ADAM19) and ADAM with thrombospondin motifs (ADAMTS4) in ONH astrocytes. Hypothesis: IOP and remodeling of the ECM in the LC of the ONH are hallmarks of the pathogenesis of glaucoma. TGFβ2 is a profibrotic cytokine known to induce the synthesis and deposition of ECM. TGFβ2 increases ECM synthesis and deposition by ONH astrocytes within the LC, and RNA sequencing showed disintegrin and metalloproteinases (ADAMs) and ADAM with thrombospondin motifs (ADAMTS) were significantly dysregulated with TGFβ2 treatment compared to controls. Our lab has previously demonstrated that human ONH cells derived from glaucoma donors or treated with exogenous TGFβ2 increase profibrotic miRNAs and decrease anti-fibrotic miRNAs. MiR29c specifically, has been predicted to regulate members of the ADAM family proteins. Given that ADAMs and ADAMTS4 influence cell phenotype by modulating the ECM through cell adhesion, migration, proteolysis, and signaling pathways (19), we hypothesize that ONH astrocytes express ADAM19 and ADAMTS4 and that TGFβ2 and miR29c regulates ADAM19 and ADAMTS4 expression in ONH astrocytes. Significance: The existing treatments for glaucoma primarily focus on reducing IOP, which has proven effective in slowing the progression of the condition in many cases; however, it falls short of halting vision loss. To fully comprehend the intricacies of glaucoma pathology, investigating the expression of ADAM proteins in response to treatment with or without TGFβ2 in ONH astrocytes can provide insights that contribute to a better understanding of the disease and, potentially, the development of more holistic therapeutic approaches
Mechanisms contributing to inhibition of retinal ganglion cell death by cell permeable peptain-1 under glaucomatous stress
Get PDFThis study assesses the neuroprotective potential of CPP-P1, a conjugate of an anti-apoptotic peptain-1 (P1) and a cell-penetrating peptide (CPP) in in vitro, in vivo, and ex vivo glaucoma models. Primary retinal ganglion cells (RGCs) were subjected to either neurotrophic factor (NF) deprivation for 48 h or endothelin-3 (ET-3) treatment for 24 h and received either CPP-P1 or vehicle. RGC survival was analyzed using a Live/Dead assay. Axotomized human retinal explants were treated with CPP-P1 or vehicle for seven days, stained with RGC marker RBPMS, and RGC survival was analyzed. Brown Norway (BN) rats with elevated intraocular pressure (IOP) received weekly intravitreal injections of CPP-P1 or vehicle for six weeks. RGC function was evaluated using a pattern electroretinogram (PERG). RGC and axonal damage were also assessed. RGCs from ocular hypertensive rats treated with CPP-P1 or vehicle for seven days were isolated for transcriptomic analysis. RGCs subjected to 48 h of NF deprivation were used for qPCR target confirmation. NF deprivation led to a significant loss of RGCs, which was markedly reduced by CPP-P1 treatment. CPP-P1 also decreased ET-3-mediated RGC death. In ex vivo human retinal explants, CPP-P1 decreased RGC loss. IOP elevation resulted in significant RGC loss in mid-peripheral and peripheral retinas compared to that in naive rats, which was significantly reduced by CPP-P1 treatment. PERG amplitude decline in IOP-elevated rats was mitigated by CPP-P1 treatment. Following IOP elevation in BN rats, the transcriptomic analysis showed over 6,000 differentially expressed genes in the CPP-P1 group compared to the vehicle-treated group. Upregulated pathways included CREB signaling and synaptogenesis. A significant increase in Creb1 mRNA and elevated phosphorylated Creb were observed in CPP-P1-treated RGCs. Our study showed that CPP-P1 is neuroprotective through CREB signaling enhancement in several settings that mimic glaucomatous conditions. The findings from this study are significant as they address the pressing need for the development of efficacious therapeutic strategies to maintain RGC viability and functionality associated with glaucoma.Funding for this research was provided by an intramural grant from the University of North Texas HSC (D.L.S.) and by the Gates Grubstake Award (R.H.N.), Research to Prevent Blindness, NY to the Department of Ophthalmology, University of Colorado. Some funding was also provided by the Neurobiology of Aging and Alzheimer's Disease training grant: T32 AG020494 (GAJ). The work was supported in part by an extramural grant to RRK from the National Eye Institute [R01EY028179]
Optimal DVT Prophylaxis in Patients with Traumatic Hip Fracture: A Literature Review
No full textIntroduction: Hip-fracture patients face elevated life-threatening complications, including VTE and DVT. National guidelines recommend thromboprophylaxic agents such as LMWH, fondaparinux, apixaban, and warfarin. This review aims to summarize the literature investigating DVT prophylaxis in traumatic hip fracture repair, aiding healthcare professionals in clinical enhancement and agent selection. Methods: This review searched peer-reviewed articles in PubMed, Google Scholar, and Scopus. Agents considered for DVT prophylaxis included LMWH, UFH, fondaparinux, DOACs, warfarin, and aspirin. Discussion: The summary data of 9 articles suggest varying preferences for thromboprophylaxis amongst physicians managing hip fractures. LWMH is often administered subcutaneously with relatively common complications and efficient prevention of VTEs. However, due to inconvenient parenteral administration and high administration costs, low patient compliance poses a barrier. Direct Xa inhibitors, like apixaban and DOACs, have gained prominence due to easy administration, robust VTE prevention, and cost efficiency. These agents versus Lovenox yield mixed conclusions, some suggesting similar efficacy and higher incidences of hemorrhage. Fondaparinux, a synthetic anticoagulant, presents merits in VTE prevention, including a single subcutaneous injection, no need for lab monitoring, and no risk of heparin-induced thrombocytopenia. Some studies suggest fondaparinux is more effective than LWMH in preventing VTE but has a slightly higher risk of bleeding. Warfarin, a well-established anticoagulant, boasts high efficacy and safety but requires frequent lab monitoring, interacts with medications, and may lead to surgery delays. Aspirin, a widely available antiplatelet drug, is typically taken orally as a low-dose pill. Aspirin provides clinical benefits in VTE prophylaxis and becomes more appealing when considering its lower cost and decreased risks of bleeding. Conclusion: This review summarizes viable agents for VTE prevention in traumatic hip fractures. Future studies should explore how socioeconomic factors and patient health literacy impact drug adherence and efficacy. Clinicians can use this knowledge to improve outcomes in this vulnerable population
DiGeorge Syndrome in a 32-year-old male: A Cadaver Study
No full textBackground:
DiGeorge Syndrome (DGS) is one of the most encountered chromosomal syndromes in the population and is marked by the deletion of 22q11.2. Phenotypic expression varies widely between patients. Main features include cardiac and conotruncal abnormalities, craniofacial anomalies including cleft palate, thymic hypoplasia, hypocalcemia, and scoliosis. The branching pattern of the great vessels is known to be highly variable in DGS and a unique manifestation is found in this case.
Case Information:
This case report examines a 32-year-old deceased male with DGS, and a history of atrial fibrillation, pulmonary atresia-ventricular septal defect, pulmonary artery stenosis, pulmonary hypertension, and six heart surgeries. The cause of death was unspecified natural causes. Initial dissection of the thoracic cavity revealed clear signs of cardiomegaly and a severe scoliotic curve extending to the lumbar region. Further heart dissection revealed sutures and pericardial reconstruction confirming previous surgeries, likely to reconstruct the greater vessels. External findings include an aortic arch variant consisting of absent brachiocephalic trunk, a unique branching pattern of the great vessels directly from the aorta, and the wrapping of the proximal descending aorta around the trachea before descending. Pulmonary trunk adhesion to the heart's surface via scar tissue indicates surgical reconstruction. The left pulmonary artery was significantly constricted while the right pulmonary artery was expanded with immediate branching into smaller segments upon entering the lung, suggesting that more blood was shunted into the right lung. The right atrium appeared significantly enlarged with appropriate size compensations noticed in pectinate muscles and crista terminalis. The right auricle was small and only observable internally. The coronary sinus was abnormally enlarged, comparable in size to the opening of the inferior vena cava. Circular shaped scar tissue on the external surface of the sinus indicates a surgical correction. The right ventricle contained an abnormally enlarged moderator band. Dense scar tissue stenosis was visualized along the pulmonary outflow valve with sutures present along the entire circumference of outflow tract prior to pulmonary artery bifurcation indicating surgical reconstruction. Additional sutures were observed inferior to the circumferential sutures along the wall between the aorta and pulmonary trunk, potentially to seal a prior communicating shunt. The pulmonary veins and left atrium appeared normal; however, possible stenosis of the bicuspid valve was noted but further assessment is needed to confirm. The left ventricle showed enlarged papillary muscles and chordae tendinea which are hypothesized to be a byproduct of the overall increased heart size. The left ventricular wall was twice the thickness of the right ventricular wall, an expected proportion based on heart size and ventricular work. The aortic valves appeared slightly stenosed with cusp buildup. Coronary ostia appeared normal.
Conclusion:
This cadaveric case study reflects a unique cardiac presentation of DGS within an adult male. With DGS being a rather common chromosomal disorder with highly variable phenotypic expression, there is an importance to explore anatomical variants, their prevalence, and the needed surgical corrections present within patients to ensure that a more comprehensive diagnosis and care plan can be provided in future diagnostic settings
Interactive Images in Library Instruction: A Case Study
No full textThis is an original manuscript of an article published by Taylor & Francis in Medical Reference Services Quarterly on February, available online: https://doi.org/10.1080/02763869.2024.2293444This paper discusses the design and implementation of the H5P image hotspots and describes additional use cases for library instruction in order to teach learners from across the country on how different spaces can be used to create private, accessible areas where patrons can conduct telehealth appointments. The Network of the National Library of Medicine created an online class using H5P image hotspots to allow learners to virtually explore a physical space. The class used Moodle, an open-source learning platform, and H5P image hotspots to demonstrate how libraries implemented telehealth programs.This work was supported by the National Library of Medicine, National Institutes of Health under Cooperative Agreements UG4LM012345 and UG4LM013732. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health
Theranostics Using MCM-41-Based Mesoporous Silica Nanoparticles: Integrating Magnetic Resonance Imaging and Novel Chemotherapy for Breast Cancer Treatment
No full textAdvanced breast cancer remains a significant oncological challenge, requiring new approaches to improve clinical outcomes. This study investigated an innovative theranostic agent using the MCM-41-NH(2)-DTPA-Gd(3)(+)-MIH nanomaterial, which combined MRI imaging for detection and a novel chemotherapy agent (MIH 2.4Bl) for treatment. The nanomaterial was based on the mesoporous silica type, MCM-41, and was optimized for drug delivery via functionalization with amine groups and conjugation with DTPA and complexation with Gd(3+). MRI sensitivity was enhanced by using gadolinium-based contrast agents, which are crucial in identifying early neoplastic lesions. MIH 2.4Bl, with its unique mesoionic structure, allows effective interactions with biomolecules that facilitate its intracellular antitumoral activity. Physicochemical characterization confirmed the nanomaterial synthesis and effective drug incorporation, with 15% of MIH 2.4Bl being adsorbed. Drug release assays indicated that approximately 50% was released within 8 h. MRI phantom studies demonstrated the superior imaging capability of the nanomaterial, with a relaxivity significantly higher than that of the commercial agent Magnevist. In vitro cellular cytotoxicity assays, the effectiveness of the nanomaterial in killing MDA-MB-231 breast cancer cells was demonstrated at an EC(50) concentration of 12.6 mg/mL compared to an EC(50) concentration of 68.9 mg/mL in normal human mammary epithelial cells (HMECs). In vivo, MRI evaluation in a 4T1 syngeneic mouse model confirmed its efficacy as a contrast agent. This study highlighted the theranostic capabilities of MCM-41-NH(2)-DTPA-Gd(3)(+)-MIH and its potential to enhance breast cancer management.This work was supported, in part, by a grant from the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) of Brazil for scientific, technological, and innovation research: scholarships abroad (200600/2022-2), a grant from the Fundação de Amparo à Ciência e Tecnologia do Estado de Pernambuco (FACEPE; IBPG-0326-1.06/21) and through research bridge funding provided by the Department of Microbiology, Immunology, and Genetics at the University of North Texas Health Science Center
